DHCR24 encodes Delta(24)-sterol reductase (also known as seladin-1), the terminal enzyme in cholesterol biosynthesis that catalyzes the reduction of the delta-24 double bond of sterol intermediates, primarily converting desmosterol to cholesterol. The enzyme is FAD-dependent, requires NADPH as a cofactor, and is localized to the endoplasmic reticulum membrane. DHCR24 also confers neuroprotection against oxidative stress and amyloid-beta toxicity. Mutations in DHCR24 cause desmosterolosis, a rare autosomal recessive disorder of cholesterol biosynthesis characterized by multiple congenital anomalies and elevated desmosterol levels.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | REMOVE | Summary: IBA annotation for cytoplasm is incorrect. DHCR24 is an integral ER membrane protein with its catalytic domain oriented toward the cytoplasm [PMID:11007892, PMID:22010141]. The cytoplasmic annotation reflects the cytoplasmic orientation of the catalytic domain rather than true cytoplasmic localization. Reason: This annotation incorrectly implies cytoplasmic localization when the protein is actually an integral ER membrane protein with a cytoplasmic-facing catalytic domain. The UniProt record and experimental evidence clearly establish ER membrane as the primary localization [PMID:11007892, PMID:22010141]. Supporting Evidence: PMID:22010141 We showed that full-length DHCR24 is localized to the membrane of ER, whereas the predicted transmembrane (TM) domain-deleted DHCR24 mutation is localized to the cytoplasm. The change of DHCR24 localization suggests that the N-terminal TM domain is essential for the ER membrane targeting of DHCR24. |
| GO:0008202 steroid metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for steroid metabolic process is accurate. DHCR24 is a key enzyme in cholesterol biosynthesis, which is part of steroid metabolism. The annotation is at an appropriate level of specificity given that cholesterol is the precursor for all steroid hormones. Reason: DHCR24 clearly participates in steroid metabolism through its essential role in cholesterol biosynthesis. Cholesterol is both a steroid itself and the precursor for all steroid hormones. The IBA annotation is well-supported by experimental evidence [PMID:11519011]. Supporting Evidence: PMID:11519011 We identified the human DHCR24 cDNA, by the similarity between the encoded protein and a recently characterized plant enzymeβDWF1/DIM, from Arabidopsis thaliana βcatalyzing a different but partially similar reaction in steroid/sterol biosynthesis in plants. Heterologous expression, in the yeast Saccharomyces cerevisiae, of the DHCR24 cDNA, followed by enzyme-activity measurements, confirmed that it encodes DHCR24 |
| GO:0000246 Delta24(24-1) sterol reductase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for Delta24(24-1) sterol reductase activity is correct and represents a core molecular function. This term specifically describes the enzymatic activity of DHCR24 in reducing the delta-24 double bond in sterols, which is directly validated by experimental evidence [PMID:11519011]. Reason: This is the core molecular function of DHCR24, experimentally validated through multiple studies. The enzyme specifically catalyzes the reduction of the delta-24 double bond in sterol intermediates, including desmosterol, lanosterol, and zymosterol [PMID:11519011]. Supporting Evidence: PMID:11519011 Conversion of desmosterol to cholesterol by DHCR24 in vitro is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate and is increased twofold by the addition of FAD to the assay |
| GO:0050614 Delta24-sterol reductase activity | IEA GO_REF:0000003 | ACCEPT | Summary: IEA annotation for Delta24-sterol reductase activity based on EC number mapping. This is essentially the same function as GO:0000246 but with slightly different terminology. Both terms correctly describe the core enzymatic function of DHCR24. Reason: This annotation accurately describes the enzymatic activity of DHCR24. The term is based on EC:1.3.1.72 mapping which is experimentally validated [PMID:11519011]. This is a duplicate of GO:0000246 with different terminology but both are correct. Supporting Evidence: PMID:11519011 enzyme 3Ξ²-hydroxysterol Ξ 24 -reductase (DHCR24), which, in cholesterol biosynthesis, catalyzes the reduction of the Ξ 24 double bond of sterol intermediates |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA annotation for Golgi membrane based on UniProt subcellular location vocabulary. DHCR24 is detected in Golgi to