SC5D encodes lathosterol oxidase (sterol-C5-desaturase / delta7-sterol 5(6)-desaturase; EC 1.14.19.20), a non-heme di-iron oxidoreductase of the sterol desaturase family that is anchored as a multi-pass protein in the endoplasmic reticulum membrane. It introduces the C5-6 double bond into lathosterol, converting it to 7-dehydrocholesterol (7-DHC) using molecular oxygen and electrons delivered from cytochrome b5. This is the penultimate step of cholesterol biosynthesis (the Kandutsch-Russell arm), immediately upstream of DHCR7, which reduces 7-DHC to cholesterol; the enzyme can act on additional Delta(7)-sterols such as 5alpha-cholesta-7,24-dien-3beta-ol in the Bloch arm. The three conserved histidine-box motifs coordinate the di-iron center that constitutes the active site. Loss-of-function variants cause lathosterolosis, an autosomal recessive disorder with elevated lathosterol and a Smith-Lemli-Opitz-like multiple-malformation / dysmorphism phenotype with liver disease and lysosomal storage; the mouse knockout is perinatal-lethal with craniofacial and limb patterning defects consistent with impaired hedgehog signalling from cholesterol deficiency. Because its product 7-DHC is a highly reactive radical-trapping sterol, SC5D also indirectly modulates ferroptosis sensitivity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that SC5D acts in the endoplasmic reticulum membrane. This matches the experimentally determined subcellular location and the multi-pass membrane topology predicted from the sequence. Reason: SC5D is a sterol desaturase-family enzyme of cholesterol biosynthesis, a pathway localized to the ER membrane; the human protein was shown to be an integral ER membrane protein experimentally (PMID:10786622). Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Endoplasmic reticulum membrane |
| GO:0050046 delta7-sterol 5(6)-desaturase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference of the precise catalytic activity: SC5D introduces the C5(6) double bond into Delta(7)-sterols. This is the enzyme's core molecular function and is confirmed experimentally. Reason: Directly supported by cloning/complementation and by the UniProt CATALYTIC ACTIVITY (RHEA:54320/46556; EC 1.14.19.20). Represents the core MF of the gene. Supporting Evidence: PMID:10786622 introduce C5-6 double bond into lathosterol in cholesterol biosynthesis |
| GO:0000248 C-5 sterol desaturase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference of C-5 sterol desaturase activity, the more general parent of the specific Delta(7)-sterol 5(6)-desaturase reaction. Correct family-level molecular function. Reason: Consistent with the sterol desaturase family assignment and experimental characterization; a valid, if slightly more general, statement of the core catalytic function. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Belongs to the sterol desaturase family |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO inference of iron ion binding. SC5D is a non-heme di-iron sterol desaturase whose three conserved histidine-box motifs coordinate the catalytic iron center; UniProt lists an Fe cation cofactor. Reason: Well-supported for this enzyme family: the His-box motifs (138-143, 151-155, 228-233) form the metal-binding active site and the cofactor is an Fe cation, so iron ion binding is an accurate molecular function. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Name=Fe cation file:human/SC5D/SC5D-uniprot.txt The histidine box domains may contain the active site |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniProt/rat-ortholog) transfer of ER membrane localization. Redundant with the experimental IDA and IBA ER-membrane annotations and consistent with the multi-pass membrane topology. Reason: Correct localization, independently supported by the human IDA (PMID:10786622) and by the predicted transmembrane helices. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Endoplasmic reticulum membrane |
| GO:0008610 lipid biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO inference of the broad process "lipid biosynthetic process". SC5D acts in cholesterol (a sterol lipid) biosynthesis, so this is correct but general relative to the specific cholesterol/sterol biosynthesis terms also annotated. Reason: Not wrong: cholesterol biosynthesis is-a lipid biosynthetic process. It is a broad parent, but per curation guidance broad correct IEA parents can be accepted; the more specific term (GO:0006695) captures the core process. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Steroid biosynthesis; cholesterol biosynthesis |
| GO:0050046 delta7-sterol 5(6)-desaturase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniProt, via rat ortholog and RHEA/EC mapping) transfer of the precise Delta(7)-sterol 5(6)-desaturase activity. Redundant with the IBA and IDA/EXP annotations of the same activity. Reason: Correct core catalytic function backed by the RHEA reactions and EC 1.14.19.20 in the UniProt record. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt EC=1.14.19.20 |
