KDSR

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005789 endoplasmic reticulum membrane	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference that KDSR is active in the ER membrane. This is strongly supported by direct experimental evidence in human and mouse. Reason: KDSR is an integral ER membrane protein with its catalytic domain on the cytosolic face of the ER; the IBA localization is correct and at an appropriate level of specificity. Supporting Evidence: PMID:15328338 hFVT-1 is localized at the endoplasmic reticulum file:human/KDSR/KDSR-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0030148 sphingolipid biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference that KDSR is involved in sphingolipid biosynthesis. This is the core biological process of the gene. Reason: KDSR catalyses the second, obligatory step of de novo sphingolipid biosynthesis; this is directly supported by experimental and mutation data in addition to the phylogenetic inference. Supporting Evidence: file:human/KDSR/KDSR-uniprot.txt the second step of de novo sphingolipid biosynthesis PMID:19141869 FVT1 is the principal 3-ketosphinganine reductase in mammalian cells
GO:0006666 3-keto-sphinganine metabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference that KDSR participates in 3-keto-sphinganine metabolism. KDSR consumes 3-keto-sphinganine (3-ketodihydrosphingosine), its direct substrate. Reason: 3-keto-sphinganine (3-oxosphinganine) is the direct substrate of KDSR; this is a precise, correct BP for the enzyme's substrate metabolism, complementing the broader sphingolipid biosynthetic process term. Supporting Evidence: file:human/KDSR/KDSR-uniprot.txt Reaction=sphinganine + NADP(+) = 3-oxosphinganine + NADPH + H(+)
GO:0047560 3-dehydrosphinganine reductase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference of 3-dehydrosphinganine reductase (KDS reductase) activity. This is the defining molecular function of KDSR. Reason: This IBA annotation captures the core molecular function of KDSR and is concordant with direct enzymatic characterization of the purified human protein. Supporting Evidence: PMID:15328338 exhibited NADPH-dependent KDS reductase activity
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Electronic annotation of ER membrane localization from the UniProt Subcellular Location mapping, consistent with experimental evidence. Reason: The ER membrane localization is experimentally established; this IEA is accurate. Supporting Evidence: file:human/KDSR/KDSR-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0006666 3-keto-sphinganine metabolic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic annotation to 3-keto-sphinganine metabolic process based on the KDSR-like family signature (IPR045022). Reason: The InterPro family assignment correctly maps to the substrate-metabolism BP; consistent with the enzyme's characterized reaction. Supporting Evidence: file:human/KDSR/KDSR-uniprot.txt Reaction=sphinganine + NADP(+) = 3-oxosphinganine + NADPH + H(+)
GO:0030148 sphingolipid biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation (combined IEA methods / ARBA) to sphingolipid biosynthetic process, the core BP of KDSR. Reason: Correct core biological process, redundant with better-supported experimental annotations to the same term. Supporting Evidence: file:human/KDSR/KDSR-uniprot.txt the second step of de novo sphingolipid biosynthesis
GO:0047560 3-dehydrosphinganine reductase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation of the reductase molecular function from InterPro/RHEA/EC mappings (EC 1.1.1.102, RHEA:22640). Reason: Correctly assigns the defining molecular function via the enzyme's EC number and Rhea reaction; concordant with experimental data. Supporting Evidence: file:human/KDSR/KDSR-uniprot.txt EC=1.1.1.102
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a large-scale yeast two-hybrid interactome study, capturing interactions with KIF1B, HSPB1, TTR and WFS1. This term is uninformative about KDSR's molecular function. Reason: The GO:0005515 "protein binding" term conveys no specific functional information, and the underlying interactions are high-throughput Y2H hits from a neurodegeneration interactome screen with no established relevance to KDSR's enzymatic role. Per curation guidance, bare protein binding is retained but flagged as an over-annotation rather than removed. Supporting Evidence: PMID:32814053 systematic yeast two-hybrid interaction screening
GO:0030148 sphingolipid biosynthetic process	TAS Reactome:R-HSA-1660661	ACCEPT	Summary: Reactome traceable annotation placing KDSR in de novo sphingolipid biosynthesis. Reason: Reactome correctly assigns KDSR to the sphingolipid de novo biosynthesis pathway; this is the core BP. Supporting Evidence: file:human/KDSR/KDSR-uniprot.txt the second step of de novo sphingolipid biosynthesis
