Affinage

KDSR

3-ketodihydrosphingosine reductase · UniProt Q06136

Length
332 aa
Mass
36.2 kDa
Annotated
2026-06-10
13 papers in source corpus 7 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KDSR (FVT1) is the principal mammalian NADPH-dependent 3-ketodihydrosphingosine reductase, catalyzing the second step of de novo sphingolipid biosynthesis by reducing 3-ketodihydrosphingosine to dihydrosphingosine (PMID:15328338, PMID:19141869). It is an integral endoplasmic reticulum membrane protein in which an N-terminal membrane-spanning domain anchors a large hydrophilic catalytic domain on the cytosolic face of the ER, defining where this reduction occurs (PMID:15328338, PMID:19141869). Loss-of-function mutations abolish or reduce reductase activity and lower ceramide levels in skin, causing defective acylceramide synthesis and keratinization disorders including progressive symmetric erythrokeratoderma (PMID:28774589, PMID:28575652); KDSR deficiency also impairs proplatelet formation from megakaryocytes, with patient megakaryocytes showing hyperproliferation and reduced proplatelet output that is rescued by re-expression of functional KDSR, and is accompanied by thrombocytopenia (PMID:30467204). When KDSR is non-functional, its accumulated substrate is shunted through ceramide synthases to generate novel keto-type ceramide species in the stratum corneum, revealing a bypass pathway that partially compensates downstream lipid levels (PMID:30467204, PMID:34686882).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2004 High

    Established the molecular identity and enzymatic activity of human FVT1/KDSR, answering whether it served as the mammalian counterpart to yeast Tsc10p in sphingolipid synthesis.

    Evidence In vitro NADPH-dependent reductase assay with recombinant protein and TSC10-null yeast complementation

    PMID:15328338

    Open questions at the time
    • Did not establish in vivo contribution relative to other reductases
    • No structural model of the catalytic site
  2. 2004 High

    Defined the subcellular localization and membrane topology, showing the reaction occurs on the cytosolic face of the ER.

    Evidence Immunofluorescence ER colocalization and proteinase K protection topology assay

    PMID:15328338

    Open questions at the time
    • Topology assignment refined in later work (lumenal vs cytosolic active-site orientation)
    • Membrane insertion mechanism not addressed
  3. 2007 High

    Linked a specific missense substitution to disease by showing it abolishes in vitro activity while retaining residual in vivo function, explaining a tissue-restricted degenerative phenotype.

    Evidence In vitro activity comparison of bovine Ala-175 vs Thr-175 variants and yeast complementation

    PMID:17420465

    Open questions at the time
    • Mechanism of neuron-specific vulnerability not resolved
    • Human relevance of bovine variant not directly tested
  4. 2009 High

    Demonstrated KDSR is the principal cellular 3-ketosphinganine reductase and mapped the N-terminal ER-targeting domain, clarifying mechanistic divergence from yeast Tsc10p.

    Evidence siRNA knockdown with activity measurement, GFP-fusion targeting, protease domain removal, and catalytic-residue mutagenesis

    PMID:19141869

    Open questions at the time
    • Functional consequence of distinct topology not fully defined
    • No structural basis for catalytic-residue differences
  5. 2017 Medium

    Connected biallelic KDSR loss of function to human keratinization disease through reduced enzymatic activity, lowered skin ceramide, and concurrent thrombocytopenia.

    Evidence Whole-exome sequencing, patient-sample reductase activity, skin ceramide quantification, and splicing/yeast complementation assays

    PMID:28575652 PMID:28774589

    Open questions at the time
    • No reconstitution of mutant enzymes in defined system
    • Genotype-phenotype severity relationship incompletely mapped
  6. 2018 High

    Established a cell-autonomous role for KDSR in megakaryocyte proplatelet formation and validated causality through rescue and an animal model.

    Evidence Patient CD34+/iPSC-derived megakaryocyte culture with functional KDSR re-expression, zebrafish kdsr morpholino knockdown, and metabolomics

    PMID:30467204

    Open questions at the time
    • Identity of the compensatory in vivo pathway not defined
    • Molecular link between ceramide deficit and proplatelet defect unresolved
  7. 2022 Medium

    Revealed a substrate-shunting bypass in which accumulated 3-ketodihydrosphingosine is converted into novel keto-type ceramides, explaining altered skin ceramide composition under KDSR loss.

    Evidence Mass spectrometry lipidomics and structural identification of keto-ceramides in patient stratum corneum

    PMID:34686882

    Open questions at the time
    • Enzymes responsible for keto-ceramide production not directly identified
    • Functional impact of keto-ceramides on skin barrier not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of catalysis and the molecular mechanism linking ceramide deficiency to tissue-specific phenotypes (skin, platelets, neurons) remain unresolved.
  • No high-resolution structure of human KDSR
  • Compensatory bypass pathway and its regulators uncharacterized
  • Mechanistic basis for tissue selectivity of phenotypes unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1430728 Metabolism 3

