AKR1D1 is a soluble cytosolic steroid 5beta-reductase that uses NADPH to reduce the C4-C5 double bond of 3-oxo-Delta4 steroids while retaining their 3-oxo group. The resulting cis-fused A/B ring is required for bile acid biosynthesis from cholesterol. The enzyme also reduces androgen, progestogen and glucocorticoid substrates, contributing to steroid hormone metabolism. Its steroid-binding pocket and Tyr58/Glu120 catalytic dyad support this distinctive double-bond reduction. AKR1D1 is highly expressed in liver; biallelic loss-of-function variants cause congenital bile acid synthesis defect type 2, with deficient primary bile acids and accumulation of abnormal steroid intermediates.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004032 aldose reductase (NADPH) activity | IBA GO_REF:0000033 | UNDECIDED | Summary: The ancestral aldose-reduction assertion remains unresolved. Reason: The preserved PTHR11732 lineage places the aldose/alditol IBD at PTN000198921 upstream of human P51857. GO:0004032 specifies carbonyl reduction of sugars, a different reaction from steroid double-bond reduction. Human AKR1D1 structures in PMID:18407998 explain Tyr58/Glu120-dependent steroid geometry, positioning hydride transfer toward C5 rather than the substrate C3 carbonyl. This is positive evidence for distinct steroid selectivity, but these assays do not directly test the complete aldose substrate class. The ancestral donor evidence and target-specific retention or loss of sugar reduction remain unresolved. The genuine OpenScientist report acknowledges that it did not recover a direct negative aldose assay; its stronger exclusion is not adopted. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000198921 UNRESOLVED The cached lineage and IBD identify this ancestor; original aldose donor assays were not re-read and no target-specific loss was demonstrated. Supporting Evidence: PMID:18407998 Each steroid carbonyl accepts hydrogen bonds from catalytic residues Tyr 58 and Glu 120 . |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: AKR1D1 is a cytosolic steroid-metabolizing enzyme. Reason: The PTN000198921 cytosol IBD is on the preserved target lineage and includes human P51857 descendant grounding. UniProt curates cytoplasmic localization from PMID:7508385; HPA supplies an independent cytosol IDA and Reactome places the reductive reactions in cytosol. The exact original localization panel is not in the cached abstract, so its assay attribution is retained with curator deference. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000198921 SUPPORTS TRANSFER The target is on the recorded ancestor-to-leaf path; its own experimental annotation is valid descendant evidence, not circularity. Supporting Evidence: file:human/AKR1D1/AKR1D1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:7508385}. |
| GO:0016229 steroid dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: AKR1D1 catalyzes redox chemistry on steroid substrates. Reason: GO:0016229 defines any redox reaction with a sterol derivative substrate, so steroid C4-C5 reduction satisfies this family-level activity. The PTN000199026 ancestral assertion agrees with purified human product identification in PMID:21255593. This term does not require conversion of a carbonyl to an alcohol. This IBA preserves the ancestral steroid-substrate reaction class at its curated node; the generic oxidoreductase signature lacks that substrate restriction. The exact reaction is represented separately by GO:0047787. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000199026 SUPPORTS TRANSFER Cached target lineage and steroid-dehydrogenase IBD inspected; direct human steroid reduction independently supports the broad reaction class. Supporting Evidence: PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0008209 androgen metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: AKR1D1 directly metabolizes androgen substrates. Reason: The androgen-metabolism IBD at PTN000199134 includes P51857 experimental grounding. Human enzyme expressed in COS cells reduces testosterone in PMID:7508385, and purified human AKR1D1 identifies 5beta products across androgen substrates in PMID:21255593. Its own source evidence legitimately contributes to the ancestral inference. