DHCR7

Summary: Inherited ER membrane localization is consistent with the target protein.

Reason: The human sequence is an exact 475-residue match to the PTHR21257 alignment and descends from PTN000479179. The literal ER-membrane IBD is present at that node, with experimental descendant localization records; inspected NOT/IRD placements are outside the human lineage. Independent human membrane biochemistry and ER localization corroborate the inherited location.

Summary: Cholesterol biosynthesis is a directly established target function.

Reason: The current IBA names PTN001082975, which is on the human lineage, and its donor records include experimental cholesterol-biosynthesis assertions. The corresponding literal IBD record was not recovered in the inspected current IBD release, so exact historical propagation is not completely reconstructed. This is a provenance limit, not evidence of functional loss: human DHCR7 directly performs the cholesterol-forming reduction.

Summary: The delta-7 reductase activity is inherited and directly demonstrated.

Reason: PTN001847198 is on the human lineage and carries the literal GO:0047598 IBD. The target itself, mouse, rat and Arabidopsis provide experimental descendant grounding; inclusion of the human target is expected evidence for an ancestral function. The exact human sequence and direct reductase assays support retention.

Summary: ER membrane localization is well supported.

Reason: The UniProt location mapping agrees with the membrane-bound human reductase and explicit ER localization. This does not establish a separate nuclear-envelope membrane pool.

Summary: Refine the broad family membrane mapping to ER membrane.

Reason: The conserved ERG24/DHCR-like family and sterol-reductase site are genuine target matches. For this family-derived general location, human DHCR7 biochemical and localization evidence identifies the endoplasmic reticulum membrane. The refinement is not a claim that all experimentally observed membrane pools are ER.

Proposed replacements: endoplasmic reticulum membrane

Summary: Refine sterol biosynthesis to the demonstrated cholesterol pathway.

Reason: The InterPro family mapping is valid but broad. Human DHCR7 performs the C7–C8 reduction that forms cholesterol, giving a supported descendant process. The imported reference is preserved despite a different current electronic provenance assignment.

Proposed replacements: cholesterol biosynthetic process

Summary: Refine the broad oxidoreductase class to delta-7 reductase.

Reason: Family/site membership supports a sterol reductase; direct human microsomal conversion specifies the NADPH-dependent 7-dehydrocholesterol reductase reaction. The original family-level statement is retained as source evidence.

Proposed replacements: 7-dehydrocholesterol reductase activity

Summary: The electronic specific reductase assignment is supported independently.

Reason: The current ARBA00090683 mammalian branch matches the literal FunFam 1.20.120.1630:FF:000004 in the target record. Its activity conclusion agrees with direct human substrate conversion, rather than relying on an unexamined rule label.

Summary: DHCR7 performs the delta-7 step in the Bloch pathway.

Reason: The curated pathway contains reaction R-HSA-196402, whose catalyst resolves to human Q9UBM7 residues 1–475 at the ER membrane. That event reduces 7-dehydrodesmosterol to desmosterol. The modeled substrate extension is retained with curator deference; the original human study independently establishes delta-7 sterol reduction, not a separately remeasured human 7-dehydrodesmosterol assay.

Summary: DHCR7 performs the terminal step in the modified Kandutsch–Russell pathway.

Reason: The pathway contains R-HSA-6807055, which explicitly resolves through catalyst 196403 to Q9UBM7 residues 1–475 and the conversion of 7-dehydrocholesterol to cholesterol. This is catalytic participation in the pathway.

Summary: The electronic cholesterol-biosynthesis assignment is correct.

Reason: The target directly makes cholesterol from 7-dehydrocholesterol. Current electronic provenance has changed from the imported combined-method source to a UniProt mapping, while the current ARBA sterol-pathway branch and target family membership also agree. These changes do not justify rewriting the original source object.

Summary: Human DHCR7 catalyses NADPH-dependent 7-dehydrocholesterol reduction.

