Aldh1l1

UniProt ID: P28037
Organism: Rattus norvegicus
Review Status: COMPLETE
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Gene Description

Aldh1l1 encodes cytosolic 10-formyltetrahydrofolate dehydrogenase. It converts 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide with NADPH generation, and has secondary NADP-dependent aldehyde dehydrogenase activity. The review accepts formyltetrahydrofolate dehydrogenase and folate/one-carbon process terms, modifies generic oxidoreductase/catalytic and NAD(P) aldehyde-dehydrogenase parents where appropriate, keeps complex/binding context, and removes a mitochondrial localization annotation inconsistent with the cytosolic protein.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004029 aldehyde dehydrogenase (NAD+) activity
IBA
GO_REF:0000033 		MODIFY
Summary: aldehyde dehydrogenase (NAD+) activity captures part of Aldh1l1 biology, but a more specific replacement better represents the direct role (IBA, GO_REF:0000033).
Reason: aldehyde dehydrogenase (NAD+) activity is directionally related to Aldh1l1 but should be replaced by the more specific term(s): aldehyde dehydrogenase (NADP+) activity.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0005739 mitochondrion
IBA
GO_REF:0000033 		REMOVE
Summary: mitochondrion is removed because it is unsupported or uninformative for Aldh1l1's reviewed role (IBA, GO_REF:0000033).
Reason: mitochondrion is not supported as a direct or useful contextual annotation for Aldh1l1 after review against cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH. Falcon deep research confirms Aldh1l1 is the cytosolic enzyme and explicitly distinguishes it from the mitochondrial paralog ALDH1L2, which is the enzyme responsible for mitochondrial one-carbon oxidation to CO2.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
**Cytosolic/cytoplasmic** enzyme; part of the **cytosolic folate/one-carbon pathway**. Not the mitochondrial enzyme. | Cytosolic localization is a core identifier throughout the FDH/ALDH1L1 literature; mitochondrial one-carbon oxidation to CO2 is carried out by **ALDH1L2**, not ALDH1L1
GO:0006081 aldehyde metabolic process
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: aldehyde metabolic process is retained as contextual support for Aldh1l1, but it is not the core function (IBA, GO_REF:0000033).
Reason: aldehyde metabolic process is biologically related to Aldh1l1, but it is broader, downstream, or regulatory context relative to cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0006740 NADPH regeneration
IBA
GO_REF:0000033 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining NADPH regeneration as a direct annotation (IBA, GO_REF:0000033).
Reason: NADPH regeneration is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0016155 formyltetrahydrofolate dehydrogenase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IBA, GO_REF:0000033).
Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0003824 catalytic activity
IEA
GO_REF:0000002 		MODIFY
Summary: catalytic activity captures part of Aldh1l1 biology, but a more specific replacement better represents the direct role (IEA, GO_REF:0000002).
Reason: catalytic activity is directionally related to Aldh1l1 but should be replaced by the more specific term(s): formyltetrahydrofolate dehydrogenase activity.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0004030 aldehyde dehydrogenase [NAD(P)+] activity
IEA
GO_REF:0000117 		MODIFY
Summary: aldehyde dehydrogenase [NAD(P)+] activity captures part of Aldh1l1 biology, but a more specific replacement better represents the direct role (IEA, GO_REF:0000117).
Reason: aldehyde dehydrogenase [NAD(P)+] activity is directionally related to Aldh1l1 but should be replaced by the more specific term(s): aldehyde dehydrogenase (NADP+) activity.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0005737 cytoplasm
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: cytoplasm is retained as contextual support for Aldh1l1, but it is not the core function (IEA, GO_REF:0000002).
Reason: cytoplasm records localization or complex context for Aldh1l1, not the defining molecular function.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0005829 cytosol
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: cytosol is retained as contextual support for Aldh1l1, but it is not the core function (IEA, GO_REF:0000044).
Reason: cytosol records localization or complex context for Aldh1l1, not the defining molecular function.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0006730 one-carbon metabolic process
IEA
GO_REF:0000002 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining one-carbon metabolic process as a direct annotation (IEA, GO_REF:0000002). Falcon deep research places Aldh1l1 in folate-mediated one-carbon metabolism, catabolically removing one-carbon units from 10-formyl-THF and regenerating THF.
Reason: one-carbon metabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
ALDH1L1 functions in **folate-mediated one-carbon metabolism**, especially catabolic removal of 1C units from **10-formyl-THF** and regeneration of **THF** for interconnected pathways.
GO:0009258 10-formyltetrahydrofolate catabolic process
IEA
GO_REF:0000120 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (IEA, GO_REF:0000120).
Reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0016155 formyltetrahydrofolate dehydrogenase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IEA, GO_REF:0000120).
Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0016491 oxidoreductase activity
IEA
GO_REF:0000002 		MODIFY
Summary: oxidoreductase activity captures part of Aldh1l1 biology, but a more specific replacement better represents the direct role (IEA, GO_REF:0000002).
Reason: oxidoreductase activity is directionally related to Aldh1l1 but should be replaced by the more specific term(s): formyltetrahydrofolate dehydrogenase activity.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0005829 cytosol
ISO
GO_REF:0000121 		KEEP AS NON CORE
Summary: cytosol is retained as contextual support for Aldh1l1, but it is not the core function (ISO, GO_REF:0000121).
Reason: cytosol records localization or complex context for Aldh1l1, not the defining molecular function.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0004029 aldehyde dehydrogenase (NAD+) activity
ISO
GO_REF:0000121 		MODIFY
Summary: aldehyde dehydrogenase (NAD+) activity captures part of Aldh1l1 biology, but a more specific replacement better represents the direct role (ISO, GO_REF:0000121).
Reason: aldehyde dehydrogenase (NAD+) activity is directionally related to Aldh1l1 but should be replaced by the more specific term(s): aldehyde dehydrogenase (NADP+) activity.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0035999 tetrahydrofolate interconversion
ISO
GO_REF:0000121 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining tetrahydrofolate interconversion as a direct annotation (ISO, GO_REF:0000121).
Reason: tetrahydrofolate interconversion is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0016155 formyltetrahydrofolate dehydrogenase activity
ISO
GO_REF:0000121 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (ISO, GO_REF:0000121).
Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0016155 formyltetrahydrofolate dehydrogenase activity
EXP
PMID:17302434
Crystal structures of the carboxyl terminal domain of rat 10... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (EXP, PMID:17302434). Falcon deep research confirms this is the canonical, primary molecular function.
Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:17302434
10-Formyltetrahydrofolate dehydrogenase (FDH) catalyzes an NADP+-dependent dehydrogenase reaction resulting in conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO2.
file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
**Primary molecular function:** NADP+‑dependent dehydrogenase acting on **10‑formyl‑THF**, producing **THF + CO2 + NADPH** (EC 1.5.1.6).
GO:0016155 formyltetrahydrofolate dehydrogenase activity
EXP
PMID:17884809
10-formyltetrahydrofolate dehydrogenase requires a 4'-phosph... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (EXP, PMID:17884809).
Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:17884809
10-Formyltetrahydrofolate dehydrogenase (FDH) consists of two independent catalytic domains, N- and C-terminal, connected by a 100-amino acid residue linker (intermediate domain).
GO:0016155 formyltetrahydrofolate dehydrogenase activity
EXP
PMID:7822273
Cysteine 707 is involved in the dehydrogenase activity site ... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (EXP, PMID:7822273).
Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:7822273
The enzyme, 10-formyltetrahydrofolate dehydrogenase (10-FTHFDH) (EC 1.5.1.6) catalyzes both the NADP(+)-dependent oxidation of 10-formyltetrahydrofolate to tetrahydrofolate and CO2 and the NADP(+)-independent hydrolysis of 10-formyltetrahydrofolate to tetrahydrofolate and formate.
GO:0009258 10-formyltetrahydrofolate catabolic process
ISO
GO_REF:0000121 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (ISO, GO_REF:0000121).
Reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0006740 NADPH regeneration
ISO
GO_REF:0000121 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining NADPH regeneration as a direct annotation (ISO, GO_REF:0000121).
Reason: NADPH regeneration is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
UniProtKB:P28037
FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
GO:0006740 NADPH regeneration
IDA
PMID:1848231
Isolation and characterization of cDNA clones for rat liver ... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining NADPH regeneration as a direct annotation (IDA, PMID:1848231). Falcon deep research confirms the C-terminal ALDH domain oxidizes the formyl group to CO2 while reducing NADP+ to NADPH.
Reason: NADPH regeneration is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:1848231
Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde dehydrogenase activity.
file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
**Step 3:** The C-terminal ALDH domain oxidizes the transferred formyl group to **CO2**, reducing **NADP+ → NADPH**.
GO:0046655 folic acid metabolic process
IDA
PMID:1848231
Isolation and characterization of cDNA clones for rat liver ... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining folic acid metabolic process as a direct annotation (IDA, PMID:1848231).
Reason: folic acid metabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:1848231
Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde dehydrogenase activity.
GO:0005829 cytosol
IDA
PMID:1848231
Isolation and characterization of cDNA clones for rat liver ... 		KEEP AS NON CORE
Summary: cytosol is retained as contextual support for Aldh1l1, but it is not the core function (IDA, PMID:1848231). Falcon deep research confirms cytosolic localization is a core identifier throughout the FDH/ALDH1L1 literature.
Reason: cytosol records localization or complex context for Aldh1l1, not the defining molecular function.
Supporting Evidence:
PMID:1848231
Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde dehydrogenase activity.
file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
**Cytosolic/cytoplasmic** enzyme; part of the **cytosolic folate/one-carbon pathway**. Not the mitochondrial enzyme. | Cytosolic localization is a core identifier throughout the FDH/ALDH1L1 literature; mitochondrial one-carbon oxidation to CO2 is carried out by **ALDH1L2**, not ALDH1L1
GO:0009258 10-formyltetrahydrofolate catabolic process
IMP
PMID:10585460
Aspartate 142 is involved in both hydrolase and dehydrogenas... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (IMP, PMID:10585460). Falcon deep research frames Aldh1l1 as catabolically removing one-carbon units from 10-formyl-THF as CO2 while regenerating THF.
Reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:10585460
The enzyme 10-formyltetrahydrofolate dehydrogenase (FDH) catalyzes conversion of 10-formyltetrahydrofolate to tetrahydrofolate in either a dehydrogenase or hydrolase reaction.
file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
ALDH1L1 (FDH)** is typically framed as a **catabolic/regulatory folate enzyme** because it **removes** one‑carbon units from the reduced folate pool by oxidizing the **10‑formyl** group to **CO2**, while regenerating THF.
GO:0009258 10-formyltetrahydrofolate catabolic process
IDA
PMID:1848231
Isolation and characterization of cDNA clones for rat liver ... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (IDA, PMID:1848231).
Reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:1848231
Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde dehydrogenase activity.
GO:0016155 formyltetrahydrofolate dehydrogenase activity
IMP
PMID:10585460
Aspartate 142 is involved in both hydrolase and dehydrogenas... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IMP, PMID:10585460).
Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:10585460
The enzyme 10-formyltetrahydrofolate dehydrogenase (FDH) catalyzes conversion of 10-formyltetrahydrofolate to tetrahydrofolate in either a dehydrogenase or hydrolase reaction.
GO:0016155 formyltetrahydrofolate dehydrogenase activity
IDA
PMID:1848231
Isolation and characterization of cDNA clones for rat liver ... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IDA, PMID:1848231).
Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:1848231
Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde dehydrogenase activity.
GO:0033721 aldehyde dehydrogenase (NADP+) activity
IDA
PMID:17302434
Crystal structures of the carboxyl terminal domain of rat 10... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining aldehyde dehydrogenase (NADP+) activity as a direct annotation (IDA, PMID:17302434). Falcon deep research confirms the C-terminal ALDH-like domain performs the NADP+-dependent oxidation step.
Reason: aldehyde dehydrogenase (NADP+) activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:17302434
10-Formyltetrahydrofolate dehydrogenase (FDH) catalyzes an NADP+-dependent dehydrogenase reaction resulting in conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO2.
file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
a **C‑terminal aldehyde dehydrogenase (ALDH)‑like domain** that performs the NADP+‑dependent oxidation step
GO:0032991 protein-containing complex
IDA
PMID:17669278
Rat liver 10-formyltetrahydrofolate dehydrogenase, carbamoyl... 		KEEP AS NON CORE
Summary: protein-containing complex is retained as contextual support for Aldh1l1, but it is not the core function (IDA, PMID:17669278). Falcon deep research notes the enzyme assembles as a homotetramer, consistent with this complex context.
Reason: protein-containing complex records localization or complex context for Aldh1l1, not the defining molecular function.
Supporting Evidence:
PMID:17669278
An Asp/His catalytic site of 10-formyltetrahydrofolate dehydrogenase (FDH) was suggested to have a similar catalytic topology with the Asp/His catalytic site of serine proteases.
file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
ALDH1L1 is described as a **~902 amino‑acid** multidomain fusion enzyme (subunit ~100 kDa) assembling as a **tetramer**.
GO:0044877 protein-containing complex binding
IDA
PMID:17669278
Rat liver 10-formyltetrahydrofolate dehydrogenase, carbamoyl... 		KEEP AS NON CORE
Summary: protein-containing complex binding is retained as contextual support for Aldh1l1, but it is not the core function (IDA, PMID:17669278).
Reason: protein-containing complex binding records localization or complex context for Aldh1l1, not the defining molecular function.
Supporting Evidence:
PMID:17669278
An Asp/His catalytic site of 10-formyltetrahydrofolate dehydrogenase (FDH) was suggested to have a similar catalytic topology with the Asp/His catalytic site of serine proteases.
GO:0016155 formyltetrahydrofolate dehydrogenase activity
TAS
PMID:14729668
The crystal structure of the hydrolase domain of 10-formylte... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (TAS, PMID:14729668).
Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:14729668
10-Formyltetrahydrofolate dehydrogenase (FDH) converts 10-formyltetrahydrofolate, a precursor for nucleotide biosynthesis, to tetrahydrofolate.
GO:0046654 tetrahydrofolate biosynthetic process
TAS
PMID:14729668
The crystal structure of the hydrolase domain of 10-formylte... 		ACCEPT
Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining tetrahydrofolate biosynthetic process as a direct annotation (TAS, PMID:14729668).
Reason: tetrahydrofolate biosynthetic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
Supporting Evidence:
PMID:14729668
10-Formyltetrahydrofolate dehydrogenase (FDH) converts 10-formyltetrahydrofolate, a precursor for nucleotide biosynthesis, to tetrahydrofolate.
GO:0004030 aldehyde dehydrogenase [NAD(P)+] activity
IDA
PMID:1848231
Isolation and characterization of cDNA clones for rat liver ... 		MODIFY
Summary: aldehyde dehydrogenase [NAD(P)+] activity captures part of Aldh1l1 biology, but a more specific replacement better represents the direct role (IDA, PMID:1848231).
Reason: aldehyde dehydrogenase [NAD(P)+] activity is directionally related to Aldh1l1 but should be replaced by the more specific term(s): aldehyde dehydrogenase (NADP+) activity.
Supporting Evidence:
PMID:1848231
Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde dehydrogenase activity.

