DEGS1 (dihydroceramide desaturase 1 / sphingolipid delta(4)-desaturase DES1) is the endoplasmic reticulum enzyme that catalyzes the final step of de novo ceramide biosynthesis. It introduces a 4,5-trans double bond into dihydroceramide (an N-acylsphinganine) to convert it into ceramide (an N-acylsphing-4-enine), thereby turning the saturated dihydroceramide produced by the ceramide synthases into bioactive ceramide, the central hub of sphingolipid metabolism. The reaction (EC 1.14.19.17) is oxygen-dependent and iron-dependent. DEGS1 is a member of the fatty acid desaturase type 1 (DEGS) family with three conserved histidine-box motifs coordinating a di-iron center, and it receives reducing equivalents from cytochrome b5 / NAD(P)H via a free-radical mechanism. It is a multi-pass membrane protein acting on the cytoplasmic (cytosolic) face of the ER membrane; a myristoylation-dependent pool can also localize to mitochondria. DEGS1 also displays a distinct retinol (vitamin A) isomerase activity in retinal Muller glial cells. Loss-of-function variants cause hypomyelinating leukodystrophy 18 (HLD18), a severe autosomal recessive neurological disorder with accumulation of dihydroceramides and dihydro-sphingolipids and demyelination of the central and peripheral nervous systems.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0042284 sphingolipid delta-4 desaturase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assertion of the core molecular function. DEGS1/DES1 is the dihydroceramide (sphingolipid Delta4) desaturase, matching the exact GOA/UniProt catalytic activity (EC 1.14.19.17). This is the correct, well-supported core MF. Reason: Directly supported by experimental characterization of the human enzyme and by disease genetics; the IBA is at the right level of specificity for the family. Supporting Evidence: PMID:11937514 identification of the enzyme sphingolipid Delta4-desaturase (dihydroceramide desaturase) from Homo sapiens PMID:30620337 This enzyme catalyzes the insertion of a Ξ4,5- trans double bond into dihydroceramide (DhCer) to convert it to ceramide (Cer), in the final step of the de novo Cer biosynthesis pathway |
| GO:0046513 ceramide biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assertion that DEGS1 acts in ceramide biosynthesis. Correct: the delta-4 desaturase step converts dihydroceramide to ceramide as the last committed step of de novo ceramide synthesis. Reason: Core biological process; consistent with experimental and disease evidence. Supporting Evidence: PMID:30620338 DEGS1, which catalyzes the last step in the ceramide synthesis pathway |
| GO:0003824 catalytic activity | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Root-level catalytic activity from an ARBA machine-learning model. Not wrong, but far too general given that the specific desaturase MF (GO:0042284) is annotated. Reason: Uninformative parent term subsumed by the specific sphingolipid delta-4 desaturase activity; retained only as an electronic generalization. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ER membrane localization inferred electronically from the UniProt subcellular-location vocabulary. This matches the experimentally established primary site of DEGS1. Reason: ER membrane is the functional localization, corroborated by multiple experimental studies. Supporting Evidence: file:human/DEGS1/DEGS1-uniprot.txt Endoplasmic reticulum |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic lipid metabolic process from InterPro2GO. Correct but very broad; the specific ceramide/sphingolipid biosynthetic process terms are the informative annotations. Reason: High-level parent subsumed by more specific accepted BP terms (ceramide/sphingolipid biosynthetic process). |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic membrane localization from InterPro2GO. DEGS1 is indeed a multi-pass membrane protein, but this root term is uninformative relative to ER membrane. Reason: Subsumed by the specific endoplasmic reticulum membrane localization. |
