Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0034653 retinoic acid catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: retinoic acid catabolic process (GO:0034653) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: file:DANRE/cyp26a1/cyp26a1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md Zebrafish Cyp26a1 catalyzes oxidative metabolism of atRA, generating metabolites dominated by 4-hydroxy-RA (4-OH-RA) and 4-oxo-RA (4-oxo-RA) in microsome assays from transfected cells
GO:0007417 central nervous system development	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: central nervous system development (GO:0007417) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: file:DANRE/cyp26a1/cyp26a1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites
GO:0004497 monooxygenase activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: monooxygenase activity (GO:0004497) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: file:DANRE/cyp26a1/cyp26a1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md CYP26 enzymes are described as membrane-anchored microsomal (endoplasmic reticulum, ER) cytochrome P450s with a heme center
GO:0005506 iron ion binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: iron ion binding (GO:0005506) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: file:DANRE/cyp26a1/cyp26a1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md each catalytic cycle requires electrons supplied from NADPH via cytochrome P450 oxidoreductase (POR), which uses FAD and FMN cofactors
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: endoplasmic reticulum membrane (GO:0005789) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: file:DANRE/cyp26a1/cyp26a1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md Cyp26a1 is best supported as a microsomal/ER membrane-anchored cytochrome P450, i.e., positioned to access intracellular RA pools and regulate RA available for nuclear receptor signaling
GO:0008401 retinoic acid 4-hydroxylase activity	IEA GO_REF:0000117	ACCEPT	Summary: retinoic acid 4-hydroxylase activity (GO:0008401) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: file:DANRE/cyp26a1/cyp26a1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md Reviews of CYP26A1 metabolism emphasize 4-hydroxylation as the primary transformation for CYP26A1 (and CYP26B1)
GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: file:DANRE/cyp26a1/cyp26a1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites
GO:0020037 heme binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: heme binding (GO:0020037) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: file:DANRE/cyp26a1/cyp26a1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md CYP26 enzymes are described as membrane-anchored microsomal (endoplasmic reticulum, ER) cytochrome P450s with a heme center
GO:0034653 retinoic acid catabolic process	IEA GO_REF:0000117	ACCEPT	Summary: retinoic acid catabolic process (GO:0034653) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: file:DANRE/cyp26a1/cyp26a1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md They convert RA into more polar, generally less active metabolites, supporting clearance and preventing ectopic signaling
GO:0062182 all-trans retinoic acid 4-hydrolase activity	IEA GO_REF:0000116	ACCEPT	Summary: all-trans retinoic acid 4-hydrolase activity (GO:0062182) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: file:DANRE/cyp26a1/cyp26a1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md Cell/microsome assays of zebrafish CYP26 family members show activity toward RA isomers (atRA, 9-cis RA, 13-cis RA) and no detectable metabolism of retinol or retinal under the tested conditions, supporting specialization for RA
GO:0005789 endoplasmic reticulum membrane	ISS GO_REF:0000024	ACCEPT	Summary: endoplasmic reticulum membrane (GO:0005789) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: file:DANRE/cyp26a1/cyp26a1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md Experimental enzymology for zebrafish cyp26a1 was performed using microsomes isolated from transfected cells, which is consistent with ER-derived membrane localization
GO:0062182 all-trans retinoic acid 4-hydrolase activity	EXP PMID:8939936 Identification of the retinoic acid-inducible all-trans-reti...	ACCEPT	Summary: all-trans retinoic acid 4-hydrolase activity (GO:0062182) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md Zebrafish Cyp26a1 catalyzes oxidative metabolism of atRA, generating metabolites dominated by 4-hydroxy-RA (4-OH-RA) and 4-oxo-RA (4-oxo-RA) in microsome assays from transfected cells
GO:0003151 outflow tract morphogenesis	IGI PMID:27893754 Cyp26 Enzymes Facilitate Second Heart Field Progenitor Addit...	KEEP AS NON CORE	Summary: outflow tract morphogenesis (GO:0003151) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:27893754 zebrafish embryos deficient for Cyp26a1 and Cyp26c1 enzymes, which promote RA degradation, have OFT defects
GO:0034672 anterior/posterior pattern specification involved in pronephros development	IMP PMID:27406002 BMP and retinoic acid regulate anterior-posterior patterning...	KEEP AS NON CORE	Summary: anterior/posterior pattern specification involved in pronephros development (GO:0034672) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:27406002 posterior kidney progenitors are protected ventrally by the RA-catabolizing enzyme Cyp26a1 file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md cyp26a1 is expressed early in presumptive anterior neural ectoderm, and later in forebrain, midbrain, anterior hindbrain, and tailbud territories, contributing to establishment of anterior RA-depleted domains opposing posterior RA synthesis
GO:0007507 heart development	IMP PMID:23990796 Depletion of retinoic acid receptors initiates a novel posit...	KEEP AS NON CORE	Summary: heart development (GO:0007507) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:23990796 Cyp26a1, an enzyme that facilitates degradation of RA
GO:0007507 heart development	IGI PMID:23990796 Depletion of retinoic acid receptors initiates a novel posit...	KEEP AS NON CORE	Summary: heart development (GO:0007507) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:23990796 Cyp26a1, an enzyme that facilitates degradation of RA
GO:0030917 midbrain-hindbrain boundary development	IGI PMID:23990796 Depletion of retinoic acid receptors initiates a novel posit...	KEEP AS NON CORE	Summary: midbrain-hindbrain boundary development (GO:0030917) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:23990796 Cyp26a1, an enzyme that facilitates degradation of RA
GO:0001944 vasculature development	IGI PMID:24667328 Cyp26 enzymes are required to balance the cardiac and vascul...	KEEP AS NON CORE	Summary: vasculature development (GO:0001944) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:24667328 Cyp26 enzymes largely act cell non-autonomously to promote appropriate cardiovascular development
GO:0055014 atrial cardiac muscle cell development	IGI PMID:24667328 Cyp26 enzymes are required to balance the cardiac and vascul...	KEEP AS NON CORE	Summary: atrial cardiac muscle cell development (GO:0055014) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:24667328 Cyp26 enzymes largely act cell non-autonomously to promote appropriate cardiovascular development
GO:0048384 retinoic acid receptor signaling pathway	IMP PMID:23975936 Retinoic acid-dependent regulation of miR-19 expression elic...	KEEP AS NON CORE	Summary: retinoic acid receptor signaling pathway (GO:0048384) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:23975936 A reporter assay confirmed that cyp26a1 is a bona fide target of miR-19 in vivo file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md a core component of RA homeostasis that sculpts spatial RA signaling territories in early embryos
GO:0003131 mesodermal-endodermal cell signaling	IMP PMID:19416885 Cyp26 enzymes function in endoderm to regulate pancreatic fi...	KEEP AS NON CORE	Summary: mesodermal-endodermal cell signaling (GO:0003131) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:19416885 the RA-degrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic field
GO:0031016 pancreas development	IMP PMID:19416885 Cyp26 enzymes function in endoderm to regulate pancreatic fi...	KEEP AS NON CORE	Summary: pancreas development (GO:0031016) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:19416885 the RA-degrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic field
GO:0031016 pancreas development	IGI PMID:19416885 Cyp26 enzymes function in endoderm to regulate pancreatic fi...	KEEP AS NON CORE	Summary: pancreas development (GO:0031016) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:19416885 the RA-degrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic field
GO:0034653 retinoic acid catabolic process	IMP PMID:19416885 Cyp26 enzymes function in endoderm to regulate pancreatic fi...	ACCEPT	Summary: retinoic acid catabolic process (GO:0034653) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: PMID:19416885 the RA-degrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic field
GO:0021797 forebrain anterior/posterior pattern specification	IGI PMID:17998248 Zebrafish model of holoprosencephaly demonstrates a key role...	KEEP AS NON CORE	Summary: forebrain anterior/posterior pattern specification (GO:0021797) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:17998248 The loss of the forebrain-specific RA-degrading enzyme cyp26a1 causes a forebrain phenotype that mimics tgif morphants
GO:0048854 brain morphogenesis	IMP PMID:17998248 Zebrafish model of holoprosencephaly demonstrates a key role...	KEEP AS NON CORE	Summary: brain morphogenesis (GO:0048854) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:17998248 The loss of the forebrain-specific RA-degrading enzyme cyp26a1 causes a forebrain phenotype that mimics tgif morphants
GO:0071299 cellular response to vitamin A	IDA PMID:17253779 Specificity of zebrafish retinol saturase: formation of all-...	KEEP AS NON CORE	Summary: cellular response to vitamin A (GO:0071299) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:17253779 all-trans-13,14-dihydroretinol is transiently oxidized to all-trans-13,14-dihydroretinoic acid before being oxidized further by Cyp26 enzymes
GO:0001756 somitogenesis	IMP PMID:17098223 Coordination of symmetric cyclic gene expression during somi...	KEEP AS NON CORE	Summary: somitogenesis (GO:0001756) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:17098223 expression of the RA-degrading enzyme cyp26a1 in the tailbud was controlled by Su(H) activity file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md microinjection of cyp26a1 mRNA reduces endogenous RA activity and yields phenotypes resembling reduced-RA conditions, consistent with a role in RA clearance
GO:0021661 rhombomere 4 morphogenesis	IMP PMID:17164423 Cyp26 enzymes generate the retinoic acid response pattern ne...	KEEP AS NON CORE	Summary: rhombomere 4 morphogenesis (GO:0021661) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:17164423 metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains during hindbrain development
GO:0021661 rhombomere 4 morphogenesis	IGI PMID:17164423 Cyp26 enzymes generate the retinoic acid response pattern ne...	KEEP AS NON CORE	Summary: rhombomere 4 morphogenesis (GO:0021661) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:17164423 metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains during hindbrain development
GO:0030902 hindbrain development	IGI PMID:17164423 Cyp26 enzymes generate the retinoic acid response pattern ne...	KEEP AS NON CORE	Summary: hindbrain development (GO:0030902) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:17164423 metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains during hindbrain development file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md Hernandez et al. (2007; published Jan 2007; https://doi.org/10.1242/dev.02706) demonstrate that zebrafish orthologs of mammalian CYP26 genes (cyp26a1, cyp26b1, cyp26c1) act redundantly to shape the RA response pattern necessary for hindbrain development
GO:0042573 retinoic acid metabolic process	IMP PMID:17164423 Cyp26 enzymes generate the retinoic acid response pattern ne...	ACCEPT	Summary: retinoic acid metabolic process (GO:0042573) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: PMID:17164423 metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains during hindbrain development file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md They convert RA into more polar, generally less active metabolites, supporting clearance and preventing ectopic signaling
GO:0042574 retinal metabolic process	IMP PMID:17164423 Cyp26 enzymes generate the retinoic acid response pattern ne...	REMOVE	Summary: retinal metabolic process (GO:0042574) is not the appropriate direct annotation for cyp26a1. Reason: The synthesized evidence supports the specific core annotations reviewed separately; this broad or wrong-context annotation should be retired rather than treated as a core function. Supporting Evidence: PMID:17164423 metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains during hindbrain development
GO:0042573 retinoic acid metabolic process	IDA PMID:16455818 A novel cytochrome P450, zebrafish Cyp26D1, is involved in m...	ACCEPT	Summary: retinoic acid metabolic process (GO:0042573) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: PMID:16455818 Cyp26D1 expressed in 293T cells could metabolize all-trans RA, 9-cis RA, and 13-cis RA file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md Cell/microsome assays of zebrafish CYP26 family members show activity toward RA isomers (atRA, 9-cis RA, 13-cis RA) and no detectable metabolism of retinol or retinal under the tested conditions, supporting specialization for RA
GO:0001568 blood vessel development	IMP PMID:15680360 Retinoic acid-metabolizing enzyme Cyp26a1 is essential for d...	KEEP AS NON CORE	Summary: blood vessel development (GO:0001568) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:15680360 the gene for the RA-degrading enzyme Cyp26a1 is mutated
GO:0030902 hindbrain development	IMP PMID:15680360 Retinoic acid-metabolizing enzyme Cyp26a1 is essential for d...	KEEP AS NON CORE	Summary: hindbrain development (GO:0030902) is retained as supported context for cyp26a1 but is not the primary/core function. Reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the central molecular role. Supporting Evidence: PMID:15680360 the gene for the RA-degrading enzyme Cyp26a1 is mutated
GO:0008401 retinoic acid 4-hydroxylase activity	IDA PMID:8939936 Identification of the retinoic acid-inducible all-trans-reti...	ACCEPT	Summary: retinoic acid 4-hydroxylase activity (GO:0008401) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md Zebrafish Cyp26a1 catalyzes oxidative metabolism of atRA, generating metabolites dominated by 4-hydroxy-RA (4-OH-RA) and 4-oxo-RA (4-oxo-RA) in microsome assays from transfected cells
GO:0042573 retinoic acid metabolic process	IDA PMID:8939936 Identification of the retinoic acid-inducible all-trans-reti...	ACCEPT	Summary: retinoic acid metabolic process (GO:0042573) is supported for cyp26a1. Reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene. Supporting Evidence: PMID:8939936 all-trans-RA is rapidly metabolized to more polar metabolites file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md Reviews of CYP26A1 metabolism emphasize 4-hydroxylation as the primary transformation for CYP26A1 (and CYP26B1), with additional products such as 18-hydroxy-RA and more polar secondary metabolites