a lesser extent than ER, where cholesterol synthesis occurs [PMID:11007892]. Reason: Golgi localization occurs to a minor extent and is not the primary functionally relevant site. The ER membrane is the established primary location for DHCR24 function in cholesterol biosynthesis. UniProt notes both localizations but emphasizes ER [PMID:11007892]. Supporting Evidence: PMID:11007892 subcellular fractionation and enzyme assays... seladin-1 is predominantly localized within the ER, and to a lesser amount in Golgi complexes |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for endoplasmic reticulum membrane is accurate and represents the primary cellular localization. This is the established site where DHCR24 performs its enzymatic function in cholesterol biosynthesis, confirmed by multiple experimental studies [PMID:11007892, PMID:22010141]. Reason: ER membrane is the correct and primary localization for DHCR24. This is where the enzyme performs its function in cholesterol biosynthesis. Multiple experimental studies confirm this localization [PMID:11007892, PMID:22010141]. Supporting Evidence: PMID:11007892 seladin-1 is predominantly localized within the ER, and to a lesser amount in Golgi complexes |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for lipid metabolic process based on UniProt keyword mapping. This is accurate but very general. More specific terms like cholesterol biosynthetic process (GO:0006695) better describe the function. Reason: While accurate, this is a very broad parent term. DHCR24 does participate in lipid metabolism through its role in cholesterol biosynthesis. However, more specific child terms provide better functional description. Supporting Evidence: PMID:11519011 in cholesterol biosynthesis, catalyzes the reduction of the Ξ 24 double bond of sterol intermediates |
| GO:0006694 steroid biosynthetic process | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for steroid biosynthetic process is accurate. DHCR24 is essential for cholesterol biosynthesis, and cholesterol is both a steroid and the precursor for all steroid hormones. Reason: DHCR24 directly participates in steroid biosynthesis through its essential role in producing cholesterol, which is a steroid molecule and the precursor for all steroid hormones [PMID:11519011]. Supporting Evidence: PMID:11519011 desmosterolosis is a cholesterol-biosynthesis disorder caused by mutations in DHCR24 |
| GO:0006695 cholesterol biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for cholesterol biosynthetic process is accurate and represents a core function. DHCR24 is the terminal enzyme in cholesterol biosynthesis, converting desmosterol to cholesterol [PMID:11519011]. Reason: This is a core biological process for DHCR24. The enzyme catalyzes the final step in cholesterol biosynthesis, converting desmosterol to cholesterol. This is experimentally validated [PMID:11519011]. Supporting Evidence: PMID:11519011 Conversion of desmosterol to cholesterol by DHCR24 in vitro is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate |
| GO:0008202 steroid metabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate IEA annotation for steroid metabolic process (also annotated with IBA evidence). The annotation is accurate as DHCR24 participates in cholesterol/steroid metabolism. Reason: Duplicate but accurate annotation. DHCR24 participates in steroid metabolism through cholesterol biosynthesis. The IBA version of this annotation was already accepted. Supporting Evidence: PMID:11519011 cholesterol-biosynthesis disorder caused by mutations in DHCR24 |
| GO:0008203 cholesterol metabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for cholesterol metabolic process is accurate. DHCR24 is directly involved in cholesterol metabolism as the terminal enzyme in cholesterol biosynthesis. Reason: DHCR24 is a key enzyme in cholesterol metabolism, specifically in the biosynthetic pathway. The annotation accurately captures this core function [PMID:11519011]. Supporting Evidence: PMID:11519011 enzyme 3Ξ²-hydroxysterol Ξ 24 -reductase (DHCR24), which, in cholesterol biosynthesis, catalyzes the reduction of the Ξ 24 double bond of sterol intermediates |