Reason: The original expressed the 475-residue human cDNA in yeast and measured microsomal 7-dehydrocholesterol-to-cholesterol conversion with mock-expression controls. NADPH was required; other tested sterols showed lower but nonzero turnover. The host species does not change the identity of the assayed human protein.

Summary: Refine the ER staining to the membrane compartment.

Reason: The inspected HPA data record reports supported ER immunofluorescence in human cell lines. Together with the membrane-bound reductase characterized biochemically, ER membrane is the supported refinement. The data record was inspected, not its microscopy pixels, and it does not resolve a unique natural isoform.

Proposed replacements: endoplasmic reticulum membrane

Summary: Joint cholesterol-epoxide hydrolase activity does not establish an autonomous DHCR7 hydrolase.

Reason: Human DHCR7 and EBP coexpression reconstituted the activity in COS-7 cells, and their knockdown reduced it in MCF-7 cells. Differential kinetics suggest a substrate-binding contribution from DHCR7, but neither isolated DHCR7 hydrolysis nor a defined catalytic subunit mechanism was established. UniProt assigns EC 3.3.2.11 and the cholesterol-5,6-epoxide hydrolase subunit name while explicitly leaving each component's precise role unresolved. The over-annotation concerns autonomous DHCR7 enables activity, not the genuine complex activity; its positive subunit contribution remains in contributes_to_molecular_function in the core synthesis.

Summary: Human and mouse perturbations support cholesterol synthesis through DHCR7.

Reason: The original author proof shows knockout-associated 7-dehydrocholesterol accumulation and reduced labeled cholesterol production, with human HT1080 and mouse Pfa1 experiments distinguished. Reconstitution supports the target pathway role. The linked 2026 correction clarifies viability-background normalization in Extended Data Fig. 2a,b and reports unchanged effects and conclusions, rather than revising this cholesterol-conversion evidence.

Summary: DHCR7 perturbation changes the terminal cholesterol-synthesis step.

Reason: Human HEK293T knockout and re-expression experiments alter 7-dehydrocholesterol abundance and associated cholesterol-pathway phenotypes. This supports participation alongside the independent direct human reductase assay.

Summary: Perturbation and reconstitution support the established reductase function.

Reason: Human DHCR7 loss and rescue alter the substrate pool and labeled cholesterol output. These cellular experiments support the existing activity but are not presented as a purified-enzyme kinetic measurement. The author proof and its linked viability-normalization correction were assessed separately.

Summary: Human DHCR7 activity is supported by cellular and immunopurified-protein experiments.

Reason: The study combines substrate accumulation after knockout with re-expression and an immunopurified FLAG-DHCR7 NADPH-consumption assay supplied with 7-dehydrocholesterol. NADPH consumption is not itself a direct chemical identification of cholesterol; the earlier microsomal product analysis independently establishes that reaction.

Summary: DHCR7 promotes ferroptosis susceptibility by consuming protective 7-dehydrocholesterol.

Reason: Knockout, reconstitution and SC5D epistasis support a metabolic effect on ferroptosis in the tested cells and tumors. GO:0160020 includes processes that increase ferroptosis, so this is a valid contextual regulation annotation; it is not a separate death-execution activity. The 2026 correction explains resazurin blank normalization and reports equivalent effects after two reanalyses.

Summary: The cholesterol-substrate balance modulates ferroptosis in the tested systems.

Reason: DHCR7 loss increases 7-dehydrocholesterol and resistance to ferroptosis-inducing treatments, whereas restoring DHCR7 reverses this phenotype; SC5D-dependent substrate production is required. This satisfies positive regulation in context, without making ferroptosis execution a core molecular role.

Summary: Retain the observed association with TMEM147 without inventing a mechanistic binding class.