Core Functions

Cyp26a1 hydroxylates all-trans retinoic acid to drive retinoic acid catabolism at the endoplasmic reticulum membrane.

Molecular Function:

all-trans retinoic acid 4-hydrolase activity

Directly Involved In:

retinoic acid catabolic process retinoic acid metabolic process

Cellular Locations:

endoplasmic reticulum membrane

Supporting Evidence:

file:DANRE/cyp26a1/cyp26a1-uniprot.txt
A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
PMID:8939936
all-trans-RA is rapidly metabolized to more polar metabolites
file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
ER/microsomal cytochrome P450 enzyme that **hydroxylates/oxidizes retinoic acid**, producing **4-OH-RA and 4-oxo-RA** (major products), thereby reducing RA signaling capacity

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:15680360

Retinoic acid-metabolizing enzyme Cyp26a1 is essential for determining territories of hindbrain and spinal cord in zebrafish.

The zebrafish cyp26a1/giraffe mutant disrupts RA-dependent hindbrain, spinal cord, vascular, and other developmental patterning.

"the gene for the RA-degrading enzyme Cyp26a1 is mutated"

PMID:16455818

A novel cytochrome P450, zebrafish Cyp26D1, is involved in metabolism of all-trans retinoic acid.

Zebrafish Cyp26-family enzymes metabolize all-trans retinoic acid and related retinoids, supporting RA-catabolism annotations.

"Cyp26D1 expressed in 293T cells could metabolize all-trans RA, 9-cis RA, and 13-cis RA"

PMID:17098223

Coordination of symmetric cyclic gene expression during somitogenesis by Suppressor of Hairless involves regulation of retinoic acid catabolism.

Cyp26a1 regulation of retinoic acid metabolism contributes to symmetric cyclic gene expression and somitogenesis.

"expression of the RA-degrading enzyme cyp26a1 in the tailbud was controlled by Su(H) activity"

PMID:17164423

Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development.

Cyp26 enzymes shape RA-responsive hindbrain domains by metabolizing retinoic acid.

"metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains during hindbrain development"

PMID:17253779

Specificity of zebrafish retinol saturase: formation of all-trans-13,14-dihydroretinol and all-trans-7,8- dihydroretinol.

Zebrafish retinoid metabolism includes Cyp26-dependent oxidation of retinoid metabolites.

"all-trans-13,14-dihydroretinol is transiently oxidized to all-trans-13,14-dihydroretinoic acid before being oxidized further by Cyp26 enzymes"

PMID:17998248

Zebrafish model of holoprosencephaly demonstrates a key role for TGIF in regulating retinoic acid metabolism.

Forebrain patterning is affected by altered RA metabolism, including loss of cyp26a1-mediated RA degradation.

"The loss of the forebrain-specific RA-degrading enzyme cyp26a1 causes a forebrain phenotype that mimics tgif morphants"

PMID:19416885

Cyp26 enzymes function in endoderm to regulate pancreatic field size.

Cyp26 enzymes restrict RA signaling to define pancreatic field size and position.

"the RA-degrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic field"

PMID:23975936

Retinoic acid-dependent regulation of miR-19 expression elicits vertebrate axis defects.

miR-19 regulation of CYP26A1 affects retinoic acid metabolism during vertebrate axis formation.

"A reporter assay confirmed that cyp26a1 is a bona fide target of miR-19 in vivo"

PMID:23990796

Depletion of retinoic acid receptors initiates a novel positive feedback mechanism that promotes teratogenic increases in retinoic acid.

Cyp26a1 participates in feedback control of embryonic RA levels during heart development.

"Cyp26a1, an enzyme that facilitates degradation of RA"

PMID:24667328

Cyp26 enzymes are required to balance the cardiac and vascular lineages within the anterior lateral plate mesoderm.

Cyp26a1/cyp26c1 limit RA levels to maintain cardiac and vascular progenitor field boundaries.

"Cyp26 enzymes largely act cell non-autonomously to promote appropriate cardiovascular development"

PMID:27406002

BMP and retinoic acid regulate anterior-posterior patterning of the non-axial mesoderm across the dorsal-ventral axis.

Cyp26a1 protects posterior kidney progenitors from RA during non-axial mesoderm patterning.

"posterior kidney progenitors are protected ventrally by the RA-catabolizing enzyme Cyp26a1"

PMID:27893754

Cyp26 Enzymes Facilitate Second Heart Field Progenitor Addition and Maintenance of Ventricular Integrity.

Cyp26a1/cyp26c1-mediated RA degradation supports outflow tract development and ventricular integrity.

"zebrafish embryos deficient for Cyp26a1 and Cyp26c1 enzymes, which promote RA degradation, have OFT defects"

PMID:8939936

Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase.

Zebrafish P450RAI/Cyp26a1 metabolizes all-trans retinoic acid to polar metabolites.

"all-trans-RA is rapidly metabolized to more polar metabolites"

file:DANRE/cyp26a1/cyp26a1-uniprot.txt

UniProtKB entry P79739 for Danio rerio cyp26a1

UniProt summarizes Cyp26a1 as a cytochrome P450 enzyme that metabolizes all-trans retinoic acid.

"A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid"

file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md

Falcon deep research on zebrafish cyp26a1 (Edison Scientific Literature)

Zebrafish Cyp26a1 oxidizes all-trans retinoic acid in microsome assays to 4-OH-RA and 4-oxo-RA, the canonical CYP26A1 reaction products.

"Zebrafish Cyp26a1 catalyzes oxidative metabolism of atRA, generating metabolites dominated by **4-hydroxy-RA (4-OH-RA)** and **4-oxo-RA (4-oxo-RA)** in microsome assays from transfected cells "
4-hydroxylation is the primary transformation for CYP26A1, with additional products including 18-hydroxy-RA and more polar secondary metabolites.

"Reviews of CYP26A1 metabolism emphasize **4-hydroxylation as the primary transformation** for CYP26A1 (and CYP26B1), with additional products such as **18-hydroxy-RA** and more polar secondary metabolites "
Zebrafish CYP26 enzymes act on retinoic acid isomers but do not metabolize retinol or retinal, indicating specialization for retinoic acid rather than upstream retinoids.

"Cell/microsome assays of zebrafish CYP26 family members show activity toward **RA isomers** (atRA, 9-cis RA, 13-cis RA) and **no detectable metabolism of retinol or retinal** under the tested conditions, supporting specialization for RA "
Cyp26a1 is a membrane-anchored microsomal (ER) cytochrome P450 with a heme center, requiring electrons from NADPH via cytochrome P450 oxidoreductase (POR).

"CYP26 enzymes are described as **membrane-anchored microsomal (endoplasmic reticulum, ER) cytochrome P450s** with a heme center and class II P450 electron-transfer architecture: each catalytic cycle requires electrons supplied from **NADPH via cytochrome P450 oxidoreductase (POR)**, which uses **FAD and FMN** cofactors "
CYP26 enzymes are high-efficiency retinoic-acid clearance enzymes (reported Km < 100 nM in transfected-cell systems) that control RA homeostasis.

"A review summarizing CYP26 biochemical studies reports **high catalytic activity** for atRA, including **Km < 100 nM** (in COS-1 transfected cell systems) and **turnover ~1–10 pmol/min/pmol** "
cyp26a1 and its paralogs cyp26b1/cyp26c1 act redundantly to shape the retinoic-acid response pattern needed for zebrafish hindbrain development; their depletion expands RA-responsive gene expression across the hindbrain.

"Hernandez et al. (2007; published Jan 2007; https://doi.org/10.1242/dev.02706) demonstrate that zebrafish orthologs of mammalian CYP26 genes (**cyp26a1, cyp26b1, cyp26c1**) act **redundantly** to shape the RA response pattern necessary for hindbrain development "
cyp26a1 expression in anterior neural ectoderm, forebrain, midbrain, anterior hindbrain, and tailbud establishes anterior RA-depleted domains opposing posterior aldh1a2/raldh2-driven RA synthesis.

"cyp26a1 is expressed early in presumptive anterior neural ectoderm, and later in forebrain, midbrain, anterior hindbrain, and tailbud territories, contributing to establishment of anterior RA-depleted domains opposing posterior RA synthesis and shaping the rostrocaudal RA signaling landscape "
cyp26a1 is under complex RA- and Fgf-driven feedback/feedforward control, conferring robustness of the embryonic RA gradient.

"cyp26a1 is under complex feedback and feedforward control by RA and Fgf signaling "
Overexpression of cyp26a1 mRNA reduces endogenous RA activity and produces reduced-RA phenotypes, confirming a functional role in RA clearance.

"microinjection of cyp26a1 mRNA reduces endogenous RA activity and yields phenotypes resembling reduced-RA conditions, consistent with a role in RA clearance "
The primary molecular function of zebrafish Cyp26a1 is as an ER/microsomal cytochrome P450 that hydroxylates/oxidizes retinoic acid, reducing RA signaling capacity.

"ER/microsomal cytochrome P450 enzyme that **hydroxylates/oxidizes retinoic acid**, producing **4-OH-RA and 4-oxo-RA** (major products), thereby reducing RA signaling capacity "

Suggested Experiments

Experiment: Generate single and compound cyp26a1/cyp26b1/cyp26c1 CRISPR/Cas9 mutants and compare retinoic-acid reporter activity and hox/krox20 rhombomere boundary positioning to dissect each paralog's spatial contribution.