| GO:0016126 sterol biosynthetic process | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for sterol biosynthetic process is accurate. DHCR24 is essential for sterol biosynthesis, specifically in the final step of converting sterol intermediates to cholesterol. Reason: DHCR24 is a key enzyme in sterol biosynthesis, catalyzing the reduction of the delta-24 double bond in various sterol intermediates including desmosterol, lanosterol, and zymosterol [PMID:11519011]. Supporting Evidence: PMID:11519011 catalyzes the reduction of the Ξ 24 double bond of sterol intermediates |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for oxidoreductase activity is accurate but very general. DHCR24 is indeed an oxidoreductase, specifically a FAD-dependent oxidoreductase that uses NADPH. More specific terms like GO:0016628 provide better functional description. Reason: DHCR24 is a FAD-dependent oxidoreductase that catalyzes redox reactions using NADPH as electron donor. While accurate, more specific child terms better describe the function [PMID:11519011]. Supporting Evidence: PMID:11519011 member of a recently defined family of flavin adenine dinucleotide (FAD)-dependent oxidoreductases |
| GO:0050660 flavin adenine dinucleotide binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation for FAD binding based on InterPro domain mapping. This is accurate as DHCR24 contains a FAD-binding domain and FAD enhances its enzymatic activity [PMID:11519011]. Reason: DHCR24 is a FAD-dependent oxidoreductase with a conserved FAD-binding domain. Addition of FAD increases enzymatic activity twofold, suggesting noncovalent FAD binding [PMID:11519011]. Supporting Evidence: PMID:11519011 Conversion of desmosterol to cholesterol by DHCR24 in vitro is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate and is increased twofold by the addition of FAD to the assay |
| GO:0071949 FAD binding | IEA GO_REF:0000002 | ACCEPT | Summary: Duplicate IEA annotation for FAD binding (same as GO:0050660). The annotation is accurate as DHCR24 is a FAD-dependent enzyme. Reason: Duplicate of GO:0050660 but accurate. DHCR24 requires FAD as a cofactor for its oxidoreductase activity [PMID:11519011]. Supporting Evidence: PMID:11519011 member of a recently defined family of flavin adenine dinucleotide (FAD)-dependent oxidoreductases |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | REMOVE | Summary: Generic protein binding annotation from a large-scale crosslinking mass spectrometry study of intact cell nuclei [PMID:30021884]. The WITH field indicates interaction with PGRMC1 (O00264). The DHCR24-PGRMC1 interaction was detected by crosslinking mass spectrometry (both are ER membrane proteins involved in sterol biology), but the generic protein binding term is uninformative. Reason: Protein binding without specificity is uninformative per curation guidelines. The interaction was detected in a high-throughput crosslinking study and the functional significance of the DHCR24-PGRMC1 interaction is not well characterized. Supporting Evidence: PMID:30021884 Here we use crosslinking mass spectrometry (XL-MS) to chart the protein-protein interactions in intact human nuclei. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: Generic protein binding annotation from OpenCell high-throughput endogenous tagging study [PMID:35271311]. The WITH field indicates interaction with PGRMC1 (O00264). While PGRMC1 is a known sterol-binding ER membrane protein, the generic protein binding term is uninformative per curation guidelines. Reason: Non-specific protein binding annotation from high-throughput study lacks functional context. The curation guidelines explicitly state to avoid this vague term. A more specific MF term should be used if the interaction is validated. Supporting Evidence: PMID:35271311 We combined genome engineering, confocal live-cell imaging, mass spectrometry, and data science to systematically map the localization and interactions of human proteins. |
| GO:0006695 cholesterol biosynthetic process | TAS Reactome:R-HSA-191273 | ACCEPT | Summary: TAS annotation from Reactome for cholesterol biosynthetic process. This is a core function of DHCR24 as the terminal enzyme in cholesterol biosynthesis. Reason: DHCR24 is the terminal enzyme in cholesterol biosynthesis. This Reactome annotation accurately captures this core biological process [PMID:11519011]. Supporting Evidence: PMID:11519011 desmosterolosis is a cholesterol-biosynthesis disorder caused by mutations in DHCR24 |