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Human FVT-1 (KDSR) functions as a 3-ketodihydrosphingosine (KDS) reductase: recombinant hFVT-1 exhibits NADPH-dependent KDS reductase activity in vitro, and forced expression in TSC10-null yeast suppresses growth defects, establishing it as the mammalian KDS reductase. In vitro enzyme assay with purified recombinant protein, yeast complementation (TSC10-null rescue), overexpression in cultured cells The Journal of biological chemistry High 15328338
2004 hFVT-1 (KDSR) localizes to the endoplasmic reticulum, and the large hydrophilic domain containing putative active-site residues faces the cytosolic side of the ER membrane, indicating that KDS is reduced to dihydrosphingosine on the cytosolic face of the ER. Immunofluorescence microscopy (ER colocalization) and proteinase K digestion topology assay The Journal of biological chemistry High 15328338
2009 FVT1 (KDSR) is the principal 3-ketosphinganine reductase in mammalian cells: siRNA silencing of FVT1 directly reduced cellular reductase activity in proportion to FVT1 levels. The N-terminal membrane-spanning domain of FVT1 (absent in yeast Tsc10p) targets it to the ER lumen and confers distinct topology relative to yeast Tsc10p. Mutation of conserved catalytic residues differentially affected FVT1 vs. Tsc10p activity, revealing mechanistic differences between the two orthologs. siRNA knockdown with enzymatic activity measurement; N-terminal GFP fusion for ER-targeting domain mapping; factor Xa protease domain removal; active-site mutagenesis Journal of lipid research High 19141869
2007 A missense mutation (Ala-175→Thr) in bovine FVT1 (KDSR) abolishes 3-ketodihydrosphingosine reductase activity in vitro, yet the mutant protein retains sufficient residual in vivo activity to complement a yeast knockout, explaining why SMA-affected calves are viable but develop neuron-specific degeneration. In vitro enzyme assay comparing Ala-175 vs. Thr-175 variants; yeast complementation assay Proceedings of the National Academy of Sciences of the United States of America High 17420465
2017 Loss-of-function mutations in KDSR reduce ceramide levels in skin and impair KDSR enzymatic activity, causing defective acylceramide synthesis and leading to skin hyperkeratosis; thrombocytopenia is also present, indicating KDSR activity is required for normal platelet function. Whole-exome sequencing identifying mutations; KDSR enzymatic activity measurement in patient samples; ceramide level quantification in skin The Journal of investigative dermatology Medium 28774589
2017 KDSR mutations causing exon skipping (including a recurrent silent third-base change) disrupt KDSR function as demonstrated by yeast complementation failure, establishing that loss of KDSR enzymatic activity underlies progressive symmetric erythrokeratoderma. Splicing assay (cDNA sequencing), yeast complementation, immunohistochemistry American journal of human genetics Medium 28575652
2018 KDSR insufficiency impairs proplatelet formation from megakaryocytes: CD34+-derived megakaryocytes from KDSR-deficient patients showed hyperproliferation and reduced proplatelet formation, reversed by re-expression of functional KDSR in iPSC-derived megakaryocytes. Kdsr depletion in zebrafish recapitulated thrombocytopenia. A compensatory in vivo pathway partially normalizes downstream ceramide levels. CD34+ stem cell-derived megakaryocyte culture, iPSC differentiation with KDSR rescue, zebrafish kdsr morpholino knockdown, broad metabolomics screen Haematologica High 30467204
2022 In patients with biallelic KDSR mutations, the KDSR substrate 3-ketodihydrosphingosine accumulates and is processed by ceramide synthases to produce novel keto-type ceramides (up to 10% of ceramide species) in the stratum corneum, revealing a bypass pathway when KDSR is non-functional and demonstrating that tight intermediate regulation during sphingolipid anabolism is required for normal ceramide composition. Stratum corneum lipid analysis by mass spectrometry in KDSR-mutant patients vs. controls; structural identification of keto-type ceramides Human molecular genetics Medium 34686882

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with an active site that faces the cytosolic side of the endoplasmic reticulum membrane. The Journal of biological chemistry 80 15328338
2017 Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma. American journal of human genetics 69 28575652
2017 Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia. The Journal of investigative dermatology 52 28774589
2007 A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy. Proceedings of the National Academy of Sciences of the United States of America 41 17420465
1993 FVT-1, a novel human transcription unit affected by variant translocation t(2;18)(p11;q21) of follicular lymphoma. Blood 40 8417785
2018 Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia. Haematologica 33 30467204
2009 Tsc10p and FVT1: topologically distinct short-chain reductases required for long-chain base synthesis in yeast and mammals. Journal of lipid research 23 19141869
2022 Formation of keto-type ceramides in palmoplantar keratoderma based on biallelic KDSR mutations in patients. Human molecular genetics 14 34686882
2020 A Homozygotic Mutation in KDSR may Cause Keratinization Disorders and Thrombocytopenia: A Case Report. Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih 6 32972506
2022 Case report: Compound heterozygous mutations in the KDSR gene cause progressive keratodermia and thrombocytopenia. Frontiers in pediatrics 2 35958175
2022 Variable skin findings in two siblings with KDSR mutations manifesting in PERIOPTER syndrome. Pediatric dermatology 1 36263748
2026 Vitamin D remodels the tumor microenvironment to suppress gastric cancer progression through cancer-associated fibroblasts-secreted exosomal miR-378c targeting KDSR. Archives of pharmacal research 0 42105149
2020 Spinal Muscular Atrophy in Blonde D'Aquitaine Calves Is Not Associated With FVT1 Gene Mutation. Frontiers in veterinary science 0 32714947

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