Hypothesis: cyp26a1 has a non-redundant role in clearing retinoic acid from anterior/hindbrain territories that is not fully compensated by cyp26b1 or cyp26c1.

Type: CRISPR/Cas9 genetics with retinoic-acid reporter imaging and in situ hybridization

Experiment: Express and purify recombinant Cyp26a1, incubate with all-trans, 9-cis, and 13-cis retinoic acid, and quantify the metabolite profile and kinetic parameters by LC-MS/MS to define substrate and regiochemical specificity.

Hypothesis: Recombinant zebrafish Cyp26a1 preferentially 4-hydroxylates all-trans retinoic acid rather than 9-cis or 13-cis isomers.

Type: in vitro cytochrome P450 enzyme assay with LC-MS/MS metabolite profiling

Experiment: Apply temporally controlled cyp26a1 loss-of-function and rescue, then quantify progenitor markers and retinoic-acid reporter activity in each tissue to test whether progenitor protection is a direct cyp26a1 function.

Hypothesis: Endogenous cyp26a1 is required to protect specific progenitor populations (posterior kidney, second heart field, pancreas) from retinoic-acid excess.

Type: conditional/temporal gene perturbation with marker quantification

Deep Research

Falcon

(cyp26a1-deep-research-falcon.md)

Research report: Danio rerio **cyp26a1** (UniProt **P79739**) — functional annotation Falcon Edison Scientific Literature 31 citations 2 artifacts 2026-05-30T11:41:47.224097

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000021 The requested information can be found in several figures throughout the document. Figure 1 illustrates the retinoic acid (RA) resp (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Danio rerio cyp26a1 (UniProt P79739) — functional annotation

Scope and identity verification (critical)

The UniProt target (P79739) is annotated as Cytochrome P450 26A1 (Cyp26a1) from Danio rerio (zebrafish), also described as P450RAI / retinoic acid 4-hydroxylase. Primary zebrafish developmental biology literature consistently uses cyp26a1 to denote the major retinoic acid (RA)–degrading cytochrome P450 during gastrulation and hindbrain patterning (white2007complexregulationof pages 1-2, hernandez2007cyp26enzymesgenerate pages 1-2). Biochemical assays using zebrafish cyp26a1 expressed in cells show metabolism of all-trans retinoic acid to 4-hydroxy-RA and 4-oxo-RA, matching the expected CYP26A1 reaction chemistry (gu2006anovelcytochrome pages 5-7, gu2006anovelcytochrome pages 3-5). These converge with authoritative reviews describing CYP26A1 as an RA-hydroxylating/clearing enzyme (thatcher2009theroleof pages 5-7, thatcher2009theroleof pages 2-4).

1) Key concepts and definitions (current understanding)

Retinoic acid (RA) signaling and “RA gradients”

RA (typically all-trans retinoic acid, atRA) is a lipophilic signaling molecule that controls transcription through retinoid receptors; in embryos, RA acts as a dose-dependent positional cue (a morphogen-like signal). A core concept is RA homeostasis: spatially and temporally patterned RA availability arises from the balance of RA synthesis (e.g., ALDH1A2/RALDH2) and RA catabolism by CYP26 enzymes, producing territories of high vs low RA signaling (hernandez2007cyp26enzymesgenerate pages 1-2, roberts2020regulatingretinoicacid pages 5-7).

In zebrafish hindbrain development, experimental evidence supports that RA can convey graded positional information over long distances, and that regulated degradation by Cyp26a1 is a key mechanism establishing a robust RA distribution across the hindbrain field (white2007complexregulationof pages 1-2). A complementary “gradient-free” framing is that dynamic expression of RA-degrading enzymes sculpts nested domains of RA responsiveness, even when RA is externally provided uniformly (hernandez2007cyp26enzymesgenerate pages 1-2).

CYP26 enzymes

The CYP26 subfamily (including CYP26A1) are specialized retinoic-acid hydroxylases/oxidases. They convert RA into more polar, generally less active metabolites, supporting clearance and preventing ectopic signaling (roberts2020regulatingretinoicacid pages 5-7, thatcher2009theroleof pages 5-7). A key systems-level concept is that CYP26 expression can create “RA sinks” that buffer fluctuations in RA synthesis and protect sensitive tissues (roberts2020regulatingretinoicacid pages 5-7, white2007complexregulationof pages 1-2).

2) Molecular function (reaction, substrates, specificity) and biochemical mechanism

Catalyzed reaction and products

Zebrafish Cyp26a1 catalyzes oxidative metabolism of atRA, generating metabolites dominated by 4-hydroxy-RA (4-OH-RA) and 4-oxo-RA (4-oxo-RA) in microsome assays from transfected cells (gu2006anovelcytochrome pages 5-7, gu2006anovelcytochrome pages 3-5). Reviews of CYP26A1 metabolism emphasize 4-hydroxylation as the primary transformation for CYP26A1 (and CYP26B1), with additional products such as 18-hydroxy-RA and more polar secondary metabolites (thatcher2009theroleof pages 5-7). A broader metabolite spectrum for CYP26 enzymes includes 4-OH-RA, 4-oxo-RA, 18-OH-RA, 5,8-epoxy-RA, and dihydroxy/oxo-hydroxy derivatives, followed by further processing (e.g., glucuronidation) and elimination (roberts2020regulatingretinoicacid pages 7-10).

Substrate specificity

Cell/microsome assays of zebrafish CYP26 family members show activity toward RA isomers (atRA, 9-cis RA, 13-cis RA) and no detectable metabolism of retinol or retinal under the tested conditions, supporting specialization for RA (gu2006anovelcytochrome pages 1-2, gu2006anovelcytochrome pages 3-5).

Cofactors and catalytic requirements (current expert understanding)

CYP26 enzymes are described as membrane-anchored microsomal (endoplasmic reticulum, ER) cytochrome P450s with a heme center and class II P450 electron-transfer architecture: each catalytic cycle requires electrons supplied from NADPH via cytochrome P450 oxidoreductase (POR), which uses FAD and FMN cofactors (roberts2020regulatingretinoicacid pages 7-10, roberts2020regulatingretinoicacid pages 5-7). Zebrafish Cyp26 proteins contain conserved P450 domains including an anchor domain, oxygen-binding and heme-binding motifs, consistent with ER/microsomal P450 enzymes (gu2006anovelcytochrome pages 5-7, gu2006anovelcytochrome pages 1-2).

Quantitative enzymology (from authoritative synthesis)

A review summarizing CYP26 biochemical studies reports high catalytic activity for atRA, including Km < 100 nM (in COS-1 transfected cell systems) and turnover ~1–10 pmol/min/pmol, emphasizing that CYP26 enzymes are highly efficient RA-clearing enzymes relative to other RA-hydroxylating CYPs (roberts2020regulatingretinoicacid pages 7-10). (These values are not zebrafish-specific measurements in the extracted text, but are presented as general CYP26 properties.)

3) Subcellular localization and where the protein acts

Cyp26a1 is best supported as a microsomal/ER membrane-anchored cytochrome P450, i.e., positioned to access intracellular RA pools and regulate RA available for nuclear receptor signaling (roberts2020regulatingretinoicacid pages 7-10, roberts2020regulatingretinoicacid pages 5-7). Experimental enzymology for zebrafish cyp26a1 was performed using microsomes isolated from transfected cells, which is consistent with ER-derived membrane localization (gu2006anovelcytochrome pages 5-7, gu2006anovelcytochrome pages 3-5).

4) Biological roles and pathways in zebrafish (evidence-based)

A. Hindbrain and anterior–posterior (A–P) patterning during gastrulation

White et al. (2007; published Nov 2007; https://doi.org/10.1371/journal.pbio.0050304) provide evidence that RA provides graded positional information and that cyp26a1 expression/regulation contributes to a robust RA gradient across the hindbrain field (white2007complexregulationof pages 1-2). They further show that cyp26a1 is under complex feedback and feedforward control by RA and Fgf signaling, which can confer robustness to changes in RA synthesis and embryo size (white2007complexregulationof pages 1-2).

Hernandez et al. (2007; published Jan 2007; https://doi.org/10.1242/dev.02706) demonstrate that zebrafish orthologs of mammalian CYP26 genes (cyp26a1, cyp26b1, cyp26c1) act redundantly to shape the RA response pattern necessary for hindbrain development. When these RA-degrading enzymes are depleted, RA-responsive gene expression expands across the hindbrain, and dynamic CYP26 expression becomes essential for exogenous RA to rescue RA-depleted embryos (hernandez2007cyp26enzymesgenerate pages 1-2).

B. Spatial expression territories that restrict RA signaling

In zebrafish, cyp26a1 is expressed early in presumptive anterior neural ectoderm, and later in forebrain, midbrain, anterior hindbrain, and tailbud territories, contributing to establishment of anterior RA-depleted domains opposing posterior RA synthesis and shaping the rostrocaudal RA signaling landscape (drummond2013theroleof pages 1-3). This spatial arrangement is a recurring motif in hindbrain patterning: posterior RA production (aldh1a2/raldh2) vs anterior degradation (cyp26a1) (drummond2013theroleof pages 1-3).

C. Developmental phenotypes as functional readouts

Zebrafish functional perturbation evidence includes cyp26a1 overexpression experiments: microinjection of cyp26a1 mRNA reduces endogenous RA activity and yields phenotypes resembling reduced-RA conditions, consistent with a role in RA clearance (gu2006anovelcytochrome pages 3-5). Microsome assays and developmental perturbations together support that zebrafish cyp26a1 functionally restricts RA signaling to appropriate domains (gu2006anovelcytochrome pages 5-7, gu2006anovelcytochrome pages 3-5).

5) Recent developments and latest research (prioritizing 2024 zebrafish sources)

Direct 2023–2024 zebrafish primary literature focusing specifically on cyp26a1 mechanistic biology was limited in the retrieved corpus; however, 2024 studies demonstrate ongoing real-world use of cyp26a1 as a pathway marker and node in RA-linked phenotyping.

5.1 Developmental toxicology at environmentally relevant exposures (Schmandt et al., 2024)

Schmandt et al. (Toxics; published 16 May 2024; https://doi.org/10.3390/toxics12050368) used zebrafish to test nM triphenyl phosphate (TPhP) developmental exposure and included qPCR of cyp26a1 and raldh2 as markers of RA metabolism/signaling involvement. They chronically exposed embryos from ~4 hpf to 5 dpf at 0.5, 1, and 5 µg/L (≈ 1.5–15 nM) (schmandt2024environmentallyrelevantconcentrations pages 2-4). At 5 µg/L, mean larval length was significantly reduced by 0.14 mm (3.29 vs 3.14 mm, p = 0.00012) (schmandt2024environmentallyrelevantconcentrations pages 6-9). Importantly for functional annotation practice, they report no significant effect on RNA levels of the RA marker genes (in their text: cyp6a1 and raldh2; with raldh2 described as involved in RA production and inactivation respectively), supporting their conclusion that the observed cardiotoxicity at nM doses did not act primarily via RXR/RA signaling (schmandt2024environmentallyrelevantconcentrations pages 6-9). This study exemplifies how cyp26a1 (and allied RA-pathway genes) are deployed to discriminate mechanisms in toxicology screens.