| GO:0033489 cholesterol biosynthetic process via desmosterol | TAS Reactome:R-HSA-6807047 | MODIFY | Summary: TAS annotation from Reactome for cholesterol biosynthesis via desmosterol. This is the primary pathway where DHCR24 functions, converting desmosterol to cholesterol in the Bloch pathway. Reason: This specifically describes the Bloch pathway where DHCR24 catalyzes the conversion of desmosterol to cholesterol. This is the primary route and core function of DHCR24 [PMID:11519011]. GO:0033489 is obsolete in the GO release 2026-07-26 as a pathway variant (replaced_by GO:0006695); the replacement duplicates the existing cholesterol biosynthetic process annotations. Proposed replacements: cholesterol biosynthetic process Supporting Evidence: PMID:11519011 Conversion of desmosterol to cholesterol by DHCR24 in vitro is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate |
| GO:0033490 cholesterol biosynthetic process via lathosterol | TAS Reactome:R-HSA-6807062 | MODIFY | Summary: TAS annotation from Reactome for cholesterol biosynthesis via lathosterol (Kandutsch-Russell pathway). DHCR24 can act on various sterol intermediates including those in this alternate pathway. Reason: DHCR24 functions in both the Bloch and Kandutsch-Russell pathways of cholesterol biosynthesis. It can reduce the delta-24 double bond in various sterol intermediates [PMID:25637936]. GO:0033490 is obsolete in the GO release 2026-07-26 as a pathway variant (replaced_by GO:0006695); the replacement duplicates the existing cholesterol biosynthetic process annotations. Proposed replacements: cholesterol biosynthetic process Supporting Evidence: PMID:25637936 DHCR24 is positioned not only at the end of the Bloch pathway but also at the gateway of the Kandutsch-Russell pathway... able to act on any of the intermediates in the Bloch pathway to divert them into the Kandutsch-Russell pathway |
| GO:0007265 Ras protein signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation for Ras signaling transferred from orthologs. While DHCR24/seladin-1 mediates response to Ras-induced senescence [PMID:15577914], this is a stress response function rather than core Ras signaling. Reason: DHCR24/seladin-1 responds to oncogenic Ras stress but is not a core component of Ras signaling. It mediates Ras-induced senescence through p53 interactions [PMID:15577914]. This is a secondary, non-core function. Supporting Evidence: PMID:15577914 Seladin-1 (also known as Dhcr24) as a key mediator of Ras-induced senescence. Following oncogenic and oxidative stress, Seladin-1 binds p53 amino terminus |
| GO:0008104 intracellular protein localization | IEA GO_REF:0000107 | REMOVE | Summary: IEA annotation for intracellular protein localization from ortholog transfer. This is vague and lacks supporting evidence for DHCR24 having a role in localizing other proteins. Reason: No evidence that DHCR24 functions in protein localization. This appears to be an over-annotation from ortholog transfer without validation. The primary function is enzymatic in cholesterol biosynthesis. Supporting Evidence: PMID:11519011 enzyme 3Ξ²-hydroxysterol Ξ 24 -reductase (DHCR24), which, in cholesterol biosynthesis, catalyzes the reduction of the Ξ 24 double bond of sterol intermediates |
| GO:0008285 negative regulation of cell population proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation for negative regulation of proliferation. DHCR24/seladin-1 does mediate Ras-induced senescence and suppresses transformation [PMID:15577914], supporting an anti-proliferative role. Reason: DHCR24/seladin-1 mediates oncogenic stress-induced senescence and suppresses cellular transformation [PMID:15577914]. This is a validated but non-core function distinct from its primary enzymatic role. Supporting Evidence: PMID:15577914 Ablation of Seladin-1 causes the bypass of Ras-induced senescence in rodent and human fibroblasts, and allows Ras to transform these cells |
| GO:0009725 response to hormone | IEA GO_REF:0000107 | REMOVE | Summary: IEA annotation for response to hormone from ortholog transfer. This is too vague without specifying which hormones. Cholesterol biosynthesis is regulated by hormones but this annotation lacks specificity. Reason: Overly broad annotation without supporting evidence for specific hormone responses by DHCR24. While cholesterol biosynthesis is hormonally regulated, this vague annotation provides no functional insight. Supporting Evidence: PMID:11519011 enzyme 3Ξ²-hydroxysterol Ξ 24 -reductase (DHCR24), which, in cholesterol biosynthesis, catalyzes the reduction of the Ξ 24 double bond of sterol intermediates |