Core Functions

Aldh1l1 oxidizes 10-formyltetrahydrofolate to tetrahydrofolate and CO2 while regenerating NADPH.

Molecular Function:
formyltetrahydrofolate dehydrogenase activity
Directly Involved In:
10-formyltetrahydrofolate catabolic process tetrahydrofolate interconversion NADPH regeneration folic acid metabolic process
Supporting Evidence:
  • UniProtKB:P28037
    FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.

References

file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
Falcon deep research report on rat Aldh1l1 (cytosolic 10-formyltetrahydrofolate dehydrogenase)
  • Rat Aldh1l1 (UniProt P28037) is the cytosolic 10-formyltetrahydrofolate dehydrogenase (FDH/10-FTHFDH, EC 1.5.1.6), a multidomain tetrameric folate/one-carbon enzyme that is explicitly distinct from the mitochondrial paralog ALDH1L2.
    "The UniProt accession **P28037** corresponds to **rat Aldh1l1**, encoding **cytosolic 10‑formyltetrahydrofolate dehydrogenase** (common synonyms: **ALDH1L1**, **FDH**, **10‑FTHFDH**; EC **1.5.1.6**). The literature consistently describes this protein as a **cytosolic**, **multidomain**, **tetrameric** enzyme in folate/one‑carbon metabolism, and explicitly distinguishes it from the related **mitochondrial paralog ALDH1L2** (which has a mitochondrial leader peptide and different compartmental role)."
  • The canonical reaction oxidizes 10-formyl-THF to THF plus CO2 in an NADP+-dependent dehydrogenase reaction, generating NADPH; an NADP+-independent hydrolase activity that releases formate proceeds at ~21% of the dehydrogenase rate.
    "ALDH1L1 also exhibits an **NADP+‑independent hydrolase** activity that releases **formate** from 10‑formyl‑THF, but this hydrolase reaction is part of a coupled mechanism in the intact enzyme; in recombinant enzyme work, the hydrolase activity was reported to proceed at **~21%** of the dehydrogenase rate."
  • ALDH1L1 is cytosolic and part of the cytosolic folate/one-carbon pathway; mitochondrial one-carbon oxidation to CO2 is carried out by the paralog ALDH1L2, supporting removal of the mitochondrion annotation for rat Aldh1l1.
    "**Cytosolic/cytoplasmic** enzyme; part of the **cytosolic folate/one-carbon pathway**. Not the mitochondrial enzyme. | Cytosolic localization is a core identifier throughout the FDH/ALDH1L1 literature; mitochondrial one-carbon oxidation to CO2 is carried out by **ALDH1L2**, not ALDH1L1"
  • ALDH1L1 is a ~902 aa multidomain fusion enzyme (~100 kDa subunits) that assembles as a tetramer, with an N-terminal folate-binding/hydrolase domain, a 4'-phosphopantetheine carrier/linker domain, and a C-terminal ALDH-like domain.
    "ALDH1L1 is described as a **~902 amino‑acid** multidomain fusion enzyme (subunit ~100 kDa) assembling as a **tetramer**. It contains (i) an **N‑terminal folate‑binding/hydrolase domain**, (ii) an **intermediate carrier/linker domain** homologous to acyl‑carrier modules that bears a **4′‑phosphopantetheine (4′‑PP)** prosthetic group, and (iii) a **C‑terminal aldehyde dehydrogenase (ALDH)‑like domain** that performs the NADP+‑dependent oxidation step."
  • Key catalytic residues: His106 and Asp142 (hydrolase center), Ser354 (4'-phosphopantetheine attachment), and Glu673 and Cys707 (ALDH dehydrogenase center).
    "**His106** and **Asp142** define the hydrolase active center; **Ser354** carries the **4′-phosphopantetheine (4′-PP)** prosthetic group; **Glu673** and **Cys707** are key ALDH-domain catalytic residues for the oxidative step."
  • Rat ALDH1L1 is an unusually abundant metabolic enzyme, comprising about 1.2% of total rat liver cytosolic protein, with highest expression in liver, kidney, and pancreas.
    "Highly expressed in **liver, kidney, pancreas**; in rat liver cytosol ALDH1L1 can comprise about **1.2% of total cytosolic protein**, indicating an unusually abundant metabolic enzyme."
  • Aldh1l1 is widely used as a pan-astrocyte marker/promoter in neuroscience (e.g. Aldh1l1-EGFP/Rpl10a TRAP), an expression-pattern application that does not change the enzyme's core biochemical identity.
    "ALDH1L1 is widely used as a **pan-astrocyte marker/promoter** in neuroscience, although this reflects expression pattern rather than the primary enzymatic function."
GO_REF:0000002
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Aldh1l1 annotations including catalytic activity; cytoplasm; one-carbon metabolic process; oxidoreductase activity.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
GO_REF:0000033
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Aldh1l1 annotations including NADPH regeneration; aldehyde dehydrogenase (NAD+) activity; aldehyde metabolic process; formyltetrahydrofolate dehydrogenase activity; mitochondrion.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
GO_REF:0000044
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Aldh1l1 annotations including cytosol.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
GO_REF:0000117
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Aldh1l1 annotations including aldehyde dehydrogenase [NAD(P)+] activity.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
GO_REF:0000120
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Aldh1l1 annotations including 10-formyltetrahydrofolate catabolic process; formyltetrahydrofolate dehydrogenase activity.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
GO_REF:0000121
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Aldh1l1 annotations including 10-formyltetrahydrofolate catabolic process; NADPH regeneration; aldehyde dehydrogenase (NAD+) activity; cytosol; formyltetrahydrofolate dehydrogenase activity; and 1 other terms.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
PMID:10585460
Aspartate 142 is involved in both hydrolase and dehydrogenase catalytic centers of 10-formyltetrahydrofolate dehydrogenase
  • For Aldh1l1, this publication supports direct annotations to 10-formyltetrahydrofolate catabolic process; formyltetrahydrofolate dehydrogenase activity.
    "The enzyme 10-formyltetrahydrofolate dehydrogenase (FDH) catalyzes conversion of 10-formyltetrahydrofolate to tetrahydrofolate in either a dehydrogenase or hydrolase reaction."
PMID:14729668
The crystal structure of the hydrolase domain of 10-formyltetrahydrofolate dehydrogenase: mechanism of hydrolysis and its interplay with the dehydrogenase domain
  • For Aldh1l1, this publication supports direct annotations to formyltetrahydrofolate dehydrogenase activity; tetrahydrofolate biosynthetic process.
    "10-Formyltetrahydrofolate dehydrogenase (FDH) converts 10-formyltetrahydrofolate, a precursor for nucleotide biosynthesis, to tetrahydrofolate."
PMID:17302434
Crystal structures of the carboxyl terminal domain of rat 10-formyltetrahydrofolate dehydrogenase: implications for the catalytic mechanism of aldehyde dehydrogenases
  • For Aldh1l1, this publication supports direct annotations to aldehyde dehydrogenase (NADP+) activity; formyltetrahydrofolate dehydrogenase activity.
    "10-Formyltetrahydrofolate dehydrogenase (FDH) catalyzes an NADP+-dependent dehydrogenase reaction resulting in conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO2."
PMID:17669278
Rat liver 10-formyltetrahydrofolate dehydrogenase, carbamoyl phosphate synthetase 1 and betaine homocysteine S-methytransferase were co-purified on Kunitz-type soybean trypsin inhibitor-coupled sepharose CL-4B
  • For Aldh1l1, this publication was reviewed as context for protein-containing complex; protein-containing complex binding.
    "An Asp/His catalytic site of 10-formyltetrahydrofolate dehydrogenase (FDH) was suggested to have a similar catalytic topology with the Asp/His catalytic site of serine proteases."
PMID:17884809
10-formyltetrahydrofolate dehydrogenase requires a 4'-phosphopantetheine prosthetic group for catalysis
  • For Aldh1l1, this publication supports direct annotations to formyltetrahydrofolate dehydrogenase activity.
    "10-Formyltetrahydrofolate dehydrogenase (FDH) consists of two independent catalytic domains, N- and C-terminal, connected by a 100-amino acid residue linker (intermediate domain)."
PMID:1848231
Isolation and characterization of cDNA clones for rat liver 10-formyltetrahydrofolate dehydrogenase
  • For Aldh1l1, this publication provides evidence/provenance for direct annotations to 10-formyltetrahydrofolate catabolic process; NADPH regeneration; folic acid metabolic process and contextual annotations to aldehyde dehydrogenase [NAD(P)+] activity; cytosol.
    "Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde dehydrogenase activity."
PMID:7822273
Cysteine 707 is involved in the dehydrogenase activity site of rat 10-formyltetrahydrofolate dehydrogenase
  • For Aldh1l1, this publication supports direct annotations to formyltetrahydrofolate dehydrogenase activity.
    "The enzyme, 10-formyltetrahydrofolate dehydrogenase (10-FTHFDH) (EC 1.5.1.6) catalyzes both the NADP(+)-dependent oxidation of 10-formyltetrahydrofolate to tetrahydrofolate and CO2 and the NADP(+)-independent hydrolysis of 10-formyltetrahydrofolate to tetrahydrofolate and formate."