5.2 Metabolic/liver developmental model implicating RA metabolism (Zeng et al., 2024)

Zeng et al. (Frontiers in Cell and Developmental Biology; published 18 April 2024; https://doi.org/10.3389/fcell.2024.1381362) generated CRISPR/Cas9 cobll1a knockout zebrafish and integrated RNA-seq, WISH, and qRT-PCR. They report that cobll1a−/− embryos exhibit impaired digestive organ development at 4 dpf and transcriptomic changes implicating disrupted RA signaling and lipid metabolism (zeng2024zebrafishcobll1aregulates pages 1-2). Within RA metabolism genes, they report down-regulation of RA synthesis-related genes (rdh10, aldh1a2) and up-regulation of the RA catabolism gene cyp26a1, alongside downregulation of multiple RAR genes (p < 0.05 for these RA-related comparisons as described) (zeng2024zebrafishcobll1aregulates pages 9-10). WISH localized expression of rdh10/aldh1a2/cyp26a1/rbp4 to intestine or liver-associated expression territories in their assay context (zeng2024zebrafishcobll1aregulates pages 9-10). Functionally, this positions cyp26a1 as an interpretable readout and potential effector within RA-linked liver/lipid homeostasis models.

6) Current applications and real-world implementations

Mechanistic developmental toxicology: cyp26a1 is used as a transcript marker of RA catabolism in zebrafish assays designed to test whether chemical exposures act through RA/RXR signaling vs alternative developmental pathways (e.g., tbx5a cascade), including at environmentally relevant dose ranges (schmandt2024environmentallyrelevantconcentrations pages 2-4, schmandt2024environmentallyrelevantconcentrations pages 6-9).
Disease-relevant metabolic modeling: CRISPR zebrafish genetic models that phenocopy aspects of liver dysfunction and lipid dysregulation can incorporate cyp26a1 as an RA-catabolism node/biomarker to connect transcriptional changes to RA homeostasis hypotheses (zeng2024zebrafishcobll1aregulates pages 1-2, zeng2024zebrafishcobll1aregulates pages 9-10).
Quantitative developmental systems biology: cyp26a1 regulation is central in computational–experimental models of how embryos generate robust morphogen distributions—a template for modern developmental systems approaches to buffering and scaling (white2007complexregulationof pages 1-2).

7) Expert opinions and analysis (authoritative synthesis)

CYP26 enzymes as homeostatic “buffer” and tissue-protection system

Roberts (2020; Journal of Developmental Biology; published Mar 2020; https://doi.org/10.3390/jdb8010006) frames CYP26 enzymes as essential regulators of RA availability, required to generate RA gradients and to protect tissues from inappropriate RA signaling, integrating structure/biochemistry and developmental roles (roberts2020regulatingretinoicacid pages 5-7, roberts2020regulatingretinoicacid pages 7-10). This review also emphasizes mechanistic enzymology (ER/microsomal localization, POR/NADPH electron transfer) that underpins how CYP26 enzymes implement homeostatic control (roberts2020regulatingretinoicacid pages 7-10).

CYP26A1 as a dominant RA clearance route and pharmacology-relevant enzyme family

Thatcher & Isoherranen (2009; Expert Opinion on Drug Metabolism & Toxicology; published Jul 2009; https://doi.org/10.1517/17425250903032681) emphasize the centrality of CYP26-mediated clearance in RA biology and detail the metabolite profile and 4-hydroxylation primacy, supporting the view of CYP26A1 as a key determinant of tissue RA exposure (thatcher2009theroleof pages 5-7). They also document historical discovery of zebrafish P450RAI as CYP26A1 in the context of RA-responsive programs such as fin regeneration (thatcher2009theroleof pages 2-4).

8) Relevant figures (image evidence)

Figures retrieved from White et al. (2007) include cyp26a1 expression and RA-patterning/gradient modeling schematics and data panels that visually summarize the RA response landscape and conceptual model of RA–Fgf–cyp26a1 interactions (white2007complexregulationof media 35639faa, white2007complexregulationof media 9940ff21, white2007complexregulationof media 66fdd7c8, white2007complexregulationof media 3e7a30e7).

Summary table (functional annotation at a glance)

Function/Reaction	Substrates & products	Subcellular localization	Developmental roles/processes in zebrafish	Regulation/feedback	Recent applications (2024 studies)	Key evidence sources with DOI/URL and year
Retinoic-acid catabolic cytochrome P450; major RA-degrading enzyme during gastrulation that helps generate a robust hindbrain RA gradient (white2007complexregulationof pages 1-2, hernandez2007cyp26enzymesgenerate pages 1-2)	Oxidizes all-trans RA to more polar metabolites; family products include 4-OH-RA, 4-oxo-RA, 18-OH-RA and other oxidized derivatives (gu2006anovelcytochrome pages 1-2, roberts2020regulatingretinoicacid pages 7-10, thatcher2009theroleof pages 5-7)	Membrane-anchored microsomal/ER cytochrome P450; heme-containing class II P450 inferred for zebrafish Cyp26a1 (roberts2020regulatingretinoicacid pages 7-10, roberts2020regulatingretinoicacid pages 5-7, thatcher2009theroleof pages 2-4)	Establishes anterior RA-poor territory and posterior-to-anterior RA patterning; required for hindbrain AP patterning, rhombomere identity, and protection from excess RA; loss expands posterior hindbrain fates anteriorly (white2007complexregulationof pages 1-2, drummond2013theroleof pages 1-3, hernandez2007cyp26enzymesgenerate pages 1-2)	Under complex feedback/feedforward control by RA and Fgf signaling; RA can induce cyp26a1 expression, creating adaptive buffering/homeostasis of RA availability (white2007complexregulationof pages 1-2, roberts2020regulatingretinoicacid pages 5-7)	Used conceptually as a readout of RA-pathway perturbation in zebrafish developmental studies and toxicology assays (schmandt2024environmentallyrelevantconcentrations pages 1-2, schmandt2024environmentallyrelevantconcentrations pages 6-9, zeng2024zebrafishcobll1aregulates pages 1-2)	White 2007, PLoS Biol, doi:10.1371/journal.pbio.0050304, https://doi.org/10.1371/journal.pbio.0050304; Hernandez 2007, Development, doi:10.1242/dev.02706, https://doi.org/10.1242/dev.02706
Enzymatic reaction detail: RA 4-hydroxylase/oxidase activity demonstrated in zebrafish microsomal assays (gu2006anovelcytochrome pages 3-5, gu2006anovelcytochrome pages 5-7)	Zebrafish Cyp26A1 microsomes mainly generate 4-OH-RA and 4-oxo-RA from all-trans RA; related CYP26 enzymes can also metabolize 9-cis RA and 13-cis RA, but not retinol/retinal in the cited assay system (gu2006anovelcytochrome pages 1-2, gu2006anovelcytochrome pages 5-7, gu2006anovelcytochrome pages 3-5)	Activity assayed in microsomes from transfected cells, consistent with ER-derived membrane localization (gu2006anovelcytochrome pages 5-7, gu2006anovelcytochrome pages 3-5)	Restricts inappropriate RA signaling during somitogenesis and axial patterning; cyp26a1 overexpression reduces endogenous RA activity and alters hindbrain-somite patterning/asymmetric somites (gu2006anovelcytochrome pages 3-5, gu2006anovelcytochrome pages 5-7)	RA inducibility supports negative-feedback RA clearance; CYP26 enzymes act as RA sinks to sharpen signaling boundaries (thatcher2009theroleof pages 2-4, roberts2020regulatingretinoicacid pages 5-7)	Supports use of cyp26a1 as a mechanistic biomarker for compounds or mutations that disturb RA metabolism/signaling (thatcher2009theroleof pages 2-4, zeng2024zebrafishcobll1aregulates pages 1-2)	Gu 2006, Mol Endocrinol, doi:10.1210/me.2005-0362, https://doi.org/10.1210/me.2005-0362; Thatcher & Isoherranen 2009, Expert Opin Drug Metab Toxicol, doi:10.1517/17425250903032681, https://doi.org/10.1517/17425250903032681
Spatially restricted embryonic RA-clearance factor in anterior neural ectoderm/hindbrain field (drummond2013theroleof pages 1-3, hernandez2007cyp26enzymesgenerate pages 1-2)	Functional effect is depletion of local RA available for receptor signaling rather than transport of another substrate (drummond2013theroleof pages 1-3, roberts2020regulatingretinoicacid pages 5-7)	Expressed in presumptive anterior neural ectoderm, then forebrain, midbrain, anterior hindbrain, and tailbud during early development (gene-expression territory rather than protein compartment) (drummond2013theroleof pages 1-3)	Creates RA-depleted anterior domains opposing posterior aldh1a2/raldh2 synthesis; essential for proper hindbrain segmentation and regional identity (drummond2013theroleof pages 1-3, hernandez2007cyp26enzymesgenerate pages 1-2)	Integrated with transcriptional regulators such as zic factors that influence embryonic RA signaling territories (drummond2013theroleof pages 1-3)	Provides a developmental pathway node for dissecting hindbrain patterning and cranial motor-neuron specification mechanisms (drummond2013theroleof pages 1-3)	Drummond 2013, BMC Dev Biol, doi:10.1186/1471-213X-13-31, https://doi.org/10.1186/1471-213X-13-31
General CYP26 biochemistry/current understanding: high-efficiency RA clearance enzyme family controlling RA homeostasis (roberts2020regulatingretinoicacid pages 5-7, roberts2020regulatingretinoicacid pages 7-10)	High catalytic activity toward all-trans RA; review cites Km < 100 nM and turnover ~1–10 pmol/min/pmol in transfected-cell systems for CYP26 enzymes; metabolites subsequently glucuronidated and eliminated (roberts2020regulatingretinoicacid pages 7-10)	ER/microsomal enzyme requiring POR-mediated electron transfer from NADPH via FAD and FMN; contains heme-binding domain (roberts2020regulatingretinoicacid pages 7-10, thatcher2009theroleof pages 2-4)	Protects RA-sensitive tissues and helps establish local RA gradients across multiple developmental contexts; zebrafish hindbrain is a canonical example (roberts2020regulatingretinoicacid pages 5-7, white2007complexregulationof pages 1-2)	Negative feedback is a central systems-level property of CYP26-mediated RA homeostasis (roberts2020regulatingretinoicacid pages 5-7, roberts2020regulatingretinoicacid pages 7-10)	Basis for pharmacologic CYP26 inhibition/modulation concepts and for interpreting RA-pathway toxicity in zebrafish and other vertebrates (thatcher2009theroleof pages 2-4, roberts2020regulatingretinoicacid pages 7-10)	Roberts 2020, J Dev Biol, doi:10.3390/jdb8010006, https://doi.org/10.3390/jdb8010006; Thatcher & Isoherranen 2009, doi:10.1517/17425250903032681, https://doi.org/10.1517/17425250903032681
2024 zebrafish toxicology application: cyp26a1 measured as an RA-pathway marker during environmentally relevant TPhP exposure (schmandt2024environmentallyrelevantconcentrations pages 1-2, schmandt2024environmentallyrelevantconcentrations pages 6-9, schmandt2024environmentallyrelevantconcentrations pages 2-4)	Not a direct substrate study; cyp26a1 transcript assessed alongside raldh2 to test whether TPhP acts through RA/RXR signaling (schmandt2024environmentallyrelevantconcentrations pages 6-9)	Whole-larva qPCR readout at 5 dpf; localization not the focus (schmandt2024environmentallyrelevantconcentrations pages 2-4)	In this assay, no significant change in cyp26a1/raldh2 at 5 µg/L TPhP suggested the nM TPhP phenotype was not mediated by RXR/RA signaling; affected larvae were shorter and showed pericardial edema (0.14 mm decrease at 5 µg/L; 3.29 vs 3.14 mm; p=0.00012) (schmandt2024environmentallyrelevantconcentrations pages 6-9)	Demonstrates utility of cyp26a1 as a pathway-discrimination marker distinguishing RA/RXR effects from tbx5a-associated cardiotoxicity (schmandt2024environmentallyrelevantconcentrations pages 6-9)	Real-world implementation in developmental toxicology screening at environmentally relevant concentrations 0.5–5 µg/L (1.5–15 nM) (schmandt2024environmentallyrelevantconcentrations pages 1-2, schmandt2024environmentallyrelevantconcentrations pages 2-4)	Schmandt 2024, Toxics, doi:10.3390/toxics12050368, https://doi.org/10.3390/toxics12050368
2024 zebrafish disease/metabolism application: cyp26a1 upregulation marks disrupted RA metabolism in cobll1a mutants (zeng2024zebrafishcobll1aregulates pages 9-10, zeng2024zebrafishcobll1aregulates pages 1-2)	Not a direct enzymology study; cyp26a1 used as the RA-catabolism gene indicator within altered retinol/RA metabolic networks (zeng2024zebrafishcobll1aregulates pages 9-10)	WISH detected expression of rdh10, aldh1a2, cyp26a1 and rbp4 in intestine or liver-associated territories in the study context (zeng2024zebrafishcobll1aregulates pages 9-10)	cobll1a−/− embryos showed impaired digestive-organ development at 4 dpf, altered RA-pathway gene expression, increased lipid synthesis and reduced lipid catabolism; cyp26a1 was upregulated while aldh1a2/rdh10 and RAR genes were downregulated (zeng2024zebrafishcobll1aregulates pages 9-10, zeng2024zebrafishcobll1aregulates pages 1-2)	Shows cyp26a1 participates in broader RA-lipid homeostasis networks; RA catabolism shifts accompany hepatic/lipid phenotypes (zeng2024zebrafishcobll1aregulates pages 9-10)	Application in metabolic disease modeling/NAFLD-related liver biology using CRISPR zebrafish mutants; lipid-pathway genes changed significantly (p < 0.01 for listed lipid-anabolism genes) (zeng2024zebrafishcobll1aregulates pages 1-2, zeng2024zebrafishcobll1aregulates pages 9-10)	Zeng 2024, Front Cell Dev Biol, doi:10.3389/fcell.2024.1381362, https://doi.org/10.3389/fcell.2024.1381362