| GO:0000248 C-5 sterol desaturase activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara ortholog transfer (from rat) of C-5 sterol desaturase activity. Consistent with the experimental and phylogenetic annotations of the same family-level function. Reason: Accurate family-level molecular function; redundant with the IBA/EXP annotations of GO:0000248. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Belongs to the sterol desaturase family |
| GO:0006695 cholesterol biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniProt/UniPathway) transfer of cholesterol biosynthetic process. SC5D catalyzes the penultimate step of cholesterol biosynthesis, so this is the correct core biological process. Reason: Directly matches the enzyme's role and the UniProt PATHWAY statement; independently supported by human IDA and disease evidence. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Steroid biosynthesis; cholesterol biosynthesis |
| GO:0006695 cholesterol biosynthetic process | TAS Reactome:R-HSA-6807047 | ACCEPT | Summary: Reactome (TAS) placement of SC5D in cholesterol biosynthesis via the desmosterol/Bloch pathway. Correct: SC5D also desaturates the Bloch-arm intermediate 5alpha-cholesta-7,24-dien-3beta-ol. Reason: SC5D participates in both the Bloch and Kandutsch-Russell arms; its Delta(7)-sterol 5(6)-desaturase activity applies to the corresponding Bloch intermediate. Core biological process. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Steroid biosynthesis; cholesterol biosynthesis |
| GO:0006695 cholesterol biosynthetic process | TAS Reactome:R-HSA-9969901 | ACCEPT | Summary: Reactome (TAS) placement of SC5D in cholesterol biosynthesis from zymosterol (modified Kandutsch-Russell pathway), the lathosterol arm in which SC5D acts. Correct core biological process. Reason: This is the canonical arm containing the SC5D-catalyzed lathosterol -> 7-dehydrocholesterol step; well supported. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Catalyzes the penultimate step |
| GO:0050046 delta7-sterol 5(6)-desaturase activity | EXP PMID:38297129 7-Dehydrocholesterol is an endogenous suppressor of ferropto... | ACCEPT | Summary: Experimental (EXP) annotation of Delta(7)-sterol 5(6)-desaturase activity from the Nature ferroptosis study, which characterized SC5D FUNCTION and CATALYTIC ACTIVITY as the enzyme producing 7-DHC. Confirms the core catalytic function. Reason: Experimental support for the precise reaction; underpins the UniProt CATALYTIC ACTIVITY entries. Core molecular function. Supporting Evidence: PMID:38297129 an unexpected prosurvival file:human/SC5D/SC5D-uniprot.txt Catalyzes the penultimate step |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:10786622 cDNA cloning of the mammalian sterol C5-desaturase and the e... | ACCEPT | Summary: Experimental (IDA) determination that SC5D is an integral endoplasmic reticulum membrane protein, from the cloning study that also demonstrated the enzymatic activity by yeast-mutant complementation. Reason: Primary experimental evidence for the ER-membrane location; the core cellular component for this enzyme. Supporting Evidence: PMID:10786622 Mammalian SC5D was presumed as an integral file:human/SC5D/SC5D-uniprot.txt Endoplasmic reticulum membrane |
| GO:0006695 cholesterol biosynthetic process | IDA PMID:10786622 cDNA cloning of the mammalian sterol C5-desaturase and the e... | ACCEPT | Summary: Experimental (IDA) annotation to cholesterol biosynthetic process from the cloning/complementation study, which functionally showed SC5D introduces the C5-6 double bond into lathosterol in cholesterol biosynthesis. This is the correct core biological process. Reason: Direct experimental support for SC5D's role in cholesterol biosynthesis. The more specific child term previously proposed here as a NEW annotation (GO:0033490, cholesterol biosynthetic process via lathosterol) is obsolete in the GO release 2026-07-26 with replaced_by GO:0006695, so this term is the core process annotation. Supporting Evidence: PMID:10786622 introduce C5-6 double bond into lathosterol in cholesterol biosynthesis |
| GO:0050046 delta7-sterol 5(6)-desaturase activity | IDA PMID:10786622 cDNA cloning of the mammalian sterol C5-desaturase and the e... | ACCEPT | Summary: Experimental (IDA) annotation of Delta(7)-sterol 5(6)-desaturase activity. The human cDNA functionally complemented a sterol-C5-desaturase-defective yeast mutant, directly demonstrating the catalytic activity. Reason: Direct experimental demonstration of the core catalytic function via yeast complementation. Supporting Evidence: PMID:10786622 functional complementation of a defective yeast mutant proves that the human and |
| GO:0110076 negative regulation of ferroptosis | IMP PMID:38297129 7-Dehydrocholesterol is an endogenous suppressor of ferropto... | KEEP AS NON CORE | Summary: Loss-of-function (IMP) evidence that SC5D negatively regulates ferroptosis. As a distal-cholesterol-biosynthesis enzyme, SC5D produces 7-DHC, a potent radical-trapping sterol that shields (phospho)lipids from autoxidation; loss of SC5D lowers 7-DHC and sensitizes cells to ferroptosis. This is a real but indirect, non-core role mediated by the 7-DHC product. Reason: Supported experimentally, but the effect is a downstream/indirect consequence of SC5D's catalytic product (7-DHC) rather than a distinct molecular activity of SC5D itself; the core function is C5-sterol desaturation in cholesterol biosynthesis. Keep as a non-core process. Supporting Evidence: PMID:38297129 we now show that 7-DHC accumulation |