| GO:0030148 sphingolipid biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: Sphingolipid biosynthetic process from InterPro2GO. Correct: ceramide made by DEGS1 is the precursor of all downstream sphingolipids. A valid, appropriately specific BP. Reason: Consistent with the enzyme's role at the hub of de novo sphingolipid synthesis. Supporting Evidence: PMID:30620337 This enzyme catalyzes the insertion of a Ξ4,5- trans double bond into dihydroceramide (DhCer) to convert it to ceramide (Cer), in the final step of the de novo Cer biosynthesis pathway |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mitochondrial membrane localization from the UniProt subcellular-location vocabulary. A myristoylation-dependent pool of DEGS1 is genuinely targeted to mitochondria, but this is a secondary, non-core localization relative to the ER. Reason: Experimentally observed but secondary; myristoylation retargets part of the enzyme to mitochondria, raising ceramide/apoptosis. Not the primary functional site. Supporting Evidence: PMID:19647031 DES1 myristoylation targets part of the recombinant protein to the mitochondria in COS-7 cells file:human/DEGS1/DEGS1-uniprot.txt Mitochondrion membrane |
| GO:0042284 sphingolipid delta-4 desaturase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The core desaturase MF assigned electronically via combined IEA methods (InterPro, Rhea:46544, EC 1.14.19.17). Correct and matches the experimentally verified activity. Reason: Duplicate electronic support for the well-established core molecular function. Supporting Evidence: file:human/DEGS1/DEGS1-uniprot.txt Reaction=an N-acylsphinganine + 2 Fe(II)-[cytochrome b5] + O2 + 2 H(+) |
| GO:0050251 retinol isomerase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Retinol isomerase activity from Rhea mapping (RHEA:19141, all-trans-retinol = 11-cis-retinol). DEGS1 has a genuine, experimentally demonstrated retinol isomerase (vitamin A isomerase) activity in retinal Muller cells, distinct from its core dihydroceramide desaturase role. Reason: Real moonlighting activity but tissue-restricted and secondary to de novo ceramide synthesis; keep as non-core. Supporting Evidence: PMID:23143414 retinol-isomerase activity is a unique feature of DES1, and not a general property of membrane desaturases or diiron-binding proteins |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from the HuRI high-throughput binary interactome (interaction with ARLN, Q8WVX3-2). Uninformative as a molecular function and not a curated biological partnership. Reason: Generic protein binding from a systematic two-hybrid screen conveys no functional information for DEGS1; per curation policy, mark as over-annotated rather than remove. Supporting Evidence: PMID:32296183 a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI' |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from the HuRI high-throughput binary interactome (second reported interactor, SEMA4G, Q9NTN9-2). Uninformative as a molecular function. Reason: Generic protein binding from a systematic two-hybrid screen conveys no functional information for DEGS1; per curation policy, mark as over-annotated rather than remove. Supporting Evidence: PMID:32296183 a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI' |
| GO:0030148 sphingolipid biosynthetic process | TAS Reactome:R-HSA-1660661 | ACCEPT | Summary: Reactome (Sphingolipid de novo biosynthesis) traceable assertion that DEGS1 acts in sphingolipid biosynthesis. Correct and consistent with the accepted BP. Reason: Authoritative pathway annotation of the de novo sphingolipid biosynthesis role. Supporting Evidence: Reactome:R-HSA-428259 catalyzes the desaturation of dihydroceramide to form ceramide |
| GO:0042284 sphingolipid delta-4 desaturase activity | TAS Reactome:R-HSA-428259 | ACCEPT | Summary: Reactome traceable assertion of the core desaturase reaction (DEGS1 dehydrogenates dihydroceramide). Correct core molecular function. Reason: Matches the experimentally established dihydroceramide desaturase activity. Supporting Evidence: Reactome:R-HSA-428259 catalyzes the desaturation of dihydroceramide to form ceramide |