Table: This table summarizes the verified function, reaction chemistry, localization, developmental roles, regulation, and 2024 zebrafish applications of Danio rerio cyp26a1 (UniProt P79739). It is useful as a compact evidence-based functional annotation reference anchored to the cited source contexts.

Key takeaways for functional annotation of zebrafish cyp26a1 (P79739)

Primary molecular function: ER/microsomal cytochrome P450 enzyme that hydroxylates/oxidizes retinoic acid, producing 4-OH-RA and 4-oxo-RA (major products), thereby reducing RA signaling capacity (gu2006anovelcytochrome pages 5-7, thatcher2009theroleof pages 5-7).
Primary pathway role: a core component of RA homeostasis that sculpts spatial RA signaling territories in early embryos and is necessary for correct hindbrain patterning and RA responsiveness (white2007complexregulationof pages 1-2, hernandez2007cyp26enzymesgenerate pages 1-2).
Where it acts: consistent with a membrane-anchored ER/microsomal P450 requiring POR/NADPH electron transfer (roberts2020regulatingretinoicacid pages 7-10, roberts2020regulatingretinoicacid pages 5-7).
How it is used today (2024): widely implemented as a pathway marker/readout in zebrafish toxicology and developmental/metabolic genetics to test or interpret RA pathway perturbation (schmandt2024environmentallyrelevantconcentrations pages 6-9, zeng2024zebrafishcobll1aregulates pages 9-10).

URLs and publication dates (most relevant)

White RJ et al. “Complex Regulation of cyp26a1 Creates a Robust Retinoic Acid Gradient in the Zebrafish Embryo.” PLoS Biology (Nov 2007). https://doi.org/10.1371/journal.pbio.0050304 (white2007complexregulationof pages 1-2)
Hernandez RE et al. “Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development.” Development (Jan 2007). https://doi.org/10.1242/dev.02706 (hernandez2007cyp26enzymesgenerate pages 1-2)
Drummond DL et al. “The role of Zic transcription factors in regulating hindbrain retinoic acid signaling.” BMC Developmental Biology (Aug 2013). https://doi.org/10.1186/1471-213X-13-31 (drummond2013theroleof pages 1-3)
Gu X et al. “A novel cytochrome P450, zebrafish Cyp26D1, is involved in metabolism of all-trans retinoic acid.” Molecular Endocrinology (Jul 2006). https://doi.org/10.1210/me.2005-0362 (gu2006anovelcytochrome pages 5-7)
Roberts C. “Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes.” Journal of Developmental Biology (Mar 2020). https://doi.org/10.3390/jdb8010006 (roberts2020regulatingretinoicacid pages 7-10)
Thatcher JE, Isoherranen N. “The role of CYP26 enzymes in retinoic acid clearance.” Expert Opinion on Drug Metabolism & Toxicology (Jul 2009). https://doi.org/10.1517/17425250903032681 (thatcher2009theroleof pages 5-7)
Schmandt B et al. “Environmentally Relevant Concentrations of Triphenyl Phosphate (TPhP) Impact Development in Zebrafish.” Toxics (Published 16 May 2024; received 20 Apr 2024; accepted 13 May 2024). https://doi.org/10.3390/toxics12050368 (schmandt2024environmentallyrelevantconcentrations pages 2-4)
Zeng T et al. “Zebrafish cobll1a regulates lipid homeostasis via the RA signaling pathway.” Frontiers in Cell and Developmental Biology (Published 18 Apr 2024; received 3 Feb 2024; accepted 4 Apr 2024). https://doi.org/10.3389/fcell.2024.1381362 (zeng2024zebrafishcobll1aregulates pages 1-2)

References

(white2007complexregulationof pages 1-2): Richard J White, Qing Nie, Arthur D Lander, and Thomas F Schilling. Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biology, 5:e304, Nov 2007. URL: https://doi.org/10.1371/journal.pbio.0050304, doi:10.1371/journal.pbio.0050304. This article has 274 citations and is from a highest quality peer-reviewed journal.
(hernandez2007cyp26enzymesgenerate pages 1-2): Rafael E. Hernandez, Aaron P. Putzke, Jonathan P. Myers, Lilyana Margaretha, and Cecilia B. Moens. Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development. Development, 134:177-187, Jan 2007. URL: https://doi.org/10.1242/dev.02706, doi:10.1242/dev.02706. This article has 270 citations and is from a domain leading peer-reviewed journal.
(gu2006anovelcytochrome pages 5-7): Xingxing Gu, Fang Xu, Wei Song, Xiaolin Wang, Ping Hu, Yumin Yang, Xiang Gao, and Qingshun Zhao. A novel cytochrome p450, zebrafish cyp26d1, is involved in metabolism of all-trans retinoic acid. Molecular endocrinology, 20 7:1661-72, Jul 2006. URL: https://doi.org/10.1210/me.2005-0362, doi:10.1210/me.2005-0362. This article has 29 citations.
(gu2006anovelcytochrome pages 3-5): Xingxing Gu, Fang Xu, Wei Song, Xiaolin Wang, Ping Hu, Yumin Yang, Xiang Gao, and Qingshun Zhao. A novel cytochrome p450, zebrafish cyp26d1, is involved in metabolism of all-trans retinoic acid. Molecular endocrinology, 20 7:1661-72, Jul 2006. URL: https://doi.org/10.1210/me.2005-0362, doi:10.1210/me.2005-0362. This article has 29 citations.
(thatcher2009theroleof pages 5-7): Jayne E Thatcher and Nina Isoherranen. The role of cyp26 enzymes in retinoic acid clearance. Expert Opinion on Drug Metabolism & Toxicology, 5:875-886, Jul 2009. URL: https://doi.org/10.1517/17425250903032681, doi:10.1517/17425250903032681. This article has 268 citations and is from a peer-reviewed journal.
(thatcher2009theroleof pages 2-4): Jayne E Thatcher and Nina Isoherranen. The role of cyp26 enzymes in retinoic acid clearance. Expert Opinion on Drug Metabolism & Toxicology, 5:875-886, Jul 2009. URL: https://doi.org/10.1517/17425250903032681, doi:10.1517/17425250903032681. This article has 268 citations and is from a peer-reviewed journal.
(roberts2020regulatingretinoicacid pages 5-7): Catherine Roberts. Regulating retinoic acid availability during development and regeneration: the role of the cyp26 enzymes. Journal of Developmental Biology, 8:6, Mar 2020. URL: https://doi.org/10.3390/jdb8010006, doi:10.3390/jdb8010006. This article has 52 citations.
(roberts2020regulatingretinoicacid pages 7-10): Catherine Roberts. Regulating retinoic acid availability during development and regeneration: the role of the cyp26 enzymes. Journal of Developmental Biology, 8:6, Mar 2020. URL: https://doi.org/10.3390/jdb8010006, doi:10.3390/jdb8010006. This article has 52 citations.
(gu2006anovelcytochrome pages 1-2): Xingxing Gu, Fang Xu, Wei Song, Xiaolin Wang, Ping Hu, Yumin Yang, Xiang Gao, and Qingshun Zhao. A novel cytochrome p450, zebrafish cyp26d1, is involved in metabolism of all-trans retinoic acid. Molecular endocrinology, 20 7:1661-72, Jul 2006. URL: https://doi.org/10.1210/me.2005-0362, doi:10.1210/me.2005-0362. This article has 29 citations.
(drummond2013theroleof pages 1-3): Danna L Drummond, Caroline S Cheng, Lyndsay G Selland, Jennifer C Hocking, Lisa B Prichard, and Andrew J Waskiewicz. The role of zic transcription factors in regulating hindbrain retinoic acid signaling. BMC Developmental Biology, 13:31-31, Aug 2013. URL: https://doi.org/10.1186/1471-213x-13-31, doi:10.1186/1471-213x-13-31. This article has 27 citations and is from a peer-reviewed journal.
(schmandt2024environmentallyrelevantconcentrations pages 2-4): Benjamin Schmandt, Mfon Diduff, Gabrielle Smart, and Larissa M. Williams. Environmentally relevant concentrations of triphenyl phosphate (tphp) impact development in zebrafish. Toxics, 12:368, May 2024. URL: https://doi.org/10.3390/toxics12050368, doi:10.3390/toxics12050368. This article has 12 citations.
(schmandt2024environmentallyrelevantconcentrations pages 6-9): Benjamin Schmandt, Mfon Diduff, Gabrielle Smart, and Larissa M. Williams. Environmentally relevant concentrations of triphenyl phosphate (tphp) impact development in zebrafish. Toxics, 12:368, May 2024. URL: https://doi.org/10.3390/toxics12050368, doi:10.3390/toxics12050368. This article has 12 citations.
(zeng2024zebrafishcobll1aregulates pages 1-2): Ting Zeng, Jinrui Lv, Jiaxin Liang, Binling Xie, Ling Liu, Yuanyuan Tan, Junwei Zhu, Jifan Jiang, and Huaping Xie. Zebrafish cobll1a regulates lipid homeostasis via the ra signaling pathway. Frontiers in Cell and Developmental Biology, Apr 2024. URL: https://doi.org/10.3389/fcell.2024.1381362, doi:10.3389/fcell.2024.1381362. This article has 5 citations.
(zeng2024zebrafishcobll1aregulates pages 9-10): Ting Zeng, Jinrui Lv, Jiaxin Liang, Binling Xie, Ling Liu, Yuanyuan Tan, Junwei Zhu, Jifan Jiang, and Huaping Xie. Zebrafish cobll1a regulates lipid homeostasis via the ra signaling pathway. Frontiers in Cell and Developmental Biology, Apr 2024. URL: https://doi.org/10.3389/fcell.2024.1381362, doi:10.3389/fcell.2024.1381362. This article has 5 citations.
(white2007complexregulationof media 35639faa): Richard J White, Qing Nie, Arthur D Lander, and Thomas F Schilling. Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biology, 5:e304, Nov 2007. URL: https://doi.org/10.1371/journal.pbio.0050304, doi:10.1371/journal.pbio.0050304. This article has 274 citations and is from a highest quality peer-reviewed journal.
(white2007complexregulationof media 9940ff21): Richard J White, Qing Nie, Arthur D Lander, and Thomas F Schilling. Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biology, 5:e304, Nov 2007. URL: https://doi.org/10.1371/journal.pbio.0050304, doi:10.1371/journal.pbio.0050304. This article has 274 citations and is from a highest quality peer-reviewed journal.
(white2007complexregulationof media 66fdd7c8): Richard J White, Qing Nie, Arthur D Lander, and Thomas F Schilling. Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biology, 5:e304, Nov 2007. URL: https://doi.org/10.1371/journal.pbio.0050304, doi:10.1371/journal.pbio.0050304. This article has 274 citations and is from a highest quality peer-reviewed journal.
(white2007complexregulationof media 3e7a30e7): Richard J White, Qing Nie, Arthur D Lander, and Thomas F Schilling. Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biology, 5:e304, Nov 2007. URL: https://doi.org/10.1371/journal.pbio.0050304, doi:10.1371/journal.pbio.0050304. This article has 274 citations and is from a highest quality peer-reviewed journal.
(schmandt2024environmentallyrelevantconcentrations pages 1-2): Benjamin Schmandt, Mfon Diduff, Gabrielle Smart, and Larissa M. Williams. Environmentally relevant concentrations of triphenyl phosphate (tphp) impact development in zebrafish. Toxics, 12:368, May 2024. URL: https://doi.org/10.3390/toxics12050368, doi:10.3390/toxics12050368. This article has 12 citations.