| GO:0009888 tissue development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation for tissue development from ortholog transfer. While DHCR24 mutations cause developmental anomalies in desmosterolosis, this is an indirect effect of cholesterol deficiency. Reason: DHCR24 deficiency causes developmental defects in desmosterolosis patients [PMID:11519011], but this is secondary to cholesterol deficiency rather than a direct developmental role. Non-core but valid consequence. Supporting Evidence: PMID:11519011 Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies |
| GO:0016125 sterol metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation for sterol metabolic process is accurate. DHCR24 is directly involved in sterol metabolism through its enzymatic activity on various sterol intermediates. Reason: DHCR24 directly participates in sterol metabolism by catalyzing the reduction of the delta-24 double bond in multiple sterol intermediates [PMID:11519011]. Supporting Evidence: PMID:11519011 catalyzes the reduction of the Ξ 24 double bond of sterol intermediates |
| GO:0030539 male genitalia development | IEA GO_REF:0000107 | REMOVE | Summary: IEA annotation for male genitalia development from ortholog transfer. While desmosterolosis can include urogenital anomalies, this is too specific and indirect. Reason: Over-specific developmental annotation. While desmosterolosis includes congenital anomalies, singling out male genitalia development is not supported as a specific function of DHCR24. This is an indirect effect of cholesterol deficiency. Supporting Evidence: PMID:11519011 Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies |
| GO:0031639 plasminogen activation | IEA GO_REF:0000107 | REMOVE | Summary: IEA annotation for plasminogen activation from ortholog transfer. No evidence supports DHCR24 involvement in plasminogen activation. This is an erroneous transfer. Reason: No evidence linking DHCR24 to plasminogen activation. This is an incorrect ortholog transfer. DHCR24 functions in cholesterol biosynthesis, not coagulation/fibrinolysis pathways. Supporting Evidence: PMID:11519011 enzyme 3Ξ²-hydroxysterol Ξ 24 -reductase (DHCR24), which, in cholesterol biosynthesis, catalyzes the reduction of the Ξ 24 double bond of sterol intermediates |
| GO:0042987 amyloid precursor protein catabolic process | IEA GO_REF:0000107 | REMOVE | Summary: IEA annotation for APP catabolism from ortholog transfer. While DHCR24/seladin-1 protects against amyloid-beta toxicity [PMID:11007892], it does not directly catabolize APP. Reason: DHCR24/seladin-1 protects against amyloid-beta toxicity but does not catabolize APP. The protective effect is through reducing oxidative stress and caspase activation, not APP processing [PMID:11007892]. Supporting Evidence: PMID:11007892 Functional expression of seladin-1 in human neuroglioma H4 cells resulted in the inhibition of caspase 3 activation after either AΞ²-mediated toxicity or oxidative stress and protected the cells from apoptotic cell death |
| GO:0043588 skin development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation for skin development from ortholog transfer. While cholesterol is important for skin barrier function, this is an indirect effect of DHCR24 enzymatic activity. Reason: Cholesterol biosynthesis is important for skin development and barrier function. DHCR24 deficiency can affect skin, but this is secondary to its enzymatic role. Non-core but valid indirect function. Supporting Evidence: PMID:11519011 Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies |
| GO:0061024 membrane organization | IEA GO_REF:0000107 | REMOVE | Summary: IEA annotation for membrane organization from ortholog transfer. While cholesterol is crucial for membrane structure, DHCR24 does not directly organize membranes. Reason: DHCR24 produces cholesterol which affects membrane properties, but the enzyme itself does not organize membranes. This is an over-interpretation of its indirect effects through cholesterol production. Supporting Evidence: PMID:11519011 enzyme 3Ξ²-hydroxysterol Ξ 24 -reductase (DHCR24), which, in cholesterol biosynthesis, catalyzes the reduction of the Ξ 24 double bond of sterol intermediates |
| GO:0050614 Delta24-sterol reductase activity | EXP PMID:11519011 Mutations in the 3beta-hydroxysterol Delta24-reductase gene ... | ACCEPT | Summary: Experimental evidence for Delta24-sterol reductase activity from the key paper identifying DHCR24. This is the core molecular function, directly demonstrated through heterologous expression and enzyme activity measurements. Reason: Direct experimental validation of DHCR24 enzymatic activity. The study used heterologous expression in yeast followed by enzyme activity measurements to confirm Delta24-sterol reductase activity [PMID:11519011]. Supporting Evidence: PMID:11519011 Heterologous expression, in the yeast Saccharomyces cerevisiae, of the DHCR24 cDNA, followed by enzyme-activity measurements, confirmed that it encodes DHCR24 |