| GO:0046513 ceramide biosynthetic process | IDA PMID:1317856 Subcellular localization and membrane topology of serine pal... | ACCEPT | Summary: Experimental (IDA) annotation to ceramide biosynthetic process. The cited 1992 study characterized the cytosolic-facing ER de novo sphingolipid-synthesis enzymes in mouse liver, establishing the pathway context; the experimental curator (UOS_MCB) read the full text. The core process assignment is correct. Reason: Ceramide biosynthesis is the central role of DEGS1; defer to the experimental curator and accept. Supporting Evidence: PMID:1317856 Serine palmitoyltransferase, 3-dehydrosphinganine reductase and sphinganine N-acyltransferase are responsible for the first steps in sphingolipid biosynthesis |
| GO:0098554 cytoplasmic side of endoplasmic reticulum membrane | IDA PMID:1317856 Subcellular localization and membrane topology of serine pal... | ACCEPT | Summary: Experimental (IDA) is_active_in the cytoplasmic (cytosolic) side of the ER membrane. The de novo sphingolipid-synthesis enzymes, including the ceramide-forming activities, face the cytosolic side of the ER; Reactome likewise places DEGS1 on the cytosolic ER face. This is the most specific and informative CC annotation. Reason: Correct topology of the active enzyme on the cytosolic face of the ER membrane. Supporting Evidence: PMID:1317856 they face the cytosolic side of the ER, so that substrates have free access to their active sites Reactome:R-HSA-428259 enzyme associated with the cytosolic face of the endoplasmic reticulum |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence IDA to mitochondrion. Consistent with the myristoylation- dependent mitochondrial pool of DEGS1, but secondary to the ER. Reason: Genuine but non-core localization; the functional de novo ceramide-synthesis role is at the ER. Supporting Evidence: PMID:19647031 native dihydroceramide Delta4-desaturase activity was found in both the endoplasmic reticulum and mitochondria in rat hepatocytes |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:19647031 N-Myristoylation targets dihydroceramide Delta4-desaturase 1... | ACCEPT | Summary: Experimental localization of DEGS1/DES1 to the ER membrane. This is the primary functional site of the enzyme. Reason: ER membrane is the core localization; native desaturase activity is found in the ER. Supporting Evidence: PMID:19647031 native dihydroceramide Delta4-desaturase activity was found in both the endoplasmic reticulum and mitochondria in rat hepatocytes |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:30620338 DEGS1-associated aberrant sphingolipid metabolism impairs ne... | ACCEPT | Summary: Experimental ER membrane localization from the HLD18 disease-gene study. Confirms the core ER localization of DEGS1. Reason: Primary functional localization; DEGS1 catalyzes the last ceramide-synthesis step in the ER de novo pathway. Supporting Evidence: PMID:30620338 DEGS1, which catalyzes the last step in the ceramide synthesis pathway |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:9188692 The product of the MLD gene is a member of the membrane fatt... | ACCEPT | Summary: Original cloning study (MLD gene) localized the protein to the endoplasmic reticulum. Core localization, experimentally established. Reason: Foundational experimental evidence for ER localization of DEGS1/MLD. Supporting Evidence: PMID:9188692 MLD is widely expressed in human tissues and is localized to the endoplasmic reticulum |
| GO:0031966 mitochondrial membrane | EXP PMID:19647031 N-Myristoylation targets dihydroceramide Delta4-desaturase 1... | KEEP AS NON CORE | Summary: Experimental mitochondrial-membrane localization driven by N-myristoylation of DEGS1. Real but secondary; a myristoylation-dependent pool is targeted to mitochondria. Reason: Non-core; the primary de novo ceramide-synthesis function occurs at the ER. Supporting Evidence: PMID:19647031 DES1 myristoylation targets part of the recombinant protein to the mitochondria in COS-7 cells |
| GO:0031966 mitochondrial membrane | EXP PMID:30620338 DEGS1-associated aberrant sphingolipid metabolism impairs ne... | KEEP AS NON CORE | Summary: Experimental mitochondrial-membrane localization reported alongside ER in the HLD18 study. Secondary localization; keep as non-core. Reason: Non-core relative to the ER, where the core catalytic function occurs. Supporting Evidence: PMID:19647031 native dihydroceramide Delta4-desaturase activity was found in both the endoplasmic reticulum and mitochondria in rat hepatocytes |