GO:0006665 sphingolipid metabolic process	IEA GO_REF:0000041	KEEP AS NON CORE	Summary: UniPathway-based electronic annotation to the broad sphingolipid metabolic process term. Reason: Correct but less informative than the biosynthetic-process child term (GO:0030148), which is separately annotated with experimental support. Retained as a valid but general parent annotation. Supporting Evidence: file:human/KDSR/KDSR-uniprot.txt PATHWAY: Lipid metabolism; sphingolipid metabolism
GO:0047560 3-dehydrosphinganine reductase activity	TAS Reactome:R-HSA-428123	ACCEPT	Summary: Reactome traceable annotation of the KDS reductase molecular function (reaction "KDSR reduces 3-ketosphingoid"). Reason: Correctly captures the defining molecular function of KDSR. Supporting Evidence: file:human/KDSR/KDSR-uniprot.txt Reaction=sphinganine + NADP(+) = 3-oxosphinganine + NADPH + H(+)
GO:0046513 ceramide biosynthetic process	IDA PMID:1317856 Subcellular localization and membrane topology of serine pal...	KEEP AS NON CORE	Summary: Classic biochemical study localizing serine palmitoyltransferase, 3-dehydrosphinganine reductase and sphinganine N-acyltransferase to the cytosolic face of mouse liver ER. The reductase activity feeds the pathway that produces dihydroceramide/ceramide. Reason: KDSR (3-dehydrosphinganine reductase) provides sphinganine, an obligatory precursor for ceramide synthesis, and this paper measures the reductase activity as part of the early ceramide-forming pathway. However, KDSR does not itself catalyse ceramide formation, so ceramide biosynthetic process is a pathway-level annotation kept as non-core rather than a direct catalytic function. Supporting Evidence: PMID:1317856 are responsible for the first steps in sphingolipid PMID:1317856 3-oxosphinganine, sphinganine, and dihydroceramide
GO:0047560 3-dehydrosphinganine reductase activity	IDA PMID:36170811 De novo sphingolipid biosynthesis necessitates detoxificatio...	ACCEPT	Summary: Study establishing that KDSR reduces 3KDS to sphinganine and that KDSR loss causes toxic 3KDS accumulation. Supports the reductase molecular function. Reason: Directly attributes the 3KDS-reducing (3-dehydrosphinganine reductase) activity to KDSR; this is the core molecular function. Supporting Evidence: PMID:36170811 3KDS is subsequently converted to sphinganine by 3KDS reductase (KDSR)
GO:0006686 sphingomyelin biosynthetic process	IDA PMID:36170811 De novo sphingolipid biosynthesis necessitates detoxificatio...	MARK AS OVER ANNOTATED	Summary: KDSR loss affects downstream sphingomyelin levels because sphingomyelin is a major downstream product of de novo sphingolipid biosynthesis; sphingomyelins were measured as downstream readouts of the KDSR-dependent pathway. Reason: KDSR contributes to sphingomyelin biosynthesis only indirectly, by supplying the sphinganine backbone upstream; it does not catalyse any sphingomyelin-forming step. In this study cancer cells could still salvage sphingomyelin, and total sphingomyelins did not necessarily decrease on KDSR knockout. This is a distal pathway-product annotation rather than a direct function. Supporting Evidence: PMID:36170811 major downstream products of sphingolipid biosynthesis
GO:0006688 glycosphingolipid biosynthetic process	IDA PMID:34080016 Glucosylceramide and galactosylceramide, small glycosphingol...	MARK AS OVER ANNOTATED	Summary: Reference is a review of glucosylceramide and galactosylceramide biology. Glycosphingolipids are distal products of the de novo pathway that KDSR feeds, but the reference does not itself assay or even mention KDSR. Reason: Glycosphingolipid biosynthesis is several enzymatic steps downstream of KDSR (sphinganine -> ceramide -> glucosyl/galactosylceramide -> complex GSL); KDSR catalyses none of these glycosylation steps. The cited review never mentions KDSR, so this is a pathway-level over-annotation, not a direct function. Supporting Evidence: file:human/KDSR/KDSR-uniprot.txt the second step of de novo sphingolipid biosynthesis
GO:0046513 ceramide biosynthetic process	IDA PMID:16120614 Serinc, an activity-regulated protein family, incorporates s...	KEEP AS NON CORE	Summary: Study of the Serinc protein family, which forms an intracellular complex with enzymes of serine and sphingolipid biosynthesis to incorporate serine into membrane lipids. The abstract does not directly assay KDSR in ceramide synthesis. Reason: Ceramide biosynthesis is downstream of the sphinganine KDSR produces; KDSR is required for the pathway but does not catalyse a ceramide-forming step. Because only the abstract is available and the experimental (IDA) full text may implicate KDSR in the biosynthetic complex, the annotation is retained as a valid pathway-level, non-core assignment rather than removed. Supporting Evidence: PMID:16120614 enzymes involved in serine and sphingolipid biosyntheses