Artifacts

Edison artifact artifact-00

Citations

white2007complexregulationof pages 1-2
thatcher2009theroleof pages 5-7
roberts2020regulatingretinoicacid pages 7-10
drummond2013theroleof pages 1-3
gu2006anovelcytochrome pages 3-5
schmandt2024environmentallyrelevantconcentrations pages 2-4
schmandt2024environmentallyrelevantconcentrations pages 6-9
thatcher2009theroleof pages 2-4
gu2006anovelcytochrome pages 5-7
roberts2020regulatingretinoicacid pages 5-7
gu2006anovelcytochrome pages 1-2
schmandt2024environmentallyrelevantconcentrations pages 1-2
https://doi.org/10.1371/journal.pbio.0050304
https://doi.org/10.1242/dev.02706
https://doi.org/10.3390/toxics12050368
https://doi.org/10.3389/fcell.2024.1381362
https://doi.org/10.3390/jdb8010006
https://doi.org/10.1517/17425250903032681
https://doi.org/10.1371/journal.pbio.0050304;
https://doi.org/10.1210/me.2005-0362;
https://doi.org/10.1186/1471-213X-13-31
https://doi.org/10.3390/jdb8010006;
https://doi.org/10.1210/me.2005-0362
https://doi.org/10.1371/journal.pbio.0050304,
https://doi.org/10.1242/dev.02706,
https://doi.org/10.1210/me.2005-0362,
https://doi.org/10.1517/17425250903032681,
https://doi.org/10.3390/jdb8010006,
https://doi.org/10.1186/1471-213x-13-31,
https://doi.org/10.3390/toxics12050368,
https://doi.org/10.3389/fcell.2024.1381362,

📚 Additional Documentation

Notes

(cyp26a1-notes.md)

cyp26a1 (Danio rerio) review notes

Batch 05 curation notes

Core interpretation: cyp26a1 encodes cytochrome P450 26A1, an endoplasmic-reticulum retinoic-acid hydroxylase that catabolizes all-trans retinoic acid and thereby shapes retinoic-acid signaling during zebrafish development. Developmental patterning annotations are treated as downstream consequences of this core retinoic-acid metabolic activity.
Key UniProt support: Catalyzes the hydroxylation of carbon hydrogen bonds of atRA primarily at C-4.
Existing GOA annotations were reviewed against this core role; broad, inferred, or downstream phenotype annotations were kept as non-core unless they overstate the direct function.