| GO:0042284 sphingolipid delta-4 desaturase activity | EXP PMID:11937514 Identification and characterization of a sphingolipid delta ... | ACCEPT | Summary: Experimental characterization of the human sphingolipid Delta4-desaturase (dihydroceramide desaturase) by heterologous expression. This is the primary experimental basis for the core molecular function and UniProt's EC 1.14.19.17. Reason: Direct experimental evidence for the core catalytic activity of DEGS1. Supporting Evidence: PMID:11937514 identification of the enzyme sphingolipid Delta4-desaturase (dihydroceramide desaturase) from Homo sapiens |
| GO:0042284 sphingolipid delta-4 desaturase activity | IMP PMID:30620338 DEGS1-associated aberrant sphingolipid metabolism impairs ne... | ACCEPT | Summary: IMP evidence: the HLD18 A280V patient variant reduces DEGS1 enzymatic activity by ~80%, with accumulation of dihydro-sphingolipid substrate, directly demonstrating the sphingolipid delta-4 desaturase activity of the gene product. Reason: Loss-of-function/mutant evidence supports the core desaturase MF. Supporting Evidence: PMID:30620338 The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells PMID:30620338 The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species |
| GO:0006686 sphingomyelin biosynthetic process | IDA PMID:24209621 A four-step cycle driven by PI(4)P hydrolysis directs sterol... | KEEP AS NON CORE | Summary: Experimental (IDA) annotation to sphingomyelin biosynthetic process. Ceramide produced by DEGS1 is the precursor of sphingomyelin, so DEGS1 feeds this downstream process. The experimental curator (UOS_MCB) read the full text; this is a downstream, non-core BP. Reason: Downstream complex-sphingolipid process dependent on DEGS1-derived ceramide; secondary to the core ceramide-synthesis function. Supporting Evidence: PMID:24209621 OSBP-mediated back transfer of PI(4)P might coordinate the transfer of other lipid species at the ER-Golgi interface |
| GO:0006688 glycosphingolipid biosynthetic process | IDA PMID:34080016 Glucosylceramide and galactosylceramide, small glycosphingol... | KEEP AS NON CORE | Summary: Experimental (IDA) annotation to glycosphingolipid biosynthetic process. Glucosyl- and galactosyl-ceramides are built from ceramide, the product of DEGS1, so DEGS1 feeds glycosphingolipid synthesis. Downstream, non-core role. Reason: DEGS1 supplies ceramide for downstream glycosphingolipid synthesis; secondary to the core desaturase function. Supporting Evidence: PMID:34080016 GlcCer is a founder molecule for synthesis of hundreds of glycosphingolipids (GSLs) |
| GO:0046513 ceramide biosynthetic process | IDA PMID:16120614 Serinc, an activity-regulated protein family, incorporates s... | ACCEPT | Summary: Experimental (IDA) annotation to ceramide biosynthetic process. The cited study of the Serinc protein family placed DEGS1 among the ER sphingolipid-biosynthetic enzymes; the experimental curator read the full text. Correct core BP. Reason: Core biological process of DEGS1; ceramide biosynthesis via delta-4 desaturation. Supporting Evidence: PMID:16120614 A Serinc protein forms an intracellular complex with key enzymes involved in serine and sphingolipid biosyntheses |
| GO:0098554 cytoplasmic side of endoplasmic reticulum membrane | IDA PMID:16120614 Serinc, an activity-regulated protein family, incorporates s... | ACCEPT | Summary: Experimental (IDA) is_active_in the cytoplasmic side of the ER membrane, consistent with the cytosolic orientation of the de novo sphingolipid-synthesis machinery and with Reactome's placement of DEGS1 on the cytosolic ER face. Reason: Correct, specific active-site topology of DEGS1 at the cytosolic face of the ER. Supporting Evidence: PMID:16120614 co-localizes with lipid biosynthetic enzymes in endoplasmic reticulum membranes Reactome:R-HSA-428259 enzyme associated with the cytosolic face of the endoplasmic reticulum |