GO:0098554 cytoplasmic side of endoplasmic reticulum membrane	IDA PMID:19416851 Identification of small subunits of mammalian serine palmito...	ACCEPT	Summary: Annotation that KDSR is active on the cytoplasmic side of the ER membrane. This is the most precise localization consistent with the enzyme's topology. Reason: KDSR's large catalytic domain, bearing the active-site and NADPH-binding residues, faces the cytosol at the ER membrane; the cytoplasmic-side term is the most accurate CC and reflects where catalysis occurs. Supporting Evidence: PMID:15328338 which contains putative active site residues, faces the cytosol file:human/KDSR/KDSR-uniprot.txt TOPO_DOM 26..270
GO:0005789 endoplasmic reticulum membrane	EXP PMID:15328338 FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with...	ACCEPT	Summary: Direct experimental (immunofluorescence) demonstration that human FVT-1/KDSR localizes to the endoplasmic reticulum. Reason: Robust experimental support for ER membrane localization. Supporting Evidence: PMID:15328338 hFVT-1 is localized at the endoplasmic reticulum
GO:0005789 endoplasmic reticulum membrane	EXP PMID:19141869 Tsc10p and FVT1: topologically distinct short-chain reductas...	ACCEPT	Summary: Experimental localization and topology study placing FVT1/KDSR at the ER membrane. Reason: Confirms ER membrane localization by independent experimental methods. Supporting Evidence: PMID:19141869 oriented to place
GO:0047560 3-dehydrosphinganine reductase activity	EXP PMID:15328338 FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with...	ACCEPT	Summary: Purified recombinant human FVT-1/KDSR exhibits NADPH-dependent KDS reductase activity in vitro, and rescues KDS reductase-deficient yeast. Reason: Direct enzymatic demonstration of the defining molecular function; core function. Supporting Evidence: PMID:15328338 exhibited NADPH-dependent KDS reductase activity
GO:0006666 3-keto-sphinganine metabolic process	IMP PMID:19141869 Tsc10p and FVT1: topologically distinct short-chain reductas...	ACCEPT	Summary: Silencing/mutation of FVT1 alters 3-ketosphinganine reductase activity, implicating KDSR in 3-keto-sphinganine metabolism. Reason: Loss-of-function evidence supports KDSR's role in metabolizing its substrate 3-keto-sphinganine. Supporting Evidence: PMID:19141869 FVT1 is the principal 3-ketosphinganine reductase in mammalian cells
GO:0030148 sphingolipid biosynthetic process	IMP PMID:19141869 Tsc10p and FVT1: topologically distinct short-chain reductas...	ACCEPT	Summary: Mutational/silencing evidence that FVT1/KDSR is required for long-chain base (sphingoid) synthesis, i.e. sphingolipid biosynthesis. Reason: Core biological process supported by loss-of-function data. Supporting Evidence: PMID:19141869 required for long-chain base synthesis in yeast and mammals
GO:0047560 3-dehydrosphinganine reductase activity	IMP PMID:19141869 Tsc10p and FVT1: topologically distinct short-chain reductas...	ACCEPT	Summary: FVT1 silencing directly correlates with cellular KDS reductase activity, identifying KDSR as the principal enzyme carrying this activity. Reason: Loss-of-function evidence for the defining molecular function; core function. Supporting Evidence: PMID:19141869 a direct correlation between FVT1 levels and reductase activity
GO:0030148 sphingolipid biosynthetic process	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity-based transfer of sphingolipid biosynthetic process from the yeast ortholog (TSC10, P38342). Reason: Correct core BP; the ortholog-based inference agrees with direct experimental data in human. Supporting Evidence: PMID:19141869 required for long-chain base synthesis in yeast and mammals
GO:0070402 NADPH binding	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity inference of NADPH binding, consistent with the Rossmann-fold NADPH-binding motif and the NADPH-dependent reductase mechanism. Reason: KDSR is an NADPH-dependent reductase with a conserved N-terminal NADPH-binding (Rossmann) region; NADPH binding is a genuine molecular function supporting the catalytic activity. Supporting Evidence: PMID:15328338 exhibited NADPH-dependent KDS reductase activity file:human/KDSR/KDSR-uniprot.txt /ligand="NADPH"