Deep Research

Falcon

(Aldh1l1-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 27 citations 2 artifacts 2026-05-31T19:16:35.845330
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000020 Figure 5 on page 20 illustrates the three-domain structure and catalytic mechanism of FDH (ALDH1L1). As shown in the diagram and de (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: Rat Aldh1l1 (UniProt P28037) — Cytosolic 10‑Formyltetrahydrofolate Dehydrogenase (ALDH1L1/FDH)

Executive summary (identity-verified)

The UniProt accession P28037 corresponds to rat Aldh1l1, encoding cytosolic 10‑formyltetrahydrofolate dehydrogenase (common synonyms: ALDH1L1, FDH, 10‑FTHFDH; EC 1.5.1.6). The literature consistently describes this protein as a cytosolic, multidomain, tetrameric enzyme in folate/one‑carbon metabolism, and explicitly distinguishes it from the related mitochondrial paralog ALDH1L2 (which has a mitochondrial leader peptide and different compartmental role). This alignment of enzymatic function, localization, and architecture verifies that the report is focused on the intended gene/protein target rather than an ambiguous symbol. (krupenko2009fdhanaldehyde pages 2-4, strickland2011phylogenyandevolution pages 1-2, krupenko2018aldh1l1andaldh1l2 pages 7-9)

1) Key concepts and definitions (current understanding)

1.1 Folate-mediated one‑carbon metabolism and the role of ALDH1L1

Folate (tetrahydrofolate, THF) coenzymes carry one‑carbon units used for essential biosynthetic and regulatory processes (e.g., nucleotide synthesis and methylation). Within this network, ALDH1L1 (FDH) is typically framed as a catabolic/regulatory folate enzyme because it removes one‑carbon units from the reduced folate pool by oxidizing the 10‑formyl group to CO2, while regenerating THF. This can limit the availability of one‑carbon units for anabolic pathways (such as de novo purine synthesis) while replenishing THF needed for other reactions (including glycine synthesis and histidine degradation). (krupenko2018aldh1l1andaldh1l2 pages 4-7, krupenko2009fdhanaldehyde pages 2-4, strickland2011phylogenyandevolution pages 4-5, rushing2022exploratorymetabolomicsunderscores pages 1-2)

1.2 Enzymatic reaction, substrates, cofactors, products

The canonical ALDH1L1 reaction is an NADP+‑dependent dehydrogenase reaction:

10‑formyl‑THF + NADP+ + H2O → THF + CO2 + NADPH + H+ (krupenko2018aldh1l1andaldh1l2 pages 4-7, krupenko2009fdhanaldehyde pages 2-4)

ALDH1L1 also exhibits an NADP+‑independent hydrolase activity that releases formate from 10‑formyl‑THF, but this hydrolase reaction is part of a coupled mechanism in the intact enzyme; in recombinant enzyme work, the hydrolase activity was reported to proceed at ~21% of the dehydrogenase rate. (krupenko2009fdhanaldehyde pages 2-4)

1.3 Protein architecture and mechanistic model

ALDH1L1 is described as a ~902 amino‑acid multidomain fusion enzyme (subunit ~100 kDa) assembling as a tetramer. It contains (i) an N‑terminal folate‑binding/hydrolase domain, (ii) an intermediate carrier/linker domain homologous to acyl‑carrier modules that bears a 4′‑phosphopantetheine (4′‑PP) prosthetic group, and (iii) a C‑terminal aldehyde dehydrogenase (ALDH)‑like domain that performs the NADP+‑dependent oxidation step. (krupenko2009fdhanaldehyde pages 2-4, krupenko2009fdhanaldehyde pages 1-2, strickland2011phylogenyandevolution pages 1-2)

Mechanistically, the reaction proceeds via: (1) hydrolytic removal of the formyl group from 10‑formyl‑THF, (2) transfer via the 4′‑PP “swinging arm” to the C‑terminal catalytic site, and (3) ALDH‑like oxidation to CO2 with reduction of NADP+ to NADPH. (krupenko2009fdhanaldehyde pages 6-8, strickland2011phylogenyandevolution pages 1-2)

A helpful visual summary of the three-domain architecture and transfer mechanism is provided in Figure 5 of Krupenko 2009. (krupenko2009fdhanaldehyde media 1b39bd26)

1.4 Key catalytic residues (residue-level experimental evidence)

Site‑directed mutagenesis and structural interpretation identify:
- Hydrolase center: His106 and Asp142 (mutations abolish both hydrolase and dehydrogenase activities). (krupenko2009fdhanaldehyde pages 6-8)
- Carrier prosthetic group site: Ser354 is the 4′‑PP attachment site. (krupenko2009fdhanaldehyde pages 6-8)
- ALDH center: Glu673 and Cys707 are key for dehydrogenase activity (mutations abolish dehydrogenase but leave hydrolase activity intact). (krupenko2009fdhanaldehyde pages 6-8)

2) Recent developments and latest research (prioritize 2023–2024)

2.1 2023 review context: SGOC metabolism as a cancer vulnerability

A 2023 review on serine‑glycine‑one‑carbon (SGOC) metabolism identifies ALDH1L1/ALDH1L2 among the “key metabolic enzymes” in folate‑mediated one‑carbon metabolism, emphasizing the compartmentalized nature of folate metabolism across cytosol and mitochondria and the increasing attention to SGOC metabolism in cancer. This positions ALDH1L1 in contemporary cancer-metabolism framing even when specific mechanistic advances are more frequently discussed for mitochondrial enzymes (e.g., SHMT2, MTHFD2).
Publication: Sun et al., Biomarker Research (Open Access), May 2023. URL: https://doi.org/10.1186/s40364-023-00487-4 (sun2023targetingserineglycineonecarbonmetabolism pages 1-2)

2.2 2024 review context: mitochondrial folate cycle prominence and ALDH1L2 distinction

A 2024 Nature Cancer review focuses strongly on the mitochondrial folate cycle and notes that mitochondrial 10‑formyl‑THF can be metabolized by ALDH1L2, which releases the one‑carbon unit as CO2 while generating NADPH; it also notes that cytosolic enzymes can generate 10‑formyl‑THF but that, in most cells, flux is typically mitochondria → cytosol via formate. Although this review emphasizes ALDH1L2, it provides a modern authoritative compartmentalization context that is important to avoid conflating ALDH1L1 (cytosolic) with ALDH1L2 (mitochondrial).
Publication: Lee et al., Nature Cancer, 2 May 2024. URL: https://doi.org/10.1038/s43018-024-00739-8 (lee2024cyclingbackto pages 2-4, lee2024cyclingbackto pages 1-2)

2.3 2024 review context: folate/1C metabolism in cancer and neurodegeneration

A 2024 review in International Journal of Molecular Sciences synthesizes folate-dependent one‑carbon metabolism in cancer and neurodegeneration, highlighting roles in nucleotide synthesis, methylation, and redox balance, and notes that studies have identified ALDH1L1 as a potential tumor suppressor. While the article is broader than ALDH1L1 specifically, it reflects the current translational emphasis on folate/1C metabolism and its links to disease.
Publication: Sobral et al., Int. J. Mol. Sci., 28 Aug 2024. URL: https://doi.org/10.3390/ijms25179339 (sobral2024unveilingthetherapeutic pages 1-2)

2.4 2023–2024 neuroscience implementation: Aldh1l1 as an astrocyte handle

A 2023 primary study used Aldh1l1‑EGFP/Rpl10a TRAP methodology in primary cortical astrocyte cultures to measure ethanol‑induced transcriptional and translational changes. While this does not establish ALDH1L1’s enzymatic function (which is biochemical), it demonstrates a major real‑world implementation: leveraging Aldh1l1 expression to isolate astrocyte translatomes.
Publication: Hashimoto et al., Frontiers in Neuroscience, 21 Jun 2023. URL: https://doi.org/10.3389/fnins.2023.1193304 (hashimoto2023ethanolinducedtranscriptionaland pages 1-2)

A 2024 study on astrocytic NF‑κB notes marker coverage considerations (e.g., GFAP not labeling all astrocytes), consistent with ALDH1L1’s continued use as a broad astrocyte marker in contemporary neurobiology.
Publication: Huat et al., Scientific Reports, Jun 2024. URL: https://doi.org/10.1038/s41598-024-65248-1 (huat2024theimpactof pages 1-2)

3) Current applications and real‑world implementations

3.1 Functional annotation applications (metabolic biology)

Because ALDH1L1 irreversibly converts 10‑formyl‑THF to THF and CO2 while generating NADPH, it is used conceptually as:
- a regulator of reduced folate pools and one‑carbon flux into biosynthetic pathways;
- a potential contributor to formate clearance (via 10‑formyl‑THF as intermediate);
- a metabolic node linking folate chemistry to glycine biosynthesis and histidine degradation via THF availability. (krupenko2018aldh1l1andaldh1l2 pages 4-7, strickland2011phylogenyandevolution pages 4-5, rushing2022exploratorymetabolomicsunderscores pages 1-2)