| GO:0050251 retinol isomerase activity | IDA PMID:23143414 Identification of DES1 as a vitamin A isomerase in MΓΌller gl... | KEEP AS NON CORE | Summary: Experimental (IDA) demonstration that DES1 is a retinol (vitamin A) isomerase (isomerase-2) in retinal Muller cells: purified DES1 has robust retinol-isomerase activity, it coimmunoprecipitates with CRALBP, and the activity is unique to DES1 among membrane desaturases. Genuine moonlighting activity, distinct from the core ceramide role. Reason: Well-supported second enzymatic activity but tissue-restricted (retina) and distinct from the primary de novo ceramide-synthesis function; keep as non-core. Supporting Evidence: PMID:23143414 retinol-isomerase activity is a unique feature of DES1, and not a general property of membrane desaturases or diiron-binding proteins PMID:23143414 coimmunoprecipitates with cellular retinaldehyde binding protein (CRALBP) |
| GO:0042284 sphingolipid delta-4 desaturase activity | IMP PMID:30620337 Loss of the sphingolipid desaturase DEGS1 causes hypomyelina... | ACCEPT | Summary: IMP evidence from the leukodystrophy study: loss of DEGS1 function (patient variants) abolishes the delta-4 desaturase step, with accumulation of dihydroceramide. Supports the core molecular function. Reason: Disease-variant/loss-of-function evidence confirms the core desaturase activity. Supporting Evidence: PMID:30620337 This enzyme catalyzes the insertion of a Ξ4,5- trans double bond into dihydroceramide (DhCer) to convert it to ceramide (Cer), in the final step of the de novo Cer biosynthesis pathway |
| GO:0043217 myelin maintenance | IMP PMID:30620337 Loss of the sphingolipid desaturase DEGS1 causes hypomyelina... | KEEP AS NON CORE | Summary: IMP annotation to myelin maintenance based on DEGS1-loss causing hypomyelinating leukodystrophy (HLD18). The dihydroceramide/ceramide imbalance disrupts myelin development and maintenance. This is a physiological consequence of the enzyme's lipid-metabolic role rather than a direct molecular function, but is experimentally supported. Reason: Tissue-level physiological role downstream of the core ceramide-synthesis function; important for disease but not the core molecular activity. Supporting Evidence: PMID:30620337 suggesting a critical role of DEGS1 in myelin development and maintenance |
| GO:0043217 myelin maintenance | IMP PMID:30620338 DEGS1-associated aberrant sphingolipid metabolism impairs ne... | KEEP AS NON CORE | Summary: IMP annotation to myelin maintenance from the second HLD18 study, where DEGS1 dysfunction causes hypomyelination and degeneration of the nervous system. Same downstream physiological role as above. Reason: Non-core physiological/disease role secondary to the core lipid-desaturase function. Supporting Evidence: PMID:30620338 DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6799350 | MARK AS OVER ANNOTATED | Summary: Plasma membrane localization from a Reactome neutrophil-degranulation pathway (specific granule exocytosis). This reflects bulk granule/membrane proteomics, not a functional DEGS1 site; DEGS1 acts at the ER, not the plasma membrane. Reason: Over-annotation from a granule-membrane proteomics pathway; inconsistent with the established ER localization and function of DEGS1. Supporting Evidence: Reactome:R-HSA-6799350 Secondary (specific) granules are peroxidase-negative and rich in antimicrobial substances |
| GO:0035579 specific granule membrane | TAS Reactome:R-HSA-6799350 | MARK AS OVER ANNOTATED | Summary: Specific granule membrane localization from the same neutrophil-degranulation pathway. Reflects granule-membrane proteomics rather than a functional DEGS1 location. Reason: Over-annotation; not the functional site of the ER-resident desaturase. Supporting Evidence: Reactome:R-HSA-6799350 Secondary (specific) granules are peroxidase-negative and rich in antimicrobial substances |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-428259 | ACCEPT | Summary: Reactome traceable assertion of ER membrane localization for the DEGS1 desaturation reaction. Correct core localization. Reason: Consistent with the ER as the functional site of DEGS1. Supporting Evidence: Reactome:R-HSA-428259 enzyme associated with the cytosolic face of the endoplasmic reticulum |