GO:0047560 3-dehydrosphinganine reductase activity	IMP PMID:28575652 Mutations in KDSR Cause Recessive Progressive Symmetric Eryt...	ACCEPT	Summary: Disease-gene study showing biallelic KDSR mutations cause progressive symmetric erythrokeratoderma, with yeast complementation and immunohistochemistry demonstrating defective KDSR function. Reason: Patient mutations that abolish/impair the reductase function, validated by yeast complementation, provide loss-of-function support for the enzymatic activity. Supporting Evidence: PMID:28575652 demonstrated that the mutations cause defects in KDSR function
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	KEEP AS NON CORE	Summary: High-throughput proteomics identification of KDSR in the membrane proteome of an NK-like cell line. Reason: Correct but very general; KDSR is an integral membrane protein, and the more specific ER membrane / cytoplasmic side of ER membrane annotations are the informative localizations. Retained as a non-core, low-specificity localization. Supporting Evidence: PMID:19946888 define the composition of the membrane
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-428123	ACCEPT	Summary: Reactome traceable annotation of ER membrane localization. Reason: Consistent with the experimentally established ER membrane localization. Supporting Evidence: file:human/KDSR/KDSR-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005783 endoplasmic reticulum	IDA PMID:15364918 Lateral diffusion of inositol 1,4,5-trisphosphate receptor t...	ACCEPT	Summary: MGI-assigned IDA to endoplasmic reticulum. The cited reference (PMID:15364918) is a study of IP3R1 lateral diffusion in neurons and does not concern KDSR, so this appears to be a mis-attributed citation; however ER localization of KDSR is itself well established. Reason: The endoplasmic reticulum localization is correct and independently supported by direct experimental evidence (PMID:15328338, PMID:19141869). The original reference appears to be a wrong-PMID citation (flagged in reference_review), but the annotation content is accurate and is retained on the basis of the other evidence. Supporting Evidence: PMID:15328338 hFVT-1 is localized at the endoplasmic reticulum
GO:0006666 3-keto-sphinganine metabolic process	IDA PMID:15364918 Lateral diffusion of inositol 1,4,5-trisphosphate receptor t...	ACCEPT	Summary: MGI-assigned IDA linking KDSR to 3-keto-sphinganine metabolism. The cited reference is an IP3R1 diffusion study unrelated to KDSR, so the citation appears mis-attributed, but the underlying biology (KDSR metabolizes 3-keto-sphinganine) is correct. Reason: KDSR reduces 3-keto-sphinganine (its substrate); the BP is correct and well supported by direct enzymology elsewhere. The original PMID is flagged as a likely wrong-identifier citation but does not affect the correctness of the annotation. Supporting Evidence: PMID:19141869 FVT1 is the principal 3-ketosphinganine reductase in mammalian cells
GO:0047560 3-dehydrosphinganine reductase activity	IDA PMID:15364918 Lateral diffusion of inositol 1,4,5-trisphosphate receptor t...	ACCEPT	Summary: MGI-assigned IDA to the reductase molecular function. The cited reference is an IP3R1 lateral-diffusion study unrelated to KDSR, so the citation is likely mis-attributed; nonetheless the reductase activity is the well-established core function of KDSR. Reason: The 3-dehydrosphinganine reductase activity is the defining, extensively validated molecular function of KDSR. The original PMID appears to be a wrong-identifier citation (flagged in reference_review), but the annotation itself is correct and supported by direct enzymology (PMID:15328338, PMID:19141869). Supporting Evidence: PMID:15328338 exhibited NADPH-dependent KDS reductase activity
GO:0005576 extracellular region	TAS PMID:8417785 FVT-1, a novel human transcription unit affected by variant ...	REMOVE	Summary: Legacy annotation (ProtInc) derived from the 1993 FVT-1 cloning paper, which described FVT-1 as a "putatively secreted protein" based on sequence prediction before its function was known. Reason: This localization is contradicted by all subsequent experimental evidence KDSR is a multi-pass integral endoplasmic reticulum membrane protein with its catalytic domain facing the cytosol, not a secreted/extracellular protein. The extracellular assignment reflects an outdated sequence-based prediction of secretion that has been superseded, and is a demonstrably wrong legacy inference. Supporting Evidence: PMID:8417785 codes for a putatively secreted protein of 36 Kd file:human/KDSR/KDSR-uniprot.txt Multi-pass

Gene Description

Existing Annotations Review

Core Functions

NADPH-dependent 3-ketodihydrosphingosine (3-dehydrosphinganine) reductase that catalyses the second step of de novo sphingolipid biosynthesis, reducing 3-ketodihydrosphingosine to dihydrosphingosine (sphinganine) at the cytosolic face of the ER membrane.

References

📚 Additional Documentation

Notes

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