📄 View Raw YAML

id: P79739
gene_symbol: cyp26a1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:7955
  label: Danio rerio
description: cyp26a1 encodes cytochrome P450 26A1, an endoplasmic-reticulum retinoic-acid hydroxylase that catabolizes all-trans
  retinoic acid and thereby shapes retinoic-acid signaling during zebrafish development. Developmental patterning annotations
  are treated as downstream consequences of this core retinoic-acid metabolic activity.
existing_annotations:
- term:
    id: GO:0034653
    label: retinoic acid catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: retinoic acid catabolic process (GO:0034653) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        Zebrafish Cyp26a1 catalyzes oxidative metabolism of atRA, generating metabolites dominated by **4-hydroxy-RA (4-OH-RA)** and **4-oxo-RA (4-oxo-RA)** in microsome assays from transfected cells
- term:
    id: GO:0007417
    label: central nervous system development
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: central nervous system development (GO:0007417) is retained as supported context for cyp26a1 but is not the primary/core
      function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
- term:
    id: GO:0004497
    label: monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: monooxygenase activity (GO:0004497) is retained as supported context for cyp26a1 but is not the primary/core
      function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        CYP26 enzymes are described as **membrane-anchored microsomal (endoplasmic reticulum, ER) cytochrome P450s** with a heme center
- term:
    id: GO:0005506
    label: iron ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: iron ion binding (GO:0005506) is retained as supported context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        each catalytic cycle requires electrons supplied from **NADPH via cytochrome P450 oxidoreductase (POR)**, which uses **FAD and FMN** cofactors
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: endoplasmic reticulum membrane (GO:0005789) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        Cyp26a1 is best supported as a **microsomal/ER membrane-anchored cytochrome P450**, i.e., positioned to access intracellular RA pools and regulate RA available for nuclear receptor signaling
- term:
    id: GO:0008401
    label: retinoic acid 4-hydroxylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: retinoic acid 4-hydroxylase activity (GO:0008401) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        Reviews of CYP26A1 metabolism emphasize **4-hydroxylation as the primary transformation** for CYP26A1 (and CYP26B1)
- term:
    id: GO:0016705
    label: oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705)
      is retained as supported context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: heme binding (GO:0020037) is retained as supported context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        CYP26 enzymes are described as **membrane-anchored microsomal (endoplasmic reticulum, ER) cytochrome P450s** with a heme center
- term:
    id: GO:0034653
    label: retinoic acid catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: retinoic acid catabolic process (GO:0034653) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        They convert RA into **more polar, generally less active metabolites**, supporting clearance and preventing ectopic signaling
- term:
    id: GO:0062182
    label: all-trans retinoic acid 4-hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  review:
    summary: all-trans retinoic acid 4-hydrolase activity (GO:0062182) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        Cell/microsome assays of zebrafish CYP26 family members show activity toward **RA isomers** (atRA, 9-cis RA, 13-cis RA) and **no detectable metabolism of retinol or retinal** under the tested conditions, supporting specialization for RA
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: endoplasmic reticulum membrane (GO:0005789) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        Experimental enzymology for zebrafish cyp26a1 was performed using **microsomes isolated from transfected cells**, which is consistent with ER-derived membrane localization
- term:
    id: GO:0062182
    label: all-trans retinoic acid 4-hydrolase activity
  evidence_type: EXP
  original_reference_id: PMID:8939936
  review:
    summary: all-trans retinoic acid 4-hydrolase activity (GO:0062182) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        Zebrafish Cyp26a1 catalyzes oxidative metabolism of atRA, generating metabolites dominated by **4-hydroxy-RA (4-OH-RA)** and **4-oxo-RA (4-oxo-RA)** in microsome assays from transfected cells
- term:
    id: GO:0003151
    label: outflow tract morphogenesis
  evidence_type: IGI
  original_reference_id: PMID:27893754
  review:
    summary: outflow tract morphogenesis (GO:0003151) is retained as supported context for cyp26a1 but is not the primary/core
      function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:27893754
      supporting_text: zebrafish embryos deficient for Cyp26a1 and Cyp26c1 enzymes, which promote RA degradation, have OFT
        defects
- term:
    id: GO:0034672
    label: anterior/posterior pattern specification involved in pronephros development
  evidence_type: IMP
  original_reference_id: PMID:27406002
  review:
    summary: anterior/posterior pattern specification involved in pronephros development (GO:0034672) is retained as supported
      context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:27406002
      supporting_text: posterior kidney progenitors are protected ventrally by the RA-catabolizing enzyme Cyp26a1
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        cyp26a1 is expressed early in presumptive anterior neural ectoderm, and later in forebrain, midbrain, anterior hindbrain, and tailbud territories, contributing to establishment of anterior RA-depleted domains opposing posterior RA synthesis
- term:
    id: GO:0007507
    label: heart development
  evidence_type: IMP
  original_reference_id: PMID:23990796
  review:
    summary: heart development (GO:0007507) is retained as supported context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:23990796
      supporting_text: Cyp26a1, an enzyme that facilitates degradation of RA
- term:
    id: GO:0007507
    label: heart development
  evidence_type: IGI
  original_reference_id: PMID:23990796
  review:
    summary: heart development (GO:0007507) is retained as supported context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:23990796
      supporting_text: Cyp26a1, an enzyme that facilitates degradation of RA
- term:
    id: GO:0030917
    label: midbrain-hindbrain boundary development
  evidence_type: IGI
  original_reference_id: PMID:23990796
  review:
    summary: midbrain-hindbrain boundary development (GO:0030917) is retained as supported context for cyp26a1 but is not
      the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:23990796
      supporting_text: Cyp26a1, an enzyme that facilitates degradation of RA
- term:
    id: GO:0001944
    label: vasculature development
  evidence_type: IGI
  original_reference_id: PMID:24667328
  review:
    summary: vasculature development (GO:0001944) is retained as supported context for cyp26a1 but is not the primary/core
      function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:24667328
      supporting_text: Cyp26 enzymes largely act cell non-autonomously to promote appropriate cardiovascular development
- term:
    id: GO:0055014
    label: atrial cardiac muscle cell development
  evidence_type: IGI
  original_reference_id: PMID:24667328
  review:
    summary: atrial cardiac muscle cell development (GO:0055014) is retained as supported context for cyp26a1 but is not the
      primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:24667328
      supporting_text: Cyp26 enzymes largely act cell non-autonomously to promote appropriate cardiovascular development
- term:
    id: GO:0048384
    label: retinoic acid receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23975936
  review:
    summary: retinoic acid receptor signaling pathway (GO:0048384) is retained as supported context for cyp26a1 but is not
      the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:23975936
      supporting_text: A reporter assay confirmed that cyp26a1 is a bona fide target of miR-19 in vivo
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        a core component of **RA homeostasis** that sculpts spatial RA signaling territories in early embryos
- term:
    id: GO:0003131
    label: mesodermal-endodermal cell signaling
  evidence_type: IMP
  original_reference_id: PMID:19416885
  review:
    summary: mesodermal-endodermal cell signaling (GO:0003131) is retained as supported context for cyp26a1 but is not the
      primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:19416885
      supporting_text: the RA-degrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic
        field
- term:
    id: GO:0031016
    label: pancreas development
  evidence_type: IMP
  original_reference_id: PMID:19416885
  review:
    summary: pancreas development (GO:0031016) is retained as supported context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:19416885
      supporting_text: the RA-degrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic
        field
- term:
    id: GO:0031016
    label: pancreas development
  evidence_type: IGI
  original_reference_id: PMID:19416885
  review:
    summary: pancreas development (GO:0031016) is retained as supported context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:19416885
      supporting_text: the RA-degrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic
        field
- term:
    id: GO:0034653
    label: retinoic acid catabolic process
  evidence_type: IMP
  original_reference_id: PMID:19416885
  review:
    summary: retinoic acid catabolic process (GO:0034653) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: PMID:19416885
      supporting_text: the RA-degrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic
        field
- term:
    id: GO:0021797
    label: forebrain anterior/posterior pattern specification
  evidence_type: IGI
  original_reference_id: PMID:17998248
  review:
    summary: forebrain anterior/posterior pattern specification (GO:0021797) is retained as supported context for cyp26a1
      but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:17998248
      supporting_text: The loss of the forebrain-specific RA-degrading enzyme cyp26a1 causes a forebrain phenotype that mimics
        tgif morphants
- term:
    id: GO:0048854
    label: brain morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:17998248
  review:
    summary: brain morphogenesis (GO:0048854) is retained as supported context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:17998248
      supporting_text: The loss of the forebrain-specific RA-degrading enzyme cyp26a1 causes a forebrain phenotype that mimics
        tgif morphants
- term:
    id: GO:0071299
    label: cellular response to vitamin A
  evidence_type: IDA
  original_reference_id: PMID:17253779
  review:
    summary: cellular response to vitamin A (GO:0071299) is retained as supported context for cyp26a1 but is not the primary/core
      function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:17253779
      supporting_text: all-trans-13,14-dihydroretinol is transiently oxidized to all-trans-13,14-dihydroretinoic acid before
        being oxidized further by Cyp26 enzymes
- term:
    id: GO:0001756
    label: somitogenesis
  evidence_type: IMP
  original_reference_id: PMID:17098223
  review:
    summary: somitogenesis (GO:0001756) is retained as supported context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:17098223
      supporting_text: expression of the RA-degrading enzyme cyp26a1 in the tailbud was controlled by Su(H) activity
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        microinjection of cyp26a1 mRNA reduces endogenous RA activity and yields phenotypes resembling reduced-RA conditions, consistent with a role in RA clearance
- term:
    id: GO:0021661
    label: rhombomere 4 morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:17164423
  review:
    summary: rhombomere 4 morphogenesis (GO:0021661) is retained as supported context for cyp26a1 but is not the primary/core
      function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:17164423
      supporting_text: metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains
        during hindbrain development
- term:
    id: GO:0021661
    label: rhombomere 4 morphogenesis
  evidence_type: IGI
  original_reference_id: PMID:17164423
  review:
    summary: rhombomere 4 morphogenesis (GO:0021661) is retained as supported context for cyp26a1 but is not the primary/core
      function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:17164423
      supporting_text: metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains
        during hindbrain development
- term:
    id: GO:0030902
    label: hindbrain development
  evidence_type: IGI
  original_reference_id: PMID:17164423
  review:
    summary: hindbrain development (GO:0030902) is retained as supported context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:17164423
      supporting_text: metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains
        during hindbrain development
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        Hernandez et al. (2007; published Jan 2007; https://doi.org/10.1242/dev.02706) demonstrate that zebrafish orthologs of mammalian CYP26 genes (**cyp26a1, cyp26b1, cyp26c1**) act **redundantly** to shape the RA response pattern necessary for hindbrain development
- term:
    id: GO:0042573
    label: retinoic acid metabolic process
  evidence_type: IMP
  original_reference_id: PMID:17164423
  review:
    summary: retinoic acid metabolic process (GO:0042573) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: PMID:17164423
      supporting_text: metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains
        during hindbrain development
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        They convert RA into **more polar, generally less active metabolites**, supporting clearance and preventing ectopic signaling
- term:
    id: GO:0042574
    label: retinal metabolic process
  evidence_type: IMP
  original_reference_id: PMID:17164423
  review:
    summary: retinal metabolic process (GO:0042574) is not the appropriate direct annotation for cyp26a1.
    action: REMOVE
    reason: The synthesized evidence supports the specific core annotations reviewed separately; this broad or wrong-context
      annotation should be retired rather than treated as a core function.
    supported_by:
    - reference_id: PMID:17164423
      supporting_text: metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains
        during hindbrain development
- term:
    id: GO:0042573
    label: retinoic acid metabolic process
  evidence_type: IDA
  original_reference_id: PMID:16455818
  review:
    summary: retinoic acid metabolic process (GO:0042573) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: PMID:16455818
      supporting_text: Cyp26D1 expressed in 293T cells could metabolize all-trans RA, 9-cis RA, and 13-cis RA
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        Cell/microsome assays of zebrafish CYP26 family members show activity toward **RA isomers** (atRA, 9-cis RA, 13-cis RA) and **no detectable metabolism of retinol or retinal** under the tested conditions, supporting specialization for RA
- term:
    id: GO:0001568
    label: blood vessel development
  evidence_type: IMP
  original_reference_id: PMID:15680360
  review:
    summary: blood vessel development (GO:0001568) is retained as supported context for cyp26a1 but is not the primary/core
      function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:15680360
      supporting_text: the gene for the RA-degrading enzyme Cyp26a1 is mutated
- term:
    id: GO:0030902
    label: hindbrain development
  evidence_type: IMP
  original_reference_id: PMID:15680360
  review:
    summary: hindbrain development (GO:0030902) is retained as supported context for cyp26a1 but is not the primary/core function.
    action: KEEP_AS_NON_CORE
    reason: This annotation is broad, inferred, or reflects downstream developmental/physiological context rather than the
      central molecular role.
    supported_by:
    - reference_id: PMID:15680360
      supporting_text: the gene for the RA-degrading enzyme Cyp26a1 is mutated
- term:
    id: GO:0008401
    label: retinoic acid 4-hydroxylase activity
  evidence_type: IDA
  original_reference_id: PMID:8939936
  review:
    summary: retinoic acid 4-hydroxylase activity (GO:0008401) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        Zebrafish Cyp26a1 catalyzes oxidative metabolism of atRA, generating metabolites dominated by **4-hydroxy-RA (4-OH-RA)** and **4-oxo-RA (4-oxo-RA)** in microsome assays from transfected cells
- term:
    id: GO:0042573
    label: retinoic acid metabolic process
  evidence_type: IDA
  original_reference_id: PMID:8939936
  review:
    summary: retinoic acid metabolic process (GO:0042573) is supported for cyp26a1.
    action: ACCEPT
    reason: This annotation matches the synthesized core function or a directly supported core location/process for this gene.
    supported_by:
    - reference_id: PMID:8939936
      supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
    - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
      supporting_text: |
        Reviews of CYP26A1 metabolism emphasize **4-hydroxylation as the primary transformation** for CYP26A1 (and CYP26B1), with additional products such as **18-hydroxy-RA** and more polar secondary metabolites
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence
    similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative
    changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:15680360
  title: Retinoic acid-metabolizing enzyme Cyp26a1 is essential for determining territories of hindbrain and spinal cord in
    zebrafish.
  findings:
  - statement: The zebrafish cyp26a1/giraffe mutant disrupts RA-dependent hindbrain, spinal cord, vascular, and other developmental
      patterning.
    supporting_text: the gene for the RA-degrading enzyme Cyp26a1 is mutated
- id: PMID:16455818
  title: A novel cytochrome P450, zebrafish Cyp26D1, is involved in metabolism of all-trans retinoic acid.
  findings:
  - statement: Zebrafish Cyp26-family enzymes metabolize all-trans retinoic acid and related retinoids, supporting RA-catabolism
      annotations.
    supporting_text: Cyp26D1 expressed in 293T cells could metabolize all-trans RA, 9-cis RA, and 13-cis RA
- id: PMID:17098223
  title: Coordination of symmetric cyclic gene expression during somitogenesis by Suppressor of Hairless involves regulation
    of retinoic acid catabolism.
  findings:
  - statement: Cyp26a1 regulation of retinoic acid metabolism contributes to symmetric cyclic gene expression and somitogenesis.
    supporting_text: expression of the RA-degrading enzyme cyp26a1 in the tailbud was controlled by Su(H) activity
- id: PMID:17164423
  title: Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development.
  findings:
  - statement: Cyp26 enzymes shape RA-responsive hindbrain domains by metabolizing retinoic acid.
    supporting_text: metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains
      during hindbrain development
- id: PMID:17253779
  title: 'Specificity of zebrafish retinol saturase: formation of all-trans-13,14-dihydroretinol and all-trans-7,8- dihydroretinol.'
  findings:
  - statement: Zebrafish retinoid metabolism includes Cyp26-dependent oxidation of retinoid metabolites.
    supporting_text: all-trans-13,14-dihydroretinol is transiently oxidized to all-trans-13,14-dihydroretinoic acid before
      being oxidized further by Cyp26 enzymes
- id: PMID:17998248
  title: Zebrafish model of holoprosencephaly demonstrates a key role for TGIF in regulating retinoic acid metabolism.
  findings:
  - statement: Forebrain patterning is affected by altered RA metabolism, including loss of cyp26a1-mediated RA degradation.
    supporting_text: The loss of the forebrain-specific RA-degrading enzyme cyp26a1 causes a forebrain phenotype that mimics
      tgif morphants
- id: PMID:19416885
  title: Cyp26 enzymes function in endoderm to regulate pancreatic field size.
  findings:
  - statement: Cyp26 enzymes restrict RA signaling to define pancreatic field size and position.
    supporting_text: the RA-degrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic
      field
- id: PMID:23975936
  title: Retinoic acid-dependent regulation of miR-19 expression elicits vertebrate axis defects.
  findings:
  - statement: miR-19 regulation of CYP26A1 affects retinoic acid metabolism during vertebrate axis formation.
    supporting_text: A reporter assay confirmed that cyp26a1 is a bona fide target of miR-19 in vivo
- id: PMID:23990796
  title: Depletion of retinoic acid receptors initiates a novel positive feedback mechanism that promotes teratogenic increases
    in retinoic acid.
  findings:
  - statement: Cyp26a1 participates in feedback control of embryonic RA levels during heart development.
    supporting_text: Cyp26a1, an enzyme that facilitates degradation of RA
- id: PMID:24667328
  title: Cyp26 enzymes are required to balance the cardiac and vascular lineages within the anterior lateral plate mesoderm.
  findings:
  - statement: Cyp26a1/cyp26c1 limit RA levels to maintain cardiac and vascular progenitor field boundaries.
    supporting_text: Cyp26 enzymes largely act cell non-autonomously to promote appropriate cardiovascular development
- id: PMID:27406002
  title: BMP and retinoic acid regulate anterior-posterior patterning of the non-axial mesoderm across the dorsal-ventral
    axis.
  findings:
  - statement: Cyp26a1 protects posterior kidney progenitors from RA during non-axial mesoderm patterning.
    supporting_text: posterior kidney progenitors are protected ventrally by the RA-catabolizing enzyme Cyp26a1
- id: PMID:27893754
  title: Cyp26 Enzymes Facilitate Second Heart Field Progenitor Addition and Maintenance of Ventricular Integrity.
  findings:
  - statement: Cyp26a1/cyp26c1-mediated RA degradation supports outflow tract development and ventricular integrity.
    supporting_text: zebrafish embryos deficient for Cyp26a1 and Cyp26c1 enzymes, which promote RA degradation, have OFT defects
- id: PMID:8939936
  title: Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase.
  findings:
  - statement: Zebrafish P450RAI/Cyp26a1 metabolizes all-trans retinoic acid to polar metabolites.
    supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
- id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
  title: UniProtKB entry P79739 for Danio rerio cyp26a1
  findings:
  - statement: UniProt summarizes Cyp26a1 as a cytochrome P450 enzyme that metabolizes all-trans retinoic acid.
    supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
- id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
  title: Falcon deep research on zebrafish cyp26a1 (Edison Scientific Literature)
  findings:
  - statement: Zebrafish Cyp26a1 oxidizes all-trans retinoic acid in microsome assays to 4-OH-RA and 4-oxo-RA, the canonical CYP26A1 reaction products.
    reference_section_type: RESULTS
    supporting_text: |
      Zebrafish Cyp26a1 catalyzes oxidative metabolism of atRA, generating metabolites dominated by **4-hydroxy-RA (4-OH-RA)** and **4-oxo-RA (4-oxo-RA)** in microsome assays from transfected cells
  - statement: 4-hydroxylation is the primary transformation for CYP26A1, with additional products including 18-hydroxy-RA and more polar secondary metabolites.
    reference_section_type: RESULTS
    supporting_text: |
      Reviews of CYP26A1 metabolism emphasize **4-hydroxylation as the primary transformation** for CYP26A1 (and CYP26B1), with additional products such as **18-hydroxy-RA** and more polar secondary metabolites
  - statement: Zebrafish CYP26 enzymes act on retinoic acid isomers but do not metabolize retinol or retinal, indicating specialization for retinoic acid rather than upstream retinoids.
    reference_section_type: RESULTS
    supporting_text: |
      Cell/microsome assays of zebrafish CYP26 family members show activity toward **RA isomers** (atRA, 9-cis RA, 13-cis RA) and **no detectable metabolism of retinol or retinal** under the tested conditions, supporting specialization for RA
  - statement: Cyp26a1 is a membrane-anchored microsomal (ER) cytochrome P450 with a heme center, requiring electrons from NADPH via cytochrome P450 oxidoreductase (POR).
    reference_section_type: RESULTS
    supporting_text: |
      CYP26 enzymes are described as **membrane-anchored microsomal (endoplasmic reticulum, ER) cytochrome P450s** with a heme center and class II P450 electron-transfer architecture: each catalytic cycle requires electrons supplied from **NADPH via cytochrome P450 oxidoreductase (POR)**, which uses **FAD and FMN** cofactors
  - statement: CYP26 enzymes are high-efficiency retinoic-acid clearance enzymes (reported Km < 100 nM in transfected-cell systems) that control RA homeostasis.
    reference_section_type: DISCUSSION
    supporting_text: |
      A review summarizing CYP26 biochemical studies reports **high catalytic activity** for atRA, including **Km < 100 nM** (in COS-1 transfected cell systems) and **turnover ~1–10 pmol/min/pmol**
  - statement: cyp26a1 and its paralogs cyp26b1/cyp26c1 act redundantly to shape the retinoic-acid response pattern needed for zebrafish hindbrain development; their depletion expands RA-responsive gene expression across the hindbrain.
    reference_section_type: RESULTS
    supporting_text: |
      Hernandez et al. (2007; published Jan 2007; https://doi.org/10.1242/dev.02706) demonstrate that zebrafish orthologs of mammalian CYP26 genes (**cyp26a1, cyp26b1, cyp26c1**) act **redundantly** to shape the RA response pattern necessary for hindbrain development
  - statement: cyp26a1 expression in anterior neural ectoderm, forebrain, midbrain, anterior hindbrain, and tailbud establishes anterior RA-depleted domains opposing posterior aldh1a2/raldh2-driven RA synthesis.
    reference_section_type: RESULTS
    supporting_text: |
      cyp26a1 is expressed early in presumptive anterior neural ectoderm, and later in forebrain, midbrain, anterior hindbrain, and tailbud territories, contributing to establishment of anterior RA-depleted domains opposing posterior RA synthesis and shaping the rostrocaudal RA signaling landscape
  - statement: cyp26a1 is under complex RA- and Fgf-driven feedback/feedforward control, conferring robustness of the embryonic RA gradient.
    reference_section_type: RESULTS
    supporting_text: |
      cyp26a1 is under complex feedback and feedforward control by RA and Fgf signaling
  - statement: Overexpression of cyp26a1 mRNA reduces endogenous RA activity and produces reduced-RA phenotypes, confirming a functional role in RA clearance.
    reference_section_type: RESULTS
    supporting_text: |
      microinjection of cyp26a1 mRNA reduces endogenous RA activity and yields phenotypes resembling reduced-RA conditions, consistent with a role in RA clearance
  - statement: The primary molecular function of zebrafish Cyp26a1 is as an ER/microsomal cytochrome P450 that hydroxylates/oxidizes retinoic acid, reducing RA signaling capacity.
    reference_section_type: CONCLUSIONS
    supporting_text: |
      ER/microsomal cytochrome P450 enzyme that **hydroxylates/oxidizes retinoic acid**, producing **4-OH-RA and 4-oxo-RA** (major products), thereby reducing RA signaling capacity
core_functions:
- description: Cyp26a1 hydroxylates all-trans retinoic acid to drive retinoic acid catabolism at the endoplasmic reticulum
    membrane.
  supported_by:
  - reference_id: file:DANRE/cyp26a1/cyp26a1-uniprot.txt
    supporting_text: A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid
  - reference_id: PMID:8939936
    supporting_text: all-trans-RA is rapidly metabolized to more polar metabolites
  - reference_id: file:DANRE/cyp26a1/cyp26a1-deep-research-falcon.md
    supporting_text: |
      ER/microsomal cytochrome P450 enzyme that **hydroxylates/oxidizes retinoic acid**, producing **4-OH-RA and 4-oxo-RA** (major products), thereby reducing RA signaling capacity
  molecular_function:
    id: GO:0062182
    label: all-trans retinoic acid 4-hydrolase activity
  directly_involved_in:
  - id: GO:0034653
    label: retinoic acid catabolic process
  - id: GO:0042573
    label: retinoic acid metabolic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
suggested_questions:
- question: To what extent do cyp26a1, cyp26b1, and cyp26c1 act redundantly versus
    in distinct spatial domains to shape the embryonic retinoic-acid gradient, and
    what is the unique non-redundant contribution of cyp26a1?
- question: Is cyp26a1 transcription controlled primarily by retinoic-acid-driven
    feedback (and post-transcriptionally by miR-19) in vivo, and how does this feedback
    set the dynamic range and robustness of retinoic-acid signaling?
- question: Does zebrafish Cyp26a1 act strictly as an all-trans retinoic acid 4-hydroxylase,
    or does it also generate 18-hydroxy and other polar metabolites that retain or
    lack signaling activity?
suggested_experiments:
- hypothesis: cyp26a1 has a non-redundant role in clearing retinoic acid from anterior/hindbrain
    territories that is not fully compensated by cyp26b1 or cyp26c1.
  description: Generate single and compound cyp26a1/cyp26b1/cyp26c1 CRISPR/Cas9 mutants
    and compare retinoic-acid reporter activity and hox/krox20 rhombomere boundary
    positioning to dissect each paralog's spatial contribution.
  experiment_type: CRISPR/Cas9 genetics with retinoic-acid reporter imaging and in
    situ hybridization
- hypothesis: Recombinant zebrafish Cyp26a1 preferentially 4-hydroxylates all-trans
    retinoic acid rather than 9-cis or 13-cis isomers.
  description: Express and purify recombinant Cyp26a1, incubate with all-trans, 9-cis,
    and 13-cis retinoic acid, and quantify the metabolite profile and kinetic parameters
    by LC-MS/MS to define substrate and regiochemical specificity.
  experiment_type: in vitro cytochrome P450 enzyme assay with LC-MS/MS metabolite
    profiling
- hypothesis: Endogenous cyp26a1 is required to protect specific progenitor populations
    (posterior kidney, second heart field, pancreas) from retinoic-acid excess.
  description: Apply temporally controlled cyp26a1 loss-of-function and rescue, then
    quantify progenitor markers and retinoic-acid reporter activity in each tissue
    to test whether progenitor protection is a direct cyp26a1 function.
  experiment_type: conditional/temporal gene perturbation with marker quantification