3.2 Astrocyte profiling/manipulation (neuroscience tools)

Aldh1l1 promoter-driven systems (e.g., Aldh1l1‑EGFP/Rpl10a TRAP) are used to enrich astrocyte‑specific translating mRNAs and quantify response programs to insults such as ethanol exposure, an application that is now routine in glial biology. (hashimoto2023ethanolinducedtranscriptionaland pages 1-2)

3.3 Cancer research (biomarker and mechanism)

ALDH1L1 is widely described as being downregulated/silenced in cancers and is framed as a candidate tumor suppressor in authoritative sources. A prominent mechanistic hypothesis is that ALDH1L1 constrains one‑carbon availability for proliferation-associated biosynthesis; in many tumors this “metabolic brake” is removed. (krupenko2018aldh1l1andaldh1l2 pages 7-9)

4) Expert opinions and analysis (authoritative synthesis)

4.1 “Metabolic brake” model: ALDH1L1 as a regulator of anabolic one‑carbon use

The Krupenko reviews describe ALDH1L1 as an unusually abundant cytosolic enzyme (in liver) that can clear one‑carbon units as CO2 and thereby restrict one‑carbon flux into biosynthetic processes, while regenerating THF. This provides a coherent mechanistic rationale for why ALDH1L1 loss could benefit proliferating cancer cells (greater one‑carbon retention for purines/thymidylate/methylation), whereas ALDH1L1 expression may oppose proliferation. (krupenko2018aldh1l1andaldh1l2 pages 4-7, krupenko2009fdhanaldehyde pages 2-4, krupenko2018aldh1l1andaldh1l2 pages 7-9)

4.2 Compartmentalization and paralog distinction: ALDH1L1 vs ALDH1L2

A recurring expert emphasis is that mammalian folate/one‑carbon metabolism is compartmentalized and includes cytosolic ALDH1L1 and mitochondrial ALDH1L2. ALDH1L2 is described as producing mitochondrial NADPH and releasing CO2 in mitochondria; modern cancer metabolism reviews often focus on mitochondrial one‑carbon flux and its systemic outputs (e.g., formate overflow), so careful compartment assignment is essential when interpreting “ALDH1L” mentions. (krupenko2018aldh1l1andaldh1l2 pages 7-9, lee2024cyclingbackto pages 2-4)

5) Relevant statistics and data (from recent and/or authoritative studies)

5.1 Enzyme abundance and activity partitioning

  • Rat liver abundance: ALDH1L1 can constitute ~1.2% of total rat liver cytosolic protein, indicating very high expression for a metabolic enzyme. (krupenko2018aldh1l1andaldh1l2 pages 4-7, krupenko2009fdhanaldehyde pages 2-4)
  • Hydrolase activity: NADP+‑independent hydrolase activity proceeds at approximately 21% of the dehydrogenase rate in recombinant enzyme analyses. (krupenko2009fdhanaldehyde pages 2-4)

5.2 Metabolic consequences of ALDH1L1 loss (functional evidence)

A mouse Aldh1l1 knockout study (used here as strong mammalian functional evidence consistent with rat biochemistry) reported:
- Liver formiminoglutamate (FIGLU) increased >15‑fold (FIGLU is a marker of functional folate deficiency in histidine catabolism). (krupenko2019cytosolic10formyltetrahydrofolatedehydrogenase pages 2-3)
- Total liver folate pool decreased modestly (~1.2‑fold in males, ~1.4‑fold in females), indicating that metabolic disruptions can occur even without massive folate depletion. (krupenko2019cytosolic10formyltetrahydrofolatedehydrogenase pages 2-3)

5.3 Cancer/epigenetic regulation statistics

A key quantitative observation about ALDH1L1 in cancer is CpG‑island methylation:
- In cancer cell lines, bisulfite sequencing indicated 76–95% CpG methylation in the ALDH1L1 promoter CpG island (reported to contain 96 CpG pairs), with tumor samples showing methylation patterns not seen in matched normal tissues; methylation correlated with reduced ALDH1L1 expression. (krupenko2018aldh1l1andaldh1l2 pages 4-7, krupenko2018aldh1l1andaldh1l2 pages 7-9)

5.4 Cell metabolism data (ALDH1L1 perturbation)

In RT4 bladder cancer cells, experimental ALDH1L1 loss (shRNA/CRISPR) caused:
- ~8‑fold decrease in glycine, and decreases in metabolites linked to S‑adenosylmethionine‑utilizing pathways, with broader metabolome changes. (rushing2022exploratorymetabolomicsunderscores pages 1-2)

Aspect Summary Evidence/notes
Verified identity Rat Aldh1l1 / ALDH1L1 / FDH / 10-FTHFDH / cytosolic 10-formyltetrahydrofolate dehydrogenase, EC 1.5.1.6; UniProt target P28037 matches the literature description of a cytosolic folate enzyme distinct from mitochondrial ALDH1L2. Reviews consistently describe ALDH1L1 as the mammalian cytosolic 10-formyl-THF dehydrogenase and distinguish ALDH1L2 as the mitochondrial paralog with a leader peptide; ALDH1L2 is ~72% identical to ALDH1L1 and should not be conflated with rat ALDH1L1 (krupenko2009fdhanaldehyde pages 2-4, strickland2011phylogenyandevolution pages 1-2, krupenko2018aldh1l1andaldh1l2 pages 7-9, krupenko2018aldh1l1andaldh1l2 pages 4-7).
Catalytic reaction Overall reaction: 10-formyl-THF + NADP+ + H2O → THF + CO2 + NADPH + H+. ALDH1L1 also has a NADP+-independent hydrolase activity releasing formate from 10-formyl-THF, but this is only part of the full coupled reaction. The dehydrogenase reaction is the canonical, physiologically emphasized activity; the hydrolase activity proceeds at about 21% of the dehydrogenase rate in recombinant enzyme studies. Functionally, the reaction removes one-carbon units as CO2, replenishes THF, and helps regulate purine synthesis, histidine degradation, glycine synthesis, methylation flux, and formate clearance (krupenko2018aldh1l1andaldh1l2 pages 4-7, krupenko2009fdhanaldehyde pages 2-4, krupenko2009fdhanaldehyde pages 1-2, strickland2011phylogenyandevolution pages 1-2, rushing2022exploratorymetabolomicsunderscores pages 1-2).
Domain architecture ALDH1L1 is a multidomain/tetrameric fusion enzyme of ~902 aa with ~100 kDa subunits: N-terminal folate-binding/hydrolase domain (~residues 1–310), intermediate acyl-carrier-like linker (~311–399/419), and C-terminal ALDH-like dehydrogenase domain (~400/420–902). The enzyme is a natural fusion of folate-hydrolase, carrier, and ALDH modules; the intermediate domain couples the two catalytic centers and is essential for full FDH activity (krupenko2009fdhanaldehyde pages 2-4, strickland2011phylogenyandevolution pages 4-5, krupenko2009fdhanaldehyde pages 1-2, strickland2011phylogenyandevolution pages 1-2, krupenko2009fdhanaldehyde media 1b39bd26).
Key catalytic residues His106 and Asp142 define the hydrolase active center; Ser354 carries the 4′-phosphopantetheine (4′-PP) prosthetic group; Glu673 and Cys707 are key ALDH-domain catalytic residues for the oxidative step. Mutagenesis data: His106/Asp142 mutations abolish hydrolase and dehydrogenase activities; Glu673/Cys707 mutations abolish dehydrogenase while leaving hydrolase intact; Ser354 is the 4′-PP attachment site in the carrier domain (krupenko2009fdhanaldehyde pages 6-8, krupenko2009fdhanaldehyde media 1b39bd26).
Mechanistic steps Step 1: N-terminal domain hydrolytically removes the formyl group from 10-formyl-THF. Step 2: The formyl group is transferred onto the 4′-PP swinging arm attached to Ser354 in the intermediate domain. Step 3: The C-terminal ALDH domain oxidizes the transferred formyl group to CO2, reducing NADP+ → NADPH. The 4′-PP arm extends ~20 Å; the ALDH catalytic center lies at the end of a ~12 Å tunnel, supporting the carrier-mediated channeling model. The hydrolase step must precede dehydrogenase catalysis (krupenko2009fdhanaldehyde pages 6-8, strickland2011phylogenyandevolution pages 1-2, krupenko2009fdhanaldehyde media 1b39bd26).
Subcellular localization Cytosolic/cytoplasmic enzyme; part of the cytosolic folate/one-carbon pathway. Not the mitochondrial enzyme. Cytosolic localization is a core identifier throughout the FDH/ALDH1L1 literature; mitochondrial one-carbon oxidation to CO2 is carried out by ALDH1L2, not ALDH1L1 (krupenko2018aldh1l1andaldh1l2 pages 4-7, krupenko2009fdhanaldehyde pages 2-4, strickland2011phylogenyandevolution pages 4-5, strickland2011phylogenyandevolution pages 1-2, lee2024cyclingbackto pages 2-4).
Tissue expression highlights Highly expressed in liver, kidney, pancreas; in rat liver cytosol ALDH1L1 can comprise about 1.2% of total cytosolic protein, indicating an unusually abundant metabolic enzyme. Reviews report highest mRNA/protein abundance in liver/kidney/pancreas and absent/undetectable expression in several other tissues (e.g., placenta, spleen, thymus, small intestine, leukocytes, testis, ovary in cited surveys). Rat liver abundance (~1.2%) is repeatedly noted (krupenko2018aldh1l1andaldh1l2 pages 4-7, krupenko2009fdhanaldehyde pages 2-4).
Brain / astrocyte relevance ALDH1L1 is widely used as a pan-astrocyte marker/promoter in neuroscience, although this reflects expression pattern rather than the primary enzymatic function. In developing brain, ALDH1L1 is associated with quiescent rather than proliferating cells. Modern astrocyte studies use Aldh1l1-EGFP/Rpl10a and Aldh1l1-Cre/ERT2 tools for cell-type-specific profiling/manipulation; reviews and experimental papers note ALDH1L1 as broader astrocyte coverage than GFAP in many CNS settings (krupenko2018aldh1l1andaldh1l2 pages 4-7, hashimoto2023ethanolinducedtranscriptionaland pages 1-2, huat2024theimpactof pages 1-2).
Quantitative functional phenotypes Loss of ALDH1L1 perturbs folate-linked metabolism: in mouse liver FIGLU increased >15-fold and liver total folate decreased by ~1.2-fold (males) / ~1.4-fold (females); in RT4 cancer cells ALDH1L1 loss caused an ~8-fold decrease in glycine. These quantitative studies support ALDH1L1 as a regulator of THF availability, glycine production, histidine degradation, and methylation-linked metabolism, even when gross phenotypes are mild (krupenko2019cytosolic10formyltetrahydrofolatedehydrogenase pages 2-3, rushing2022exploratorymetabolomicsunderscores pages 1-2).
Pathway role ALDH1L1 functions in folate-mediated one-carbon metabolism, especially catabolic removal of 1C units from 10-formyl-THF and regeneration of THF for interconnected pathways. Expert interpretation: ALDH1L1 can limit flux into folate-dependent biosynthesis while sustaining THF-dependent reactions; it is linked to formate detoxification/clearance, purine biosynthesis control, glycine synthesis from serine, and cellular methylation status (krupenko2018aldh1l1andaldh1l2 pages 4-7, strickland2011phylogenyandevolution pages 4-5, rushing2022exploratorymetabolomicsunderscores pages 1-2, lee2024cyclingbackto pages 1-2).
Disease relevance: cancer ALDH1L1 is widely viewed as a candidate tumor suppressor/metabolic brake and is frequently downregulated or silenced in cancers, often via promoter/CpG island methylation. Re-expression in cancer cells is antiproliferative. Quantitative methylation detail: reported 76–95% CpG methylation in cancer cell lines; decreased expression is associated with more aggressive disease in several tumor contexts, while re-expression can induce cell-cycle arrest/apoptosis (krupenko2018aldh1l1andaldh1l2 pages 7-9, krupenko2018aldh1l1andaldh1l2 pages 4-7, sobral2024unveilingthetherapeutic pages 1-2).
Biomedical applications Functional annotation: marker of cytosolic folate catabolism and THF regeneration. Research tool: Aldh1l1 promoter-driven reporter/TRAP/Cre lines for astrocyte profiling. Translational interest: epigenetic status and metabolic consequences of ALDH1L1 loss in cancer. Useful both as a mechanistically defined folate enzyme and as a practical cell-type handle in neurobiology; however, astrocyte-tool use should not be mistaken for a change in the enzyme’s core biochemical identity (rushing2022exploratorymetabolomicsunderscores pages 1-2, hashimoto2023ethanolinducedtranscriptionaland pages 1-2, huat2024theimpactof pages 1-2).