| GO:0110076 negative regulation of ferroptosis | IMP PMID:38297130 7-Dehydrocholesterol dictates ferroptosis sensitivity. | KEEP AS NON CORE | Summary: Loss-of-function (IMP) evidence from a genome-wide CRISPR screen: SC5D is an anti-ferroptotic distal-cholesterol-biosynthesis gene. SC5D knockout increased ferroptosis susceptibility and lowered 7-DHC, and re-expression rescued the phenotype. Indirect, non-core role via the 7-DHC product. Reason: Well supported experimentally in this full-text study, but mechanistically the protection is conferred by the SC5D reaction product 7-DHC, not by an independent SC5D activity; keep as a non-core biological process. Supporting Evidence: PMID:38297130 individual deletion of CYP51A1, MSMO1, EBP and SC5D in HEK293T cells increased the susceptibility to ferroptosis PMID:38297130 Re-expression of SC5D reversed the severity of ferroptosis induced by RSL3 in SC5D KO cells |
| GO:0000248 C-5 sterol desaturase activity | EXP PMID:12189593 Lathosterolosis, a novel multiple-malformation/mental retard... | ACCEPT | Summary: Experimental (EXP) annotation of C-5 sterol desaturase activity based on the first human lathosterolosis patient, in whom the SC5D-catalyzed conversion of lathosterol to 7-dehydrocholesterol was blocked and the enzyme activity was deficient. Supports the core catalytic function. Reason: Human patient data directly link SC5D to C-5 sterol desaturase activity (loss of activity blocks lathosterol -> 7-DHC). Core molecular function. Supporting Evidence: PMID:12189593 showing a block in the conversion of lathosterol into PMID:12189593 was deficient in the patient's |
| GO:0000248 C-5 sterol desaturase activity | EXP PMID:12812989 Lathosterolosis: an inborn error of human and murine cholest... | ACCEPT | Summary: Experimental (EXP) annotation of C-5 sterol desaturase activity supported by the human patient and Sc5d-null mouse study, which established that lathosterol 5-desaturase catalyzes the conversion of lathosterol to 7-dehydrocholesterol in the next-to-last step of cholesterol synthesis. Reason: Combined human and mouse loss-of-function evidence for the core catalytic function; elevated lathosterol and decreased cholesterol on enzyme loss. Supporting Evidence: PMID:12812989 catalyzes the conversion of lathosterol to PMID:12812989 had elevated lathosterol and decreased cholesterol |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1655852 | ACCEPT | Summary: Reactome (TAS) ER-membrane localization associated with expression of lathosterol oxidase (SC5D). Consistent with the experimental IDA and the multi-pass membrane topology. Reason: Redundant with the experimentally determined ER membrane location; correct core cellular component. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-195664 | ACCEPT | Summary: Reactome (TAS) ER-membrane localization for the SC5D-catalyzed desaturation of cholesta-7,24-dien-3beta-ol (a Bloch-arm reaction). Consistent with the established ER location. Reason: Correct core cellular component; the reaction it is attached to takes place in the ER, as noted by Reactome, and matches the human IDA. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-6807053 | ACCEPT | Summary: Reactome (TAS) ER-membrane localization for the SC5D reaction that desaturates lathosterol to 7-dehydrocholesterol. Consistent with the experimental and predicted ER-membrane location. Reason: Correct core cellular component; matches human IDA and topology. Supporting Evidence: file:human/SC5D/SC5D-uniprot.txt Endoplasmic reticulum membrane |
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Download this section (compressed HTML)Q: Is SC5D's role in modulating ferroptosis (via 7-DHC) physiologically relevant in normal tissues, or primarily a cancer-context phenomenon?
Q: To what extent does SC5D contribute to the Bloch versus Kandutsch-Russell arms of cholesterol biosynthesis in different human tissues?
Experiment: Reconstitute purified human SC5D with cytochrome b5 / cytochrome b5 reductase to measure the di-iron-dependent desaturation kinetics on lathosterol versus 5alpha-cholesta-7,24-dien-3beta-ol and confirm cofactor stoichiometry.
Hypothesis: SC5D is a non-heme di-iron desaturase that uses electrons from cytochrome b5 to desaturate multiple Delta(7)-sterol substrates.
Experiment: Site-directed mutagenesis of the three histidine-box motifs to test their requirement for iron binding and catalysis, complementing the disease-variant (R29Q, Y46S, G211D) structure-function analysis.
Hypothesis: The conserved histidine-box motifs coordinate the catalytic di-iron center and are essential for C5-sterol desaturase activity.
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