cyp26a1

Gene Description

Existing Annotations Review

Core Functions

Cyp26a1 hydroxylates all-trans retinoic acid to drive retinoic acid catabolism at the endoplasmic reticulum membrane.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Danio rerio cyp26a1 (UniProt P79739) — functional annotation

Scope and identity verification (critical)

1) Key concepts and definitions (current understanding)

Retinoic acid (RA) signaling and “RA gradients”

CYP26 enzymes

2) Molecular function (reaction, substrates, specificity) and biochemical mechanism

Catalyzed reaction and products

Substrate specificity

Cofactors and catalytic requirements (current expert understanding)

Quantitative enzymology (from authoritative synthesis)

3) Subcellular localization and where the protein acts

4) Biological roles and pathways in zebrafish (evidence-based)

A. Hindbrain and anterior–posterior (A–P) patterning during gastrulation

B. Spatial expression territories that restrict RA signaling

C. Developmental phenotypes as functional readouts

5) Recent developments and latest research (prioritizing 2024 zebrafish sources)

5.1 Developmental toxicology at environmentally relevant exposures (Schmandt et al., 2024)

5.2 Metabolic/liver developmental model implicating RA metabolism (Zeng et al., 2024)

6) Current applications and real-world implementations

7) Expert opinions and analysis (authoritative synthesis)

CYP26 enzymes as homeostatic “buffer” and tissue-protection system

CYP26A1 as a dominant RA clearance route and pharmacology-relevant enzyme family

8) Relevant figures (image evidence)

Summary table (functional annotation at a glance)

Key takeaways for functional annotation of zebrafish cyp26a1 (P79739)

URLs and publication dates (most relevant)

Artifacts

Citations

📚 Additional Documentation

Notes

cyp26a1 (Danio rerio) review notes

Batch 05 curation notes

📄 View Raw YAML