Table: This table condenses the verified identity, enzymatic mechanism, localization, expression, and biomedical relevance of rat ALDH1L1 (UniProt P28037). It is designed as a quick reference for functional annotation and literature-grounded interpretation.

Subcellular site of action: cytosol/cytoplasm. (krupenko2018aldh1l1andaldh1l2 pages 4-7, krupenko2009fdhanaldehyde pages 2-4)

Primary molecular function: NADP+‑dependent dehydrogenase acting on 10‑formyl‑THF, producing THF + CO2 + NADPH (EC 1.5.1.6). (krupenko2018aldh1l1andaldh1l2 pages 4-7, krupenko2009fdhanaldehyde pages 2-4)

Pathway placement: folate‑mediated one‑carbon metabolism (catabolic one‑carbon disposal and THF regeneration), with downstream impact on glycine synthesis and methylation‑linked metabolism. (rushing2022exploratorymetabolomicsunderscores pages 1-2)

Tissue/cell-type context: high abundance in rat liver cytosol and high expression in liver/kidney/pancreas; widely leveraged as an astrocyte marker/promoter in CNS research. (krupenko2018aldh1l1andaldh1l2 pages 4-7, hashimoto2023ethanolinducedtranscriptionaland pages 1-2)

Limitations of this synthesis

Rat-specific mechanistic enzymology (e.g., full kinetic constants, substrate specificity beyond 10‑formyl‑THF, and comprehensive rat tissue atlases) was not fully captured in the retrieved full texts here. Where mammalian functional evidence is not rat-specific (e.g., mouse KO phenotypes), it is used only to support conserved mechanistic roles and should be treated as supportive rather than strictly rat-validated. (krupenko2019cytosolic10formyltetrahydrofolatedehydrogenase pages 2-3)

References

  1. (krupenko2009fdhanaldehyde pages 2-4): Sergey A. Krupenko. Fdh: an aldehyde dehydrogenase fusion enzyme in folate metabolism. Chemico-biological interactions, 178 1-3:84-93, Mar 2009. URL: https://doi.org/10.1016/j.cbi.2008.09.007, doi:10.1016/j.cbi.2008.09.007. This article has 122 citations and is from a peer-reviewed journal.

  2. (strickland2011phylogenyandevolution pages 1-2): Kyle C. Strickland, Roger S. Holmes, Natalia V. Oleinik, Natalia I. Krupenko, and Sergey A. Krupenko. Phylogeny and evolution of aldehyde dehydrogenase-homologous folate enzymes. Chemico-biological interactions, 191 1-3:122-8, May 2011. URL: https://doi.org/10.1016/j.cbi.2010.12.025, doi:10.1016/j.cbi.2010.12.025. This article has 18 citations and is from a peer-reviewed journal.

  3. (krupenko2018aldh1l1andaldh1l2 pages 7-9): Sergey A. Krupenko and Natalia I. Krupenko. Aldh1l1 and aldh1l2 folate regulatory enzymes in cancer. Advances in experimental medicine and biology, 1032:127-143, Jan 2018. URL: https://doi.org/10.1007/978-3-319-98788-0_10, doi:10.1007/978-3-319-98788-0_10. This article has 69 citations and is from a peer-reviewed journal.

  4. (krupenko2018aldh1l1andaldh1l2 pages 4-7): Sergey A. Krupenko and Natalia I. Krupenko. Aldh1l1 and aldh1l2 folate regulatory enzymes in cancer. Advances in experimental medicine and biology, 1032:127-143, Jan 2018. URL: https://doi.org/10.1007/978-3-319-98788-0_10, doi:10.1007/978-3-319-98788-0_10. This article has 69 citations and is from a peer-reviewed journal.

  5. (strickland2011phylogenyandevolution pages 4-5): Kyle C. Strickland, Roger S. Holmes, Natalia V. Oleinik, Natalia I. Krupenko, and Sergey A. Krupenko. Phylogeny and evolution of aldehyde dehydrogenase-homologous folate enzymes. Chemico-biological interactions, 191 1-3:122-8, May 2011. URL: https://doi.org/10.1016/j.cbi.2010.12.025, doi:10.1016/j.cbi.2010.12.025. This article has 18 citations and is from a peer-reviewed journal.

  6. (rushing2022exploratorymetabolomicsunderscores pages 1-2): Blake R. Rushing, Halle M. Fogle, Jaspreet Sharma, Mikyoung You, Jonathan P. McCormac, Sabrina Molina, Susan Sumner, Natalia I. Krupenko, and Sergey A. Krupenko. Exploratory metabolomics underscores the folate enzyme aldh1l1 as a regulator of glycine and methylation reactions. Molecules, 27:8394, Dec 2022. URL: https://doi.org/10.3390/molecules27238394, doi:10.3390/molecules27238394. This article has 19 citations.

  7. (krupenko2009fdhanaldehyde pages 1-2): Sergey A. Krupenko. Fdh: an aldehyde dehydrogenase fusion enzyme in folate metabolism. Chemico-biological interactions, 178 1-3:84-93, Mar 2009. URL: https://doi.org/10.1016/j.cbi.2008.09.007, doi:10.1016/j.cbi.2008.09.007. This article has 122 citations and is from a peer-reviewed journal.

  8. (krupenko2009fdhanaldehyde pages 6-8): Sergey A. Krupenko. Fdh: an aldehyde dehydrogenase fusion enzyme in folate metabolism. Chemico-biological interactions, 178 1-3:84-93, Mar 2009. URL: https://doi.org/10.1016/j.cbi.2008.09.007, doi:10.1016/j.cbi.2008.09.007. This article has 122 citations and is from a peer-reviewed journal.

  9. (krupenko2009fdhanaldehyde media 1b39bd26): Sergey A. Krupenko. Fdh: an aldehyde dehydrogenase fusion enzyme in folate metabolism. Chemico-biological interactions, 178 1-3:84-93, Mar 2009. URL: https://doi.org/10.1016/j.cbi.2008.09.007, doi:10.1016/j.cbi.2008.09.007. This article has 122 citations and is from a peer-reviewed journal.

  10. (sun2023targetingserineglycineonecarbonmetabolism pages 1-2): Wei Sun, Ruochen Liu, Xinyue Gao, Zini Lin, Hongao Tang, Hongjuan Cui, and Erhu Zhao. Targeting serine-glycine-one-carbon metabolism as a vulnerability in cancers. Biomarker Research, May 2023. URL: https://doi.org/10.1186/s40364-023-00487-4, doi:10.1186/s40364-023-00487-4. This article has 60 citations and is from a peer-reviewed journal.

  11. (lee2024cyclingbackto pages 2-4): Younghwan Lee, Karen H. Vousden, and Marc Hennequart. Cycling back to folate metabolism in cancer. Nature cancer, 5:701-715, May 2024. URL: https://doi.org/10.1038/s43018-024-00739-8, doi:10.1038/s43018-024-00739-8. This article has 55 citations and is from a highest quality peer-reviewed journal.

  12. (lee2024cyclingbackto pages 1-2): Younghwan Lee, Karen H. Vousden, and Marc Hennequart. Cycling back to folate metabolism in cancer. Nature cancer, 5:701-715, May 2024. URL: https://doi.org/10.1038/s43018-024-00739-8, doi:10.1038/s43018-024-00739-8. This article has 55 citations and is from a highest quality peer-reviewed journal.

  13. (sobral2024unveilingthetherapeutic pages 1-2): Ana Filipa Sobral, Andrea Cunha, Vera Silva, Eva Gil-Martins, Renata Silva, and Daniel José Barbosa. Unveiling the therapeutic potential of folate-dependent one-carbon metabolism in cancer and neurodegeneration. International Journal of Molecular Sciences, 25:9339, Aug 2024. URL: https://doi.org/10.3390/ijms25179339, doi:10.3390/ijms25179339. This article has 60 citations.

  14. (hashimoto2023ethanolinducedtranscriptionaland pages 1-2): Joel G. Hashimoto, Xiaolu Zhang, and Marina Guizzetti. Ethanol-induced transcriptional and translational changes in aldh1l1-egfp/rpl10a cortical astrocyte cultures. Frontiers in Neuroscience, Jun 2023. URL: https://doi.org/10.3389/fnins.2023.1193304, doi:10.3389/fnins.2023.1193304. This article has 7 citations and is from a peer-reviewed journal.

  15. (huat2024theimpactof pages 1-2): Tee Jong Huat, Judith Camats-Perna, Estella A. Newcombe, Tessa Onraet, Daniel Campbell, Josiah T. Sucic, Alessandra Martini, Stefânia Forner, Mehdi Mirzaei, Wayne Poon, Frank M. LaFerla, and Rodrigo Medeiros. The impact of astrocytic nf-κb on healthy and alzheimer’s disease brains. Scientific Reports, Jun 2024. URL: https://doi.org/10.1038/s41598-024-65248-1, doi:10.1038/s41598-024-65248-1. This article has 54 citations and is from a peer-reviewed journal.

  16. (krupenko2019cytosolic10formyltetrahydrofolatedehydrogenase pages 2-3): Natalia I. Krupenko, Jaspreet Sharma, Peter Pediaditakis, Baharan Fekry, Kristi L. Helke, Xiuxia Du, Susan Sumner, and Sergey A. Krupenko. Cytosolic 10-formyltetrahydrofolate dehydrogenase regulates glycine metabolism in mouse liver. Scientific Reports, Oct 2019. URL: https://doi.org/10.1038/s41598-019-51397-1, doi:10.1038/s41598-019-51397-1. This article has 29 citations and is from a peer-reviewed journal.