| GO:0050614 Delta24-sterol reductase activity | TAS Reactome:R-HSA-9755937 | ACCEPT | Summary: TAS annotation from Reactome for Delta24-sterol reductase activity, specifically for lanosterol reduction. This is a validated core molecular function of DHCR24. Reason: DHCR24 catalyzes the reduction of the delta-24 double bond in multiple sterols including lanosterol. This Reactome annotation correctly captures this enzymatic activity [PMID:11519011]. Supporting Evidence: file:human/DHCR24/DHCR24-uniprot.txt Reaction=lanosterol + NADPH + H(+) = 24,25-dihydrolanosterol + NADP(+) |
| GO:0000246 Delta24(24-1) sterol reductase activity | IMP PMID:11519011 Mutations in the 3beta-hydroxysterol Delta24-reductase gene ... | ACCEPT | Summary: IMP evidence for Delta24(24-1) sterol reductase activity from mutant phenotype analysis. Mutations in DHCR24 cause desmosterolosis with accumulation of desmosterol, proving this enzymatic function. Reason: Mutations in DHCR24 cause desmosterolosis with elevated desmosterol levels, directly demonstrating the enzyme's Delta24-sterol reductase activity through mutant phenotype [PMID:11519011]. Supporting Evidence: PMID:11519011 Patients with desmosterolosis have elevated levels of the cholesterol precursor desmosterol, in plasma, tissue, and cultured cells; this abnormality suggests a deficiency of the enzyme 3Ξ²-hydroxysterol Ξ 24 -reductase (DHCR24) |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:11007892 The human DIMINUTO/DWARF1 homolog seladin-1 confers resistan... | ACCEPT | Summary: NAS evidence for ER membrane localization from the seladin-1 paper. Subcellular fractionation confirmed predominant ER localization. This is the primary and functionally relevant cellular location. Reason: Experimental subcellular fractionation demonstrated that seladin-1/DHCR24 is predominantly localized to the ER membrane, where it performs its enzymatic function [PMID:11007892]. Supporting Evidence: PMID:11007892 subcellular fractionation and enzyme assays... seladin-1 is predominantly localized within the ER, and to a lesser amount in Golgi complexes |
| GO:0006695 cholesterol biosynthetic process | IMP PMID:11519011 Mutations in the 3beta-hydroxysterol Delta24-reductase gene ... | ACCEPT | Summary: IMP evidence for cholesterol biosynthetic process from mutant phenotype. DHCR24 mutations cause desmosterolosis with defective cholesterol biosynthesis, proving this core function. Reason: Mutations in DHCR24 cause desmosterolosis, a cholesterol biosynthesis disorder, directly demonstrating the enzyme's essential role in cholesterol biosynthesis [PMID:11519011]. Supporting Evidence: PMID:11519011 Our data demonstrate that desmosterolosis is a cholesterol-biosynthesis disorder caused by mutations in DHCR24 |
| GO:0033489 cholesterol biosynthetic process via desmosterol | IMP PMID:11519011 Mutations in the 3beta-hydroxysterol Delta24-reductase gene ... | MODIFY | Summary: IMP evidence for cholesterol biosynthesis via desmosterol pathway. Patients with DHCR24 mutations accumulate desmosterol, proving this is the enzyme that converts desmosterol to cholesterol. Reason: DHCR24 deficiency causes desmosterol accumulation, directly demonstrating its role in the desmosterol-to-cholesterol conversion in the Bloch pathway [PMID:11519011]. GO:0033489 is obsolete in the GO release 2026-07-26 as a pathway variant (replaced_by GO:0006695); the replacement duplicates the existing cholesterol biosynthetic process annotations. Proposed replacements: cholesterol biosynthetic process Supporting Evidence: PMID:11519011 Patients with desmosterolosis have elevated levels of the cholesterol precursor desmosterol... Conversion of desmosterol to cholesterol by DHCR24 |