Reason: The human HeLa TMEM147–GFP affinity-purification/MS experiment identifies DHCR7, with GFP and TMEM129 comparator controls and two independent experiments. The curated target–partner record agrees, although the literal current IntAct/MINT queries did not recover this paper-specific pair. TMEM147 is a translocon component; that does not show that DHCR7 performs chaperone, adaptor or translocation activity. The supported generic association is retained under the scoped project instruction.

Summary: Refine the physical association with DHCR24 to enzyme binding.

Reason: The original CHO-cell experiments used human tagged proteins and endogenous hamster DHCR7 detection, followed by reciprocal coimmunoprecipitation. DHCR24 is an independently characterized sterol-reductase enzyme, satisfying the partner-class definition of enzyme binding; no DHCR7-mediated activation of DHCR24 is required or inferred. The original instead found DHCR24-dependent enhancement of DHCR7 activity. The linked correction changes only a Figure 1 chemical label.

Proposed replacements: enzyme binding

Summary: NADP(H) binding is an integral part of the reductase mechanism.

Reason: The ISS donor G4SW86 is the bacterial MaSR1 delta-14 sterol reductase, not a DHCR7 ortholog. Its experimentally determined NADPH-bound structure supplies family-level cofactor evidence, while direct human DHCR7 activity requires NADPH. GO:0050661 includes binding of NADPH as well as NADP+. This supports cofactor binding without transferring the donor substrate specificity or proposing a separate physiological core.

Summary: Refine the broad membrane observation to ER membrane using independent localization evidence.

Reason: The curator-associated YTS membrane-proteomics result is compatible with the established membrane-bound protein. Independent human DHCR7 localization and microsomal evidence support the more informative ER-membrane term. This gene-level refinement does not reassign the unverified DHCR7 table entry or membrane fraction in PMID:19946888 to the ER. Later plasma-membrane and mitochondrial fraction observations also remain compatible with nonexclusive localization.

Proposed replacements: endoplasmic reticulum membrane

Summary: The expression model produces DHCR7 at the ER membrane.

Reason: The event output is the human Q9UBM7 protein, residues 1–475, explicitly assigned to ER membrane. This supports the location; DHCR7 being a transcriptional product does not mean it performs the transcription process.

Summary: The Bloch-pathway catalyst is modeled at ER membrane.

Reason: Reaction R-HSA-196402 resolves via catalyst 196403 to Q9UBM7 residues 1–475 in ER membrane. The target protein and its compartment are explicit, rather than inferred from pathway title alone.

Summary: The terminal cholesterol-producing catalyst is at ER membrane.

Reason: Reaction R-HSA-6807055 uses the same explicit human Q9UBM7 catalyst at ER membrane, consistent with the original membrane-bound reductase characterization.

Summary: Human DHCR7 performs a cholesterol-producing reaction.

Reason: Human cDNA expression confers microsomal reduction of 7-dehydrocholesterol to chemically identified cholesterol in yeast, a host lacking that native terminal conversion. The enzyme therefore performs a biosynthetic step rather than merely being required indirectly for cholesterol abundance.

Summary: The specific nuclear outer membrane assignment remains unresolved.

Reason: The accessible original abstract explicitly places DHCR7 in the ER, contrasting it with inner-nuclear-membrane LBR. The full original localization experiments could not be recovered, so the separately curated nuclear outer membrane claim cannot be adjudicated. Continuity with ER or observations of other nuclear-envelope proteins do not prove this specific location, but neither is the annotation rejected from abstract silence.

Summary: Refine established ER localization to ER membrane.

Reason: The source abstract explicitly assigns DHCR7 to the ER; independent human microsomal characterization establishes a membrane-bound protein. Their combined evidence supports ER membrane while leaving the source-specific nuclear outer membrane assertion unresolved.

Proposed replacements: endoplasmic reticulum membrane

Summary: Direct microsomal product analysis establishes the reductase reaction.

Reason: Human DHCR7 expression in yeast microsomes enables NADPH-dependent 7-dehydrocholesterol conversion, with mock-expression controls and cholesterol identification. This direct activity is central to the gene product.