| GO:0009055 electron transfer activity | TAS PMID:9188692 The product of the MLD gene is a member of the membrane fatt... | MARK AS OVER ANNOTATED | Summary: Electron transfer activity assigned from the desaturase family context. DEGS1 receives electrons from cytochrome b5 to drive desaturation, but it is the terminal desaturase acceptor, not an electron-carrier; this activity is better captured by the desaturase MF and its di-iron/cytochrome-b5 coupling. Reason: Mechanistically peripheral; DEGS1 is the desaturase, not an electron-transfer protein. The core MF (GO:0042284) captures the redox chemistry. Supporting Evidence: PMID:23143414 DES1 is coupled to the cytochrome b5 electron-transport chain, and acts via a free-radical mechanism |
| GO:0005783 endoplasmic reticulum | TAS PMID:9188692 The product of the MLD gene is a member of the membrane fatt... | ACCEPT | Summary: ER localization (parent of ER membrane) from the original MLD cloning study. Correct but less specific than the ER membrane annotation. Reason: Correct localization; a valid, if less specific, parent of endoplasmic reticulum membrane. Supporting Evidence: PMID:9188692 MLD is widely expressed in human tissues and is localized to the endoplasmic reticulum |
| GO:0005886 plasma membrane | TAS PMID:9188692 The product of the MLD gene is a member of the membrane fatt... | MARK AS OVER ANNOTATED | Summary: Plasma membrane localization traced to the 1997 MLD cloning paper, which localized the protein to the ER (and reported detergent-extractable membrane association), not the plasma membrane. This appears to be an over-annotation; DEGS1 is an ER/mitochondrial protein. Reason: Inconsistent with the ER localization reported in the same paper and with all other evidence; likely an over-broad membrane call. Supporting Evidence: PMID:9188692 MLD is widely expressed in human tissues and is localized to the endoplasmic reticulum |
| GO:0006636 unsaturated fatty acid biosynthetic process | TAS PMID:9188692 The product of the MLD gene is a member of the membrane fatt... | MARK AS OVER ANNOTATED | Summary: Annotation to unsaturated fatty acid biosynthesis, dating from when DEGS1 was known only as a membrane fatty acid desaturase family member. DEGS1 desaturates the sphingoid base of dihydroceramide, not free fatty acids; the ceramide/sphingolipid biosynthetic process terms are the accurate BPs. Reason: Misleading generalization from family membership; the true substrate is dihydroceramide, not a fatty acid, so this BP mischaracterizes the reaction. Supporting Evidence: PMID:9188692 We have cloned a new member of the human membrane fatty acid (lipid) desaturase gene family, MLD PMID:23143414 DES1 introduces a 4,5-trans-double bond in dihydroceramide as the final step in ceramide synthesis |
| GO:0016020 membrane | TAS PMID:9188692 The product of the MLD gene is a member of the membrane fatt... | MARK AS OVER ANNOTATED | Summary: Generic membrane localization from the original cloning study, which showed DEGS1/MLD is a multi-pass membrane protein. Correct but subsumed by the specific ER membrane annotation. Reason: Root-level term superseded by endoplasmic reticulum membrane. Supporting Evidence: PMID:9188692 MLD is widely expressed in human tissues and is localized to the endoplasmic reticulum |
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Download this section (compressed HTML)Q: Is the retinol (vitamin A) isomerase activity of DES1 a physiologically significant second function outside the retina, and does it share the di-iron active site with the dihydroceramide desaturase reaction?
Q: What determines the partitioning of DEGS1 between the ER and mitochondria, and does the mitochondrial (myristoylated) pool have a distinct pro-apoptotic ceramide-signaling role in vivo?
Experiment: Structure-function analysis of the three histidine boxes and di-iron center to define the catalytic residues required for dihydroceramide desaturation versus retinol isomerization.
Experiment: Lipidomic and myelination phenotyping of DEGS1 HLD18 patient variants in oligodendrocyte models to quantify the dihydroceramide/ceramide imbalance and test substrate-reduction (e.g. CerS-inhibitor) rescue.
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