Artifacts

Citations

  1. krupenko2009fdhanaldehyde pages 2-4
  2. krupenko2009fdhanaldehyde pages 6-8
  3. sun2023targetingserineglycineonecarbonmetabolism pages 1-2
  4. sobral2024unveilingthetherapeutic pages 1-2
  5. hashimoto2023ethanolinducedtranscriptionaland pages 1-2
  6. huat2024theimpactof pages 1-2
  7. rushing2022exploratorymetabolomicsunderscores pages 1-2
  8. strickland2011phylogenyandevolution pages 1-2
  9. strickland2011phylogenyandevolution pages 4-5
  10. krupenko2009fdhanaldehyde pages 1-2
  11. lee2024cyclingbackto pages 2-4
  12. lee2024cyclingbackto pages 1-2
  13. https://doi.org/10.1186/s40364-023-00487-4
  14. https://doi.org/10.1038/s43018-024-00739-8
  15. https://doi.org/10.3390/ijms25179339
  16. https://doi.org/10.3389/fnins.2023.1193304
  17. https://doi.org/10.1038/s41598-024-65248-1
  18. https://doi.org/10.1016/j.cbi.2008.09.007,
  19. https://doi.org/10.1016/j.cbi.2010.12.025,
  20. https://doi.org/10.1007/978-3-319-98788-0_10,
  21. https://doi.org/10.3390/molecules27238394,
  22. https://doi.org/10.1186/s40364-023-00487-4,
  23. https://doi.org/10.1038/s43018-024-00739-8,
  24. https://doi.org/10.3390/ijms25179339,
  25. https://doi.org/10.3389/fnins.2023.1193304,
  26. https://doi.org/10.1038/s41598-024-65248-1,
  27. https://doi.org/10.1038/s41598-019-51397-1,

📚 Additional Documentation

Notes

(Aldh1l1-notes.md)

Aldh1l1 notes

  • UniProtKB:P28037 states: FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide. [UniProtKB:P28037].
  • Core interpretation: cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
  • Accepted direct GO terms include: 10-formyltetrahydrofolate catabolic process, NADPH regeneration, aldehyde dehydrogenase (NADP+) activity, folic acid metabolic process, formyltetrahydrofolate dehydrogenase activity, tetrahydrofolate biosynthetic process, tetrahydrofolate interconversion.
  • Non-core/context terms are mostly localization, binding/cofactor, inferred pathway context, or exposure-response annotations; generic parent terms are modified when a specific catalytic term is available.