| GO:0005515 protein binding | IPI PMID:25637936 The terminal enzymes of cholesterol synthesis, DHCR24 and DH... | REMOVE | Summary: IPI evidence for protein binding with DHCR7. While this specific DHCR7 interaction is functionally important, the generic "protein binding" term should be avoided per curation guidelines. Reason: Generic protein binding annotation should be removed even for specific interactions. The functionally relevant DHCR7 interaction and its regulatory effect on enzyme activity is better captured by more specific functional terms. Supporting Evidence: PMID:25637936 when the DHCR24 gene is knocked down by siRNA, DHCR7 activity is also ablated. Conversely, overexpression of DHCR24 enhances DHCR7 activity, but only when a functional form of DHCR24 is used |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-196417 | ACCEPT | Summary: TAS annotation from Reactome for ER membrane localization. This is the correct primary localization where DHCR24 performs its enzymatic function. Reason: ER membrane is the established localization for DHCR24 where it catalyzes the conversion of desmosterol to cholesterol [PMID:11007892, PMID:22010141]. Supporting Evidence: PMID:22010141 The membrane topological analysis of 3Ξ²-hydroxysteroid-delta24 reductase (DHCR24) on endoplasmic reticulum |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-6807064 | ACCEPT | Summary: Another TAS annotation from Reactome for ER membrane. This is a duplicate but correct annotation for the primary cellular localization. Reason: Duplicate but accurate ER membrane localization annotation from Reactome. Multiple evidence sources confirm this localization [PMID:11007892]. Supporting Evidence: PMID:11007892 seladin-1 is predominantly localized within the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9755937 | ACCEPT | Summary: Another TAS annotation from Reactome for ER membrane. Multiple Reactome pathways correctly place DHCR24 at the ER membrane. Reason: Another duplicate but accurate ER membrane annotation. The ER is where DHCR24 performs its enzymatic function in cholesterol biosynthesis [PMID:11007892]. Supporting Evidence: PMID:11007892 seladin-1 is predominantly localized within the ER |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: HDA evidence for membrane localization from NK cell proteomics study. This is very general compared to the specific ER membrane localization established by other studies. Reason: While less specific than ER membrane annotations, this high-throughput data confirms DHCR24 is membrane-associated, consistent with its ER membrane localization [PMID:19946888]. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells |
| GO:0016628 oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor | IDA PMID:11519011 Mutations in the 3beta-hydroxysterol Delta24-reductase gene ... | ACCEPT | Summary: IDA evidence for specific oxidoreductase activity. This accurately describes DHCR24 mechanism - it reduces C-C double bonds (delta-24) using NADPH as electron donor. Reason: Direct experimental demonstration that DHCR24 is an oxidoreductase acting on CH-CH groups (the delta-24 double bond) with NADPH as acceptor. This is more specific than general oxidoreductase activity [PMID:11519011]. Supporting Evidence: PMID:11519011 Conversion of desmosterol to cholesterol by DHCR24 in vitro is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate |
| GO:0006695 cholesterol biosynthetic process | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for cholesterol biosynthetic process based on sequence similarity. This is a duplicate annotation but correctly identifies a core function. Reason: Sequence similarity-based annotation that correctly identifies DHCR24 role in cholesterol biosynthesis. This is validated by experimental evidence [PMID:11519011]. Supporting Evidence: PMID:11519011 desmosterolosis is a cholesterol-biosynthesis disorder caused by mutations in DHCR24 |
| GO:0019899 enzyme binding | IPI PMID:15577914 Regulation of cellular response to oncogenic and oxidative s... | KEEP AS NON CORE | Summary: IPI evidence for enzyme binding from the seladin-1 stress response paper. DHCR24/seladin-1 binds to Mdm2 (an E3 ubiquitin ligase) to regulate p53. This is a non-core stress response function. Reason: DHCR24/seladin-1 binds the E3 ubiquitin ligase Mdm2 during stress response, affecting p53 regulation. This is a validated but non-core function distinct from its primary enzymatic role [PMID:15577914]. Supporting Evidence: PMID:15577914 Seladin-1 binds p53 amino terminus and displaces E3 ubiquitin ligase Mdm2 from p53... Additionally, Seladin-1 associates with Mdm2 independently of p53 |
| GO:0043588 skin development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for skin development based on sequence similarity. While cholesterol is important for skin, this is an indirect effect of DHCR24 enzymatic function. Reason: Cholesterol biosynthesis impacts skin development and barrier function. DHCR24 deficiency can cause skin abnormalities, but this is secondary to its enzymatic role. Non-core indirect function. Supporting Evidence: PMID:11519011 Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies |
| GO:0005634 nucleus | IDA PMID:15577914 Regulation of cellular response to oncogenic and oxidative s... | KEEP AS NON CORE | Summary: IDA evidence for nuclear localization from stress response study. DHCR24/seladin-1 translocates to the nucleus during oncogenic and oxidative stress [PMID:15577914], though the primary functional localization is ER membrane. Reason: DHCR24/seladin-1 can localize to nucleus during stress response to interact with p53/Mdm2, but this is not the primary localization. Main function occurs at ER membrane [PMID:15577914, PMID:11007892]. Supporting Evidence: PMID:15577914 Following oncogenic and oxidative stress, Seladin-1 binds p53 amino terminus and displaces E3 ubiquitin ligase Mdm2 from p53 |
| GO:0005783 endoplasmic reticulum | IDA PMID:11007892 The human DIMINUTO/DWARF1 homolog seladin-1 confers resistan... | ACCEPT | Summary: IDA evidence for ER localization from the seladin-1 paper. This is the correct primary localization, though ER membrane (GO:0005789) is more specific. Reason: Direct experimental evidence for ER localization through subcellular fractionation. The more specific ER membrane term is also annotated [PMID:11007892]. Supporting Evidence: PMID:11007892 subcellular fractionation and enzyme assays... seladin-1 is predominantly localized within the ER |
| GO:0009888 tissue development | IMP PMID:12457401 Desmosterolosis presenting with multiple congenital anomalie... | KEEP AS NON CORE | Summary: IMP evidence for tissue development from a desmosterolosis case report showing developmental delay and anomalies. This is an indirect effect of cholesterol deficiency rather than a direct developmental role. Reason: DHCR24 deficiency causes developmental anomalies in desmosterolosis due to cholesterol deficiency. This is an indirect consequence rather than a direct developmental function [PMID:12457401]. Supporting Evidence: PMID:12457401 Desmosterolosis presenting with multiple congenital anomalies and profound developmental delay |
| GO:0042605 peptide antigen binding | IPI PMID:15577914 Regulation of cellular response to oncogenic and oxidative s... | REMOVE | Summary: IPI evidence for peptide antigen binding from the seladin-1 stress response study [PMID:15577914]. The WITH field shows UniProtKB:P04637 (p53), indicating the annotation was made based on seladin-1 binding the p53 N-terminus. However, this interaction is protein-protein binding to p53 during stress response, not peptide antigen binding in an immunological sense. The GO term peptide antigen binding (GO:0042605) refers to binding of antigenic peptides for immune presentation, which does not describe the DHCR24-p53 interaction. Reason: This is a misannotation. PMID:15577914 describes DHCR24/seladin-1 binding to the p53 amino terminus during oncogenic and oxidative stress, displacing Mdm2. This is a protein-protein interaction, not peptide antigen binding in the immunological sense. No MHC or antigen presentation function is described. Supporting Evidence: PMID:15577914 Following oncogenic and oxidative stress, Seladin-1 binds p53 amino terminus and displaces E3 ubiquitin ligase Mdm2 from p53, thus resulting in p53 accumulation. |
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Download this section (compressed HTML)Q: How does DHCR24 coordinate cholesterol biosynthesis with membrane homeostasis and cellular sterol requirements?
Q: What are the regulatory mechanisms that control DHCR24 expression and activity in response to sterol levels?
Q: How do mutations in DHCR24 lead to desmosterolosis and what are the developmental consequences of altered sterol metabolism?
Q: What determines the subcellular localization of DHCR24 and how does this affect its function in sterol metabolism?
Experiment: Lipidomics analysis to characterize the complete sterol profile in DHCR24-deficient cells and tissues
Experiment: Live-cell imaging using fluorescent sterol analogs to track cholesterol metabolism and membrane distribution in real-time
Experiment: Cryo-EM structure determination of DHCR24 to understand the molecular basis of sterol reduction and enzyme specificity
Experiment: Developmental analysis of DHCR24 mutant model organisms to study the role of cholesterol in embryogenesis and organogenesis
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Download this section (compressed HTML)π View Pathway Visualization Interactive pathway diagram with detailed annotations