📄 View Raw YAML

 
id: P28037
gene_symbol: Aldh1l1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10116
  label: Rattus norvegicus
description: 'Aldh1l1 encodes cytosolic 10-formyltetrahydrofolate dehydrogenase. It converts 10-formyltetrahydrofolate
  to tetrahydrofolate and carbon dioxide with NADPH generation, and has secondary NADP-dependent aldehyde dehydrogenase
  activity. The review accepts formyltetrahydrofolate dehydrogenase and folate/one-carbon process terms, modifies
  generic oxidoreductase/catalytic and NAD(P) aldehyde-dehydrogenase parents where appropriate, keeps complex/binding
  context, and removes a mitochondrial localization annotation inconsistent with the cytosolic protein.'
existing_annotations:
- term:
    id: GO:0004029
    label: aldehyde dehydrogenase (NAD+) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: aldehyde dehydrogenase (NAD+) activity captures part of Aldh1l1 biology, but a more specific
      replacement better represents the direct role (IBA, GO_REF:0000033).
    action: MODIFY
    reason: 'aldehyde dehydrogenase (NAD+) activity is directionally related to Aldh1l1 but should be replaced by
      the more specific term(s): aldehyde dehydrogenase (NADP+) activity.'
    proposed_replacement_terms:
    - id: GO:0033721
      label: aldehyde dehydrogenase (NADP+) activity
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: mitochondrion is removed because it is unsupported or uninformative for Aldh1l1's reviewed role
      (IBA, GO_REF:0000033).
    action: REMOVE
    reason: mitochondrion is not supported as a direct or useful contextual annotation for Aldh1l1 after
      review against cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
      Falcon deep research confirms Aldh1l1 is the cytosolic enzyme and explicitly distinguishes it from
      the mitochondrial paralog ALDH1L2, which is the enzyme responsible for mitochondrial one-carbon
      oxidation to CO2.
    additional_reference_ids:
    - file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
    - reference_id: file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
      supporting_text: |-
        **Cytosolic/cytoplasmic** enzyme; part of the **cytosolic folate/one-carbon pathway**. Not the mitochondrial enzyme. | Cytosolic localization is a core identifier throughout the FDH/ALDH1L1 literature; mitochondrial one-carbon oxidation to CO2 is carried out by **ALDH1L2**, not ALDH1L1
- term:
    id: GO:0006081
    label: aldehyde metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: aldehyde metabolic process is retained as contextual support for Aldh1l1, but it is not the core
      function (IBA, GO_REF:0000033).
    action: KEEP_AS_NON_CORE
    reason: aldehyde metabolic process is biologically related to Aldh1l1, but it is broader, downstream, or
      regulatory context relative to cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2,
      and NADPH.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0006740
    label: NADPH regeneration
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining NADPH regeneration as a direct annotation (IBA, GO_REF:0000033).
    action: ACCEPT
    reason: NADPH regeneration is a direct process-level consequence of Aldh1l1's documented role in cytosolic
      10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0016155
    label: formyltetrahydrofolate dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IBA,
      GO_REF:0000033).
    action: ACCEPT
    reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in
      cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: catalytic activity captures part of Aldh1l1 biology, but a more specific replacement better
      represents the direct role (IEA, GO_REF:0000002).
    action: MODIFY
    reason: 'catalytic activity is directionally related to Aldh1l1 but should be replaced by the more specific
      term(s): formyltetrahydrofolate dehydrogenase activity.'
    proposed_replacement_terms:
    - id: GO:0016155
      label: formyltetrahydrofolate dehydrogenase activity
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0004030
    label: aldehyde dehydrogenase [NAD(P)+] activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: aldehyde dehydrogenase [NAD(P)+] activity captures part of Aldh1l1 biology, but a more specific
      replacement better represents the direct role (IEA, GO_REF:0000117).
    action: MODIFY
    reason: 'aldehyde dehydrogenase [NAD(P)+] activity is directionally related to Aldh1l1 but should be replaced
      by the more specific term(s): aldehyde dehydrogenase (NADP+) activity.'
    proposed_replacement_terms:
    - id: GO:0033721
      label: aldehyde dehydrogenase (NADP+) activity
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: cytoplasm is retained as contextual support for Aldh1l1, but it is not the core function (IEA,
      GO_REF:0000002).
    action: KEEP_AS_NON_CORE
    reason: cytoplasm records localization or complex context for Aldh1l1, not the defining molecular
      function.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: cytosol is retained as contextual support for Aldh1l1, but it is not the core function (IEA,
      GO_REF:0000044).
    action: KEEP_AS_NON_CORE
    reason: cytosol records localization or complex context for Aldh1l1, not the defining molecular function.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0006730
    label: one-carbon metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining one-carbon metabolic process as a direct annotation (IEA, GO_REF:0000002).
      Falcon deep research places Aldh1l1 in folate-mediated one-carbon metabolism, catabolically removing
      one-carbon units from 10-formyl-THF and regenerating THF.
    action: ACCEPT
    reason: one-carbon metabolic process is a direct process-level consequence of Aldh1l1's documented role in
      cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    additional_reference_ids:
    - file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
    - reference_id: file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
      supporting_text: |-
        ALDH1L1 functions in **folate-mediated one-carbon metabolism**, especially catabolic removal of 1C units from **10-formyl-THF** and regeneration of **THF** for interconnected pathways.
- term:
    id: GO:0009258
    label: 10-formyltetrahydrofolate catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (IEA,
      GO_REF:0000120).
    action: ACCEPT
    reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's
      documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0016155
    label: formyltetrahydrofolate dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IEA,
      GO_REF:0000120).
    action: ACCEPT
    reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in
      cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: oxidoreductase activity captures part of Aldh1l1 biology, but a more specific replacement better
      represents the direct role (IEA, GO_REF:0000002).
    action: MODIFY
    reason: 'oxidoreductase activity is directionally related to Aldh1l1 but should be replaced by the more specific
      term(s): formyltetrahydrofolate dehydrogenase activity.'
    proposed_replacement_terms:
    - id: GO:0016155
      label: formyltetrahydrofolate dehydrogenase activity
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: cytosol is retained as contextual support for Aldh1l1, but it is not the core function (ISO,
      GO_REF:0000121).
    action: KEEP_AS_NON_CORE
    reason: cytosol records localization or complex context for Aldh1l1, not the defining molecular function.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0004029
    label: aldehyde dehydrogenase (NAD+) activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: aldehyde dehydrogenase (NAD+) activity captures part of Aldh1l1 biology, but a more specific
      replacement better represents the direct role (ISO, GO_REF:0000121).
    action: MODIFY
    reason: 'aldehyde dehydrogenase (NAD+) activity is directionally related to Aldh1l1 but should be replaced by
      the more specific term(s): aldehyde dehydrogenase (NADP+) activity.'
    proposed_replacement_terms:
    - id: GO:0033721
      label: aldehyde dehydrogenase (NADP+) activity
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0035999
    label: tetrahydrofolate interconversion
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining tetrahydrofolate interconversion as a direct annotation (ISO, GO_REF:0000121).
    action: ACCEPT
    reason: tetrahydrofolate interconversion is a direct process-level consequence of Aldh1l1's documented
      role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0016155
    label: formyltetrahydrofolate dehydrogenase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (ISO,
      GO_REF:0000121).
    action: ACCEPT
    reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in
      cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0016155
    label: formyltetrahydrofolate dehydrogenase activity
  evidence_type: EXP
  original_reference_id: PMID:17302434
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (EXP,
      PMID:17302434). Falcon deep research confirms this is the canonical, primary molecular function.
    action: ACCEPT
    reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in
      cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    additional_reference_ids:
    - file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:17302434
      supporting_text: 10-Formyltetrahydrofolate dehydrogenase (FDH) catalyzes an NADP+-dependent
        dehydrogenase reaction resulting in conversion of 10-formyltetrahydrofolate to tetrahydrofolate and
        CO2.
      reference_section_type: ABSTRACT
    - reference_id: file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
      supporting_text: |-
        **Primary molecular function:** NADP+‑dependent dehydrogenase acting on **10‑formyl‑THF**, producing **THF + CO2 + NADPH** (EC 1.5.1.6).
- term:
    id: GO:0016155
    label: formyltetrahydrofolate dehydrogenase activity
  evidence_type: EXP
  original_reference_id: PMID:17884809
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (EXP,
      PMID:17884809).
    action: ACCEPT
    reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in
      cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: PMID:17884809
      supporting_text: 10-Formyltetrahydrofolate dehydrogenase (FDH) consists of two independent catalytic
        domains, N- and C-terminal, connected by a 100-amino acid residue linker (intermediate domain).
      reference_section_type: ABSTRACT
- term:
    id: GO:0016155
    label: formyltetrahydrofolate dehydrogenase activity
  evidence_type: EXP
  original_reference_id: PMID:7822273
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (EXP,
      PMID:7822273).
    action: ACCEPT
    reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in
      cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: PMID:7822273
      supporting_text: The enzyme, 10-formyltetrahydrofolate dehydrogenase (10-FTHFDH) (EC 1.5.1.6) catalyzes
        both the NADP(+)-dependent oxidation of 10-formyltetrahydrofolate to tetrahydrofolate and CO2 and the
        NADP(+)-independent hydrolysis of 10-formyltetrahydrofolate to tetrahydrofolate and formate.
      reference_section_type: ABSTRACT
- term:
    id: GO:0009258
    label: 10-formyltetrahydrofolate catabolic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (ISO,
      GO_REF:0000121).
    action: ACCEPT
    reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's
      documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0006740
    label: NADPH regeneration
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining NADPH regeneration as a direct annotation (ISO, GO_REF:0000121).
    action: ACCEPT
    reason: NADPH regeneration is a direct process-level consequence of Aldh1l1's documented role in cytosolic
      10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: UniProtKB:P28037
      supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
        conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
- term:
    id: GO:0006740
    label: NADPH regeneration
  evidence_type: IDA
  original_reference_id: PMID:1848231
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining NADPH regeneration as a direct annotation (IDA, PMID:1848231). Falcon deep research
      confirms the C-terminal ALDH domain oxidizes the formyl group to CO2 while reducing NADP+ to NADPH.
    action: ACCEPT
    reason: NADPH regeneration is a direct process-level consequence of Aldh1l1's documented role in cytosolic
      10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    additional_reference_ids:
    - file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:1848231
      supporting_text: Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde
        dehydrogenase activity.
      reference_section_type: ABSTRACT
    - reference_id: file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
      supporting_text: |-
        **Step 3:** The C-terminal ALDH domain oxidizes the transferred formyl group to **CO2**, reducing **NADP+ → NADPH**.
- term:
    id: GO:0046655
    label: folic acid metabolic process
  evidence_type: IDA
  original_reference_id: PMID:1848231
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining folic acid metabolic process as a direct annotation (IDA, PMID:1848231).
    action: ACCEPT
    reason: folic acid metabolic process is a direct process-level consequence of Aldh1l1's documented role in
      cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: PMID:1848231
      supporting_text: Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde
        dehydrogenase activity.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:1848231
  review:
    summary: cytosol is retained as contextual support for Aldh1l1, but it is not the core function (IDA,
      PMID:1848231). Falcon deep research confirms cytosolic localization is a core identifier throughout
      the FDH/ALDH1L1 literature.
    action: KEEP_AS_NON_CORE
    reason: cytosol records localization or complex context for Aldh1l1, not the defining molecular function.
    additional_reference_ids:
    - file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:1848231
      supporting_text: Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde
        dehydrogenase activity.
      reference_section_type: ABSTRACT
    - reference_id: file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
      supporting_text: |-
        **Cytosolic/cytoplasmic** enzyme; part of the **cytosolic folate/one-carbon pathway**. Not the mitochondrial enzyme. | Cytosolic localization is a core identifier throughout the FDH/ALDH1L1 literature; mitochondrial one-carbon oxidation to CO2 is carried out by **ALDH1L2**, not ALDH1L1
- term:
    id: GO:0009258
    label: 10-formyltetrahydrofolate catabolic process
  evidence_type: IMP
  original_reference_id: PMID:10585460
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (IMP,
      PMID:10585460). Falcon deep research frames Aldh1l1 as catabolically removing one-carbon units from
      10-formyl-THF as CO2 while regenerating THF.
    action: ACCEPT
    reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's
      documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    additional_reference_ids:
    - file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:10585460
      supporting_text: The enzyme 10-formyltetrahydrofolate dehydrogenase (FDH) catalyzes conversion of
        10-formyltetrahydrofolate to tetrahydrofolate in either a dehydrogenase or hydrolase reaction.
      reference_section_type: ABSTRACT
    - reference_id: file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
      supporting_text: |-
        ALDH1L1 (FDH)** is typically framed as a **catabolic/regulatory folate enzyme** because it **removes** one‑carbon units from the reduced folate pool by oxidizing the **10‑formyl** group to **CO2**, while regenerating THF.
- term:
    id: GO:0009258
    label: 10-formyltetrahydrofolate catabolic process
  evidence_type: IDA
  original_reference_id: PMID:1848231
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (IDA,
      PMID:1848231).
    action: ACCEPT
    reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's
      documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: PMID:1848231
      supporting_text: Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde
        dehydrogenase activity.
      reference_section_type: ABSTRACT
- term:
    id: GO:0016155
    label: formyltetrahydrofolate dehydrogenase activity
  evidence_type: IMP
  original_reference_id: PMID:10585460
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IMP,
      PMID:10585460).
    action: ACCEPT
    reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in
      cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: PMID:10585460
      supporting_text: The enzyme 10-formyltetrahydrofolate dehydrogenase (FDH) catalyzes conversion of
        10-formyltetrahydrofolate to tetrahydrofolate in either a dehydrogenase or hydrolase reaction.
      reference_section_type: ABSTRACT
- term:
    id: GO:0016155
    label: formyltetrahydrofolate dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:1848231
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IDA,
      PMID:1848231).
    action: ACCEPT
    reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in
      cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: PMID:1848231
      supporting_text: Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde
        dehydrogenase activity.
      reference_section_type: ABSTRACT
- term:
    id: GO:0033721
    label: aldehyde dehydrogenase (NADP+) activity
  evidence_type: IDA
  original_reference_id: PMID:17302434
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining aldehyde dehydrogenase (NADP+) activity as a direct annotation (IDA, PMID:17302434).
      Falcon deep research confirms the C-terminal ALDH-like domain performs the NADP+-dependent oxidation step.
    action: ACCEPT
    reason: aldehyde dehydrogenase (NADP+) activity directly matches Aldh1l1's documented role in cytosolic
      10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    additional_reference_ids:
    - file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:17302434
      supporting_text: 10-Formyltetrahydrofolate dehydrogenase (FDH) catalyzes an NADP+-dependent
        dehydrogenase reaction resulting in conversion of 10-formyltetrahydrofolate to tetrahydrofolate and
        CO2.
      reference_section_type: ABSTRACT
    - reference_id: file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
      supporting_text: |-
        a **C‑terminal aldehyde dehydrogenase (ALDH)‑like domain** that performs the NADP+‑dependent oxidation step
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:17669278
  review:
    summary: protein-containing complex is retained as contextual support for Aldh1l1, but it is not the core
      function (IDA, PMID:17669278). Falcon deep research notes the enzyme assembles as a homotetramer,
      consistent with this complex context.
    action: KEEP_AS_NON_CORE
    reason: protein-containing complex records localization or complex context for Aldh1l1, not the defining
      molecular function.
    additional_reference_ids:
    - file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:17669278
      supporting_text: An Asp/His catalytic site of 10-formyltetrahydrofolate dehydrogenase (FDH) was
        suggested to have a similar catalytic topology with the Asp/His catalytic site of serine proteases.
      reference_section_type: ABSTRACT
    - reference_id: file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
      supporting_text: |-
        ALDH1L1 is described as a **~902 amino‑acid** multidomain fusion enzyme (subunit ~100 kDa) assembling as a **tetramer**.
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IDA
  original_reference_id: PMID:17669278
  review:
    summary: protein-containing complex binding is retained as contextual support for Aldh1l1, but it is not
      the core function (IDA, PMID:17669278).
    action: KEEP_AS_NON_CORE
    reason: protein-containing complex binding records localization or complex context for Aldh1l1, not the
      defining molecular function.
    supported_by:
    - reference_id: PMID:17669278
      supporting_text: An Asp/His catalytic site of 10-formyltetrahydrofolate dehydrogenase (FDH) was
        suggested to have a similar catalytic topology with the Asp/His catalytic site of serine proteases.
      reference_section_type: ABSTRACT
- term:
    id: GO:0016155
    label: formyltetrahydrofolate dehydrogenase activity
  evidence_type: TAS
  original_reference_id: PMID:14729668
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (TAS,
      PMID:14729668).
    action: ACCEPT
    reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in
      cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: PMID:14729668
      supporting_text: 10-Formyltetrahydrofolate dehydrogenase (FDH) converts 10-formyltetrahydrofolate, a
        precursor for nucleotide biosynthesis, to tetrahydrofolate.
      reference_section_type: ABSTRACT
- term:
    id: GO:0046654
    label: tetrahydrofolate biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:14729668
  review:
    summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH
      supports retaining tetrahydrofolate biosynthetic process as a direct annotation (TAS, PMID:14729668).
    action: ACCEPT
    reason: tetrahydrofolate biosynthetic process is a direct process-level consequence of Aldh1l1's
      documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.
    supported_by:
    - reference_id: PMID:14729668
      supporting_text: 10-Formyltetrahydrofolate dehydrogenase (FDH) converts 10-formyltetrahydrofolate, a
        precursor for nucleotide biosynthesis, to tetrahydrofolate.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004030
    label: aldehyde dehydrogenase [NAD(P)+] activity
  evidence_type: IDA
  original_reference_id: PMID:1848231
  review:
    summary: aldehyde dehydrogenase [NAD(P)+] activity captures part of Aldh1l1 biology, but a more specific
      replacement better represents the direct role (IDA, PMID:1848231).
    action: MODIFY
    reason: 'aldehyde dehydrogenase [NAD(P)+] activity is directionally related to Aldh1l1 but should be replaced
      by the more specific term(s): aldehyde dehydrogenase (NADP+) activity.'
    proposed_replacement_terms:
    - id: GO:0033721
      label: aldehyde dehydrogenase (NADP+) activity
    supported_by:
    - reference_id: PMID:1848231
      supporting_text: Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde
        dehydrogenase activity.
      reference_section_type: ABSTRACT
references:
- id: file:rat/Aldh1l1/Aldh1l1-deep-research-falcon.md
  title: Falcon deep research report on rat Aldh1l1 (cytosolic 10-formyltetrahydrofolate dehydrogenase)
  findings:
  - statement: |-
      Rat Aldh1l1 (UniProt P28037) is the cytosolic 10-formyltetrahydrofolate dehydrogenase (FDH/10-FTHFDH, EC 1.5.1.6),
      a multidomain tetrameric folate/one-carbon enzyme that is explicitly distinct from the mitochondrial paralog ALDH1L2.
    supporting_text: |-
      The UniProt accession **P28037** corresponds to **rat Aldh1l1**, encoding **cytosolic 10‑formyltetrahydrofolate dehydrogenase** (common synonyms: **ALDH1L1**, **FDH**, **10‑FTHFDH**; EC **1.5.1.6**). The literature consistently describes this protein as a **cytosolic**, **multidomain**, **tetrameric** enzyme in folate/one‑carbon metabolism, and explicitly distinguishes it from the related **mitochondrial paralog ALDH1L2** (which has a mitochondrial leader peptide and different compartmental role).
    reference_section_type: OTHER
  - statement: |-
      The canonical reaction oxidizes 10-formyl-THF to THF plus CO2 in an NADP+-dependent dehydrogenase reaction,
      generating NADPH; an NADP+-independent hydrolase activity that releases formate proceeds at ~21% of the dehydrogenase rate.
    supporting_text: |-
      ALDH1L1 also exhibits an **NADP+‑independent hydrolase** activity that releases **formate** from 10‑formyl‑THF, but this hydrolase reaction is part of a coupled mechanism in the intact enzyme; in recombinant enzyme work, the hydrolase activity was reported to proceed at **~21%** of the dehydrogenase rate.
    reference_section_type: OTHER
  - statement: |-
      ALDH1L1 is cytosolic and part of the cytosolic folate/one-carbon pathway; mitochondrial one-carbon oxidation to CO2
      is carried out by the paralog ALDH1L2, supporting removal of the mitochondrion annotation for rat Aldh1l1.
    supporting_text: |-
      **Cytosolic/cytoplasmic** enzyme; part of the **cytosolic folate/one-carbon pathway**. Not the mitochondrial enzyme. | Cytosolic localization is a core identifier throughout the FDH/ALDH1L1 literature; mitochondrial one-carbon oxidation to CO2 is carried out by **ALDH1L2**, not ALDH1L1
    reference_section_type: OTHER
  - statement: |-
      ALDH1L1 is a ~902 aa multidomain fusion enzyme (~100 kDa subunits) that assembles as a tetramer, with an
      N-terminal folate-binding/hydrolase domain, a 4'-phosphopantetheine carrier/linker domain, and a C-terminal ALDH-like domain.
    supporting_text: |-
      ALDH1L1 is described as a **~902 amino‑acid** multidomain fusion enzyme (subunit ~100 kDa) assembling as a **tetramer**. It contains (i) an **N‑terminal folate‑binding/hydrolase domain**, (ii) an **intermediate carrier/linker domain** homologous to acyl‑carrier modules that bears a **4′‑phosphopantetheine (4′‑PP)** prosthetic group, and (iii) a **C‑terminal aldehyde dehydrogenase (ALDH)‑like domain** that performs the NADP+‑dependent oxidation step.
    reference_section_type: OTHER
  - statement: |-
      Key catalytic residues: His106 and Asp142 (hydrolase center), Ser354 (4'-phosphopantetheine attachment), and
      Glu673 and Cys707 (ALDH dehydrogenase center).
    supporting_text: |-
      **His106** and **Asp142** define the hydrolase active center; **Ser354** carries the **4′-phosphopantetheine (4′-PP)** prosthetic group; **Glu673** and **Cys707** are key ALDH-domain catalytic residues for the oxidative step.
    reference_section_type: OTHER
  - statement: |-
      Rat ALDH1L1 is an unusually abundant metabolic enzyme, comprising about 1.2% of total rat liver cytosolic protein,
      with highest expression in liver, kidney, and pancreas.
    supporting_text: |-
      Highly expressed in **liver, kidney, pancreas**; in rat liver cytosol ALDH1L1 can comprise about **1.2% of total cytosolic protein**, indicating an unusually abundant metabolic enzyme.
    reference_section_type: OTHER
  - statement: |-
      Aldh1l1 is widely used as a pan-astrocyte marker/promoter in neuroscience (e.g. Aldh1l1-EGFP/Rpl10a TRAP),
      an expression-pattern application that does not change the enzyme's core biochemical identity.
    supporting_text: |-
      ALDH1L1 is widely used as a **pan-astrocyte marker/promoter** in neuroscience, although this reflects expression pattern rather than the primary enzymatic function.
    reference_section_type: OTHER
- id: GO_REF:0000002
  title: 'GO reference used by source annotation pipeline'
  findings:
  - statement: Source annotation pipeline provenance for Aldh1l1 annotations including catalytic activity;
      cytoplasm; one-carbon metabolic process; oxidoreductase activity.
    supporting_text: GO_REF entry used only to trace source annotation method; biological support was assessed
      from UniProt and cached literature where available.
    reference_section_type: TITLE
- id: GO_REF:0000033
  title: 'GO reference used by source annotation pipeline'
  findings:
  - statement: Source annotation pipeline provenance for Aldh1l1 annotations including NADPH regeneration;
      aldehyde dehydrogenase (NAD+) activity; aldehyde metabolic process; formyltetrahydrofolate dehydrogenase
      activity; mitochondrion.
    supporting_text: GO_REF entry used only to trace source annotation method; biological support was assessed
      from UniProt and cached literature where available.
    reference_section_type: TITLE
- id: GO_REF:0000044
  title: 'GO reference used by source annotation pipeline'
  findings:
  - statement: Source annotation pipeline provenance for Aldh1l1 annotations including cytosol.
    supporting_text: GO_REF entry used only to trace source annotation method; biological support was assessed
      from UniProt and cached literature where available.
    reference_section_type: TITLE
- id: GO_REF:0000117
  title: 'GO reference used by source annotation pipeline'
  findings:
  - statement: Source annotation pipeline provenance for Aldh1l1 annotations including aldehyde dehydrogenase
      [NAD(P)+] activity.
    supporting_text: GO_REF entry used only to trace source annotation method; biological support was assessed
      from UniProt and cached literature where available.
    reference_section_type: TITLE
- id: GO_REF:0000120
  title: 'GO reference used by source annotation pipeline'
  findings:
  - statement: Source annotation pipeline provenance for Aldh1l1 annotations including
      10-formyltetrahydrofolate catabolic process; formyltetrahydrofolate dehydrogenase activity.
    supporting_text: GO_REF entry used only to trace source annotation method; biological support was assessed
      from UniProt and cached literature where available.
    reference_section_type: TITLE
- id: GO_REF:0000121
  title: 'GO reference used by source annotation pipeline'
  findings:
  - statement: Source annotation pipeline provenance for Aldh1l1 annotations including
      10-formyltetrahydrofolate catabolic process; NADPH regeneration; aldehyde dehydrogenase (NAD+) activity;
      cytosol; formyltetrahydrofolate dehydrogenase activity; and 1 other terms.
    supporting_text: GO_REF entry used only to trace source annotation method; biological support was assessed
      from UniProt and cached literature where available.
    reference_section_type: TITLE
- id: PMID:10585460
  title: 'Aspartate 142 is involved in both hydrolase and dehydrogenase catalytic centers of 10-formyltetrahydrofolate
    dehydrogenase'
  findings:
  - statement: For Aldh1l1, this publication supports direct annotations to 10-formyltetrahydrofolate
      catabolic process; formyltetrahydrofolate dehydrogenase activity.
    supporting_text: The enzyme 10-formyltetrahydrofolate dehydrogenase (FDH) catalyzes conversion of
      10-formyltetrahydrofolate to tetrahydrofolate in either a dehydrogenase or hydrolase reaction.
    reference_section_type: ABSTRACT
- id: PMID:14729668
  title: 'The crystal structure of the hydrolase domain of 10-formyltetrahydrofolate dehydrogenase: mechanism of
    hydrolysis and its interplay with the dehydrogenase domain'
  findings:
  - statement: For Aldh1l1, this publication supports direct annotations to formyltetrahydrofolate
      dehydrogenase activity; tetrahydrofolate biosynthetic process.
    supporting_text: 10-Formyltetrahydrofolate dehydrogenase (FDH) converts 10-formyltetrahydrofolate, a
      precursor for nucleotide biosynthesis, to tetrahydrofolate.
    reference_section_type: ABSTRACT
- id: PMID:17302434
  title: 'Crystal structures of the carboxyl terminal domain of rat 10-formyltetrahydrofolate dehydrogenase: implications
    for the catalytic mechanism of aldehyde dehydrogenases'
  findings:
  - statement: For Aldh1l1, this publication supports direct annotations to aldehyde dehydrogenase (NADP+)
      activity; formyltetrahydrofolate dehydrogenase activity.
    supporting_text: 10-Formyltetrahydrofolate dehydrogenase (FDH) catalyzes an NADP+-dependent dehydrogenase
      reaction resulting in conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO2.
    reference_section_type: ABSTRACT
- id: PMID:17669278
  title: 'Rat liver 10-formyltetrahydrofolate dehydrogenase, carbamoyl phosphate synthetase 1 and betaine homocysteine
    S-methytransferase were co-purified on Kunitz-type soybean trypsin inhibitor-coupled sepharose CL-4B'
  findings:
  - statement: For Aldh1l1, this publication was reviewed as context for protein-containing complex;
      protein-containing complex binding.
    supporting_text: An Asp/His catalytic site of 10-formyltetrahydrofolate dehydrogenase (FDH) was suggested
      to have a similar catalytic topology with the Asp/His catalytic site of serine proteases.
    reference_section_type: ABSTRACT
- id: PMID:17884809
  title: '10-formyltetrahydrofolate dehydrogenase requires a 4''-phosphopantetheine prosthetic group for catalysis'
  findings:
  - statement: For Aldh1l1, this publication supports direct annotations to formyltetrahydrofolate
      dehydrogenase activity.
    supporting_text: 10-Formyltetrahydrofolate dehydrogenase (FDH) consists of two independent catalytic
      domains, N- and C-terminal, connected by a 100-amino acid residue linker (intermediate domain).
    reference_section_type: ABSTRACT
- id: PMID:1848231
  title: 'Isolation and characterization of cDNA clones for rat liver 10-formyltetrahydrofolate dehydrogenase'
  findings:
  - statement: For Aldh1l1, this publication provides evidence/provenance for direct annotations to
      10-formyltetrahydrofolate catabolic process; NADPH regeneration; folic acid metabolic process and
      contextual annotations to aldehyde dehydrogenase [NAD(P)+] activity; cytosol.
    supporting_text: Intact 10-formyltetrahydrofolate dehydrogenase exhibits NADP-dependent aldehyde
      dehydrogenase activity.
    reference_section_type: ABSTRACT
- id: PMID:7822273
  title: 'Cysteine 707 is involved in the dehydrogenase activity site of rat 10-formyltetrahydrofolate dehydrogenase'
  findings:
  - statement: For Aldh1l1, this publication supports direct annotations to formyltetrahydrofolate
      dehydrogenase activity.
    supporting_text: The enzyme, 10-formyltetrahydrofolate dehydrogenase (10-FTHFDH) (EC 1.5.1.6) catalyzes
      both the NADP(+)-dependent oxidation of 10-formyltetrahydrofolate to tetrahydrofolate and CO2 and the
      NADP(+)-independent hydrolysis of 10-formyltetrahydrofolate to tetrahydrofolate and formate.
    reference_section_type: ABSTRACT
core_functions:
- description: Aldh1l1 oxidizes 10-formyltetrahydrofolate to tetrahydrofolate and CO2 while regenerating
    NADPH.
  supported_by:
  - reference_id: UniProtKB:P28037
    supporting_text: 'FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase catalyzes the NADP(+)-dependent
      conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.'
  molecular_function:
    id: GO:0016155
    label: formyltetrahydrofolate dehydrogenase activity
  directly_involved_in:
  - id: GO:0009258
    label: 10-formyltetrahydrofolate catabolic process
  - id: GO:0035999
    label: tetrahydrofolate interconversion
  - id: GO:0006740
    label: NADPH regeneration
  - id: GO:0046655
    label: folic acid metabolic process