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000199134 Β· PTN000199134 SUPPORTS TRANSFER Actual target-path node and target-descendant grounding verified; purified androgen turnover independently supports the process. Supporting Evidence: PMID:7508385 In addition, the expressed enzyme showed a small but significant 5 beta-reduction activity toward 11 beta,17 alpha,21-trihydroxy-delta 4-pregnene-3,20-dione (cortisol) and 17 beta-hydroxy-delta 4-androsten-3-one (testosterone) whereas no activity was observed toward delta 4-pregnene-3,20-dione (progesterone) or delta 4-androstene-3-17-dione (androstenedione). PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0047086 ketosteroid monooxygenase activity | IBA GO_REF:0000033 | UNDECIDED | Summary: The ancestral ketosteroid-monooxygenase assertion requires unresolved source chemistry. Reason: GO:0047086 specifically inserts oxygen into progesterone to form testosterone acetate using O2/NADPH. The recorded PTN000199026 IBD lies on the human target lineage and is grounded in AKR1C1/C2/C3 annotations traced to PMID:21232532. That accessible primary abstract reports expression and IHC, including AKR1D1; the relevant full assays remain unavailable. Known steroid double-bond reduction neither demonstrates this monooxygenation nor proves its absence. The OpenScientist report also admits abstract-only access, so it does not resolve the donor experiment. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000199026 Β· PTN000199026 UNRESOLVED Actual target ancestry and source PMID recovered; exact monooxygenation evidence remains unresolved. Supporting Evidence: PMID:21232532 In this study, we examined the expression of PR-AB and the progesterone metabolizing enzymes in 31 specimens of ovarian endometriosis and 28 specimens of normal endometrium. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: The mapped cytoplasmic location agrees with the soluble enzyme. Reason: The UniProt subcellular-location mapping SL-0086 asserts the broad cytoplasmic compartment. This is supported by curated localization and independent cytosol annotations; the source itself is retained at its measured/mapped resolution. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER The cached UniProt record explicitly states cytoplasm with PMID:7508385 evidence. Supporting Evidence: file:human/AKR1D1/AKR1D1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:7508385}. |
| GO:0006699 bile acid biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: AKR1D1 catalyzes a reductive step in bile acid biosynthesis. Reason: IPR044483 identifies the steroid 5beta-reductase family. Human enzyme expression directly converts bile acid intermediates in PMID:7508385, corroborated by purified substrate/product assays and the Reactome pathways. This is catalytic participation in biosynthesis. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR044483 SUPPORTS TRANSFER The AKR1D1-specific family mapping agrees with the independently established human bile-acid reaction. Supporting Evidence: PMID:7508385 Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | IEA GO_REF:0000117 | UNDECIDED | Summary: The proposed carbonyl-to-alcohol activity remains distinct from established 5beta reduction. Reason: RHEA:53484 in cached UniProt specifies androst-4-ene-3,11,17-trione to 17beta-hydroxyandrost-4-ene-3,11-dione, attributed to PMID:11342103. Its abstract describes human AKR1D1 expression in stable HEK293 cells and steroid conversion, but does not expose the exact C17 product/controls. The full original assay was not recovered. Leave intrinsic 17-ketone/alcohol interconversion unresolved; retained 3-oxo groups in the separate 5beta-reductase reactions do not exclude a second activity. Propagation Review Root cause: UNRESOLVED Sources checked: ARBA:ARBA00092671 UNRESOLVED The exact rule predicates were not inspected. Independent UniProt RHEA:53484 points to a distinct unresolved source reaction, not a proven error in every alcohol-forming activity. Supporting Evidence: PMID:11342103 we established a stable cell line expressing human 5beta-reductase in transformed embryonic kidney (HEK-293) cells. |
| GO:0008202 steroid metabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: AKR1D1 catalyzes steroid metabolic reactions. Reason: Its bile acid precursor and hormone substrates are steroids, and purified human AKR1D1 converts their double bonds to 5beta products. The broad process encompasses these directly executed catalytic steps. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR044483 SUPPORTS TRANSFER Family mapping agrees with direct steroid-substrate assays. ARBA:ARBA00027309 UNRESOLVED Rule predicates were not inspected; the annotation judgment has independent human biochemical support. Supporting Evidence: PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: The general oxidoreductase annotation can be refined to the established steroid double-bond reductase. Reason: IPR018170/IPR020471 provide broad reductase-family recognition. Human enzyme kinetics and product analysis identify NADPH-dependent Delta4-3-oxosteroid 5beta-reduction specifically, making GO:0047787 the informative replacement. Unlike a broad localization measurement, the molecular reaction itself is resolved by these assays. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR018170 SUPPORTS TRANSFER This family-level mapping supports reductase chemistry; independent human assays justify the more specific replacement. InterPro:IPR020471 SUPPORTS TRANSFER This family-level mapping supports reductase chemistry; independent human assays justify the more specific replacement. Proposed replacements: Delta4-3-oxosteroid 5beta-reductase activity Supporting Evidence: PMID:7508385 catalyzes the reduction of the delta 4 double bond of bile acid intermediates and steroid hormones carrying the delta 4-3-one structure in the A/B cis configuration. PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0032787 monocarboxylic acid metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: AKR1D1 participates in the pathway forming monocarboxylic bile acids. Reason: The enzyme directly reduces intermediates in bile-acid biosynthesis. That pathway makes steroid monocarboxylic acids, supporting the broad metabolic process even when a particular immediate substrate still has an unoxidized side chain. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027288 UNRESOLVED Exact rule predicates were not inspected; independent pathway chemistry supports the process. Supporting Evidence: PMID:7508385 Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one. |
| GO:0042445 hormone metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: AKR1D1 directly metabolizes steroid hormones. Reason: Human AKR1D1 reduces androgen, progestogen and glucocorticoid substrates. The purified-enzyme study identifies the 5beta products and explains how substrate inhibition contributes to differing results in older preparations. Aldosterone turnover is positive, but its exact product identity was inferred because an authentic standard was unavailable. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028011 UNRESOLVED Exact rule predicates were not inspected; human hormone-substrate turnover independently establishes the process. Supporting Evidence: PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0047787 Delta4-3-oxosteroid 5beta-reductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: AKR1D1 catalyzes NADPH-dependent Delta4-3-oxosteroid 5beta-reduction. Reason: The EC:1.3.1.3, IPR044483 and listed Rhea equations agree on C4-C5 reduction with a retained 3-oxo group. Some Rhea equations are written in the reverse direction; UniProt and biochemical studies establish reductive physiological use of NADPH. Human assays and structures directly support the stereospecific activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR044483 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:11524 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:14037 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:46632 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:46636 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:46640 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:46644 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:46652 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:46656 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:46660 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:46664 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:46668 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:46672 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. RHEA:47080 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. EC:1.3.1.3 SUPPORTS TRANSFER The cached UniProt substrate/product mapping supports steroid C4-C5 reduction; human product assays independently establish the shared catalytic class. Supporting Evidence: PMID:7508385 catalyzes the reduction of the delta 4 double bond of bile acid intermediates and steroid hormones carrying the delta 4-3-one structure in the A/B cis configuration. PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0072582 17-beta-hydroxysteroid dehydrogenase (NADP+) activity | IEA GO_REF:0000116 | UNDECIDED | Summary: The proposed carbonyl-to-alcohol activity remains distinct from established 5beta reduction. Reason: RHEA:53484 in cached UniProt specifies androst-4-ene-3,11,17-trione to 17beta-hydroxyandrost-4-ene-3,11-dione, attributed to PMID:11342103. Its abstract describes human AKR1D1 expression in stable HEK293 cells and steroid conversion, but does not expose the exact C17 product/controls. The full original assay was not recovered. Leave intrinsic 17-ketone/alcohol interconversion unresolved; retained 3-oxo groups in the separate 5beta-reductase reactions do not exclude a second activity. Propagation Review Root cause: UNRESOLVED Sources checked: RHEA:53484 UNRESOLVED The cached UniProt equation and PMID:11342103 attribution were read; the original experiment establishing direct C17 reduction was not recovered. Supporting Evidence: PMID:11342103 we established a stable cell line expressing human 5beta-reductase in transformed embryonic kidney (HEK-293) cells. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: BioPlex reports association with AKR1C1 without a more specific AKR1D1 activity. Reason: The seeded partner is UniProtKB:Q04828 (AKR1C1). The primary AP-MS study supports co-complex discovery, but the gene-pair supplementary record was not independently recovered and no specific adaptor or catalytic function follows from this interaction alone. Generic protein binding is removed as uninformative; the physical association is not denied. Supporting Evidence: PMID:28514442 With more than 56,000 candidate interactions, BioPlex 2.0 contains more than 29,000 previously unknown co-associations |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: BioPlex reports association with AKR1C1 without a more specific AKR1D1 activity. Reason: The seeded partner is UniProtKB:Q04828 (AKR1C1). The primary AP-MS study supports co-complex discovery, but the gene-pair supplementary record was not independently recovered and no specific adaptor or catalytic function follows from this interaction alone. Generic protein binding is removed as uninformative; the physical association is not denied. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-193368 | ACCEPT | Summary: AKR1D1 contributes to bile-acid synthesis via 7alpha-hydroxycholesterol. Reason: The cached pathway describes steroid-ring reduction during conversion of 7alpha-hydroxycholesterol to bile acids. AKR1D1 performs the 5beta reduction step, independently supported by human enzyme assays. The pathway contains several cellular compartments; its broad summary does not place every enzyme in all of them. Supporting Evidence: PMID:7508385 Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one. |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-193775 | ACCEPT | Summary: AKR1D1 contributes to bile-acid synthesis via 24-hydroxycholesterol. Reason: The cached pathway describes steroid-ring reduction during conversion of 24-hydroxycholesterol to bile acids. AKR1D1 performs the 5beta reduction step, independently supported by human enzyme assays. The pathway contains several cellular compartments; its broad summary does not place every enzyme in all of them. Supporting Evidence: PMID:7508385 Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one. |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-193807 | ACCEPT | Summary: AKR1D1 contributes to bile-acid synthesis via 27-hydroxycholesterol. Reason: The cached pathway describes steroid-ring reduction during conversion of 27-hydroxycholesterol to bile acids. AKR1D1 performs the 5beta reduction step, independently supported by human enzyme assays. The pathway contains several cellular compartments; its broad summary does not place every enzyme in all of them. Supporting Evidence: PMID:7508385 Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-192033 | MODIFY | Summary: This Reactome reaction is steroid double-bond reduction. Reason: The cached source event explicitly converts a Delta4-3-oxosteroid to a 5beta-3-oxosteroid using NADPH. The retained carbonyl distinguishes this chemistry from GO:0008106 alcohol/aldehyde-or-ketone interconversion. GO:0047787 represents the actual event. This source-specific mapping correction leaves the separate RHEA:53484 side-activity question unresolved. Proposed replacements: Delta4-3-oxosteroid 5beta-reductase activity Supporting Evidence: Reactome:R-HSA-192033 This reaction is catalyzed by AKR1D1 (3-oxo-5-beta-steroid 4-dehydrogenase). PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-192067 | MODIFY | Summary: This Reactome reaction is steroid double-bond reduction. Reason: The cached source event explicitly converts a Delta4-3-oxosteroid to a 5beta-3-oxosteroid using NADPH. The retained carbonyl distinguishes this chemistry from GO:0008106 alcohol/aldehyde-or-ketone interconversion. GO:0047787 represents the actual event. This source-specific mapping correction leaves the separate RHEA:53484 side-activity question unresolved. Proposed replacements: Delta4-3-oxosteroid 5beta-reductase activity Supporting Evidence: Reactome:R-HSA-192067 This reaction is catalyzed by AKR1D1 (3-oxo-5-beta-steroid 4-dehydrogenase). PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-193746 | MODIFY | Summary: This Reactome reaction is steroid double-bond reduction. Reason: The cached source event explicitly converts a Delta4-3-oxosteroid to a 5beta-3-oxosteroid using NADPH. The retained carbonyl distinguishes this chemistry from GO:0008106 alcohol/aldehyde-or-ketone interconversion. GO:0047787 represents the actual event. This source-specific mapping correction leaves the separate RHEA:53484 side-activity question unresolved. Proposed replacements: Delta4-3-oxosteroid 5beta-reductase activity Supporting Evidence: Reactome:R-HSA-193746 This reaction is catalyzed by AKR1D1 (3-oxo-5-beta-steroid 4-dehydrogenase). PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-193755 | MODIFY | Summary: This Reactome reaction is steroid double-bond reduction. Reason: The indexed primary human Reactome R-HSA-193755 page recovered during this audit explicitly converts a Delta4-3-oxosteroid to a 5beta-3-oxosteroid using NADPH. The retained carbonyl distinguishes this chemistry from GO:0008106 alcohol/aldehyde-or-ketone interconversion. GO:0047787 represents the actual event. This source-specific mapping correction leaves the separate RHEA:53484 side-activity question unresolved. The normal Reactome cache fetch failed DNS; recovery batch 5 also returned no record. Direct page retrieval returned 404, but the indexed human record exposes the full equation and AKR1D1 catalyst. The missing cache remains a source gate; neither a nonexistent event nor an identifier remapping is inferred. Proposed replacements: Delta4-3-oxosteroid 5beta-reductase activity Supporting Evidence: PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-193821 | MODIFY | Summary: This Reactome reaction is steroid double-bond reduction. Reason: The cached source event explicitly converts a Delta4-3-oxosteroid to a 5beta-3-oxosteroid using NADPH. The retained carbonyl distinguishes this chemistry from GO:0008106 alcohol/aldehyde-or-ketone interconversion. GO:0047787 represents the actual event. This source-specific mapping correction leaves the separate RHEA:53484 side-activity question unresolved. Proposed replacements: Delta4-3-oxosteroid 5beta-reductase activity Supporting Evidence: Reactome:R-HSA-193821 This reaction is catalyzed by AKR1D1 (3-oxo-5-beta-steroid 4-dehydrogenase). PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-193824 | MODIFY | Summary: This Reactome reaction is steroid double-bond reduction. Reason: The cached source event explicitly converts a Delta4-3-oxosteroid to a 5beta-3-oxosteroid using NADPH. The retained carbonyl distinguishes this chemistry from GO:0008106 alcohol/aldehyde-or-ketone interconversion. GO:0047787 represents the actual event. This source-specific mapping correction leaves the separate RHEA:53484 side-activity question unresolved. Proposed replacements: Delta4-3-oxosteroid 5beta-reductase activity Supporting Evidence: Reactome:R-HSA-193824 This reaction is catalyzed by AKR1D1 (3-oxo-5-beta-steroid 4-dehydrogenase). PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: HPA assigns AKR1D1 to cytosol. Reason: The curated HPA IDA is compatible with the soluble enzyme and cytosolic pathway placement. The original HPA image was not independently re-read; localization is retained with curator deference and corroborating UniProt/Reactome evidence. Supporting Evidence: file:human/AKR1D1/AKR1D1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:7508385}. |
| GO:0005737 cytoplasm | EXP PMID:7508385 Cloning and expression of cDNA of human delta 4-3-oxosteroid... | ACCEPT | Summary: The original study supports a cytoplasmic enzyme annotation. Reason: UniProt explicitly attributes cytoplasmic localization to PMID:7508385. Its cached abstract establishes human cDNA expression and activity but not the localization method, so the experimental source is retained with curator deference at its stated broad compartment. Supporting Evidence: file:human/AKR1D1/AKR1D1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:7508385}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-192033 | ACCEPT | Summary: The steroid reduction reaction places AKR1D1 in cytosol. Reason: The cached Reactome event places AKR1D1 in cytosol. Its steroid substrate can originate in the endoplasmic reticulum membrane; that substrate compartment does not make AKR1D1 a membrane enzyme or establish a transport function. Independent curated localization corroborates cytosol. Supporting Evidence: Reactome:R-HSA-192033 AKR1D1 is localized to the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-192067 | ACCEPT | Summary: The steroid reduction reaction places AKR1D1 in cytosol. Reason: The cached Reactome event places AKR1D1 in cytosol. Its steroid substrate can originate in the endoplasmic reticulum membrane; that substrate compartment does not make AKR1D1 a membrane enzyme or establish a transport function. Independent curated localization corroborates cytosol. Supporting Evidence: Reactome:R-HSA-192067 AKR1D1 is localized to the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-193746 | ACCEPT | Summary: The steroid reduction reaction places AKR1D1 in cytosol. Reason: The cached Reactome event places AKR1D1 in cytosol. Its steroid substrate can originate in the endoplasmic reticulum membrane; that substrate compartment does not make AKR1D1 a membrane enzyme or establish a transport function. Independent curated localization corroborates cytosol. Supporting Evidence: Reactome:R-HSA-193746 AKR1D1 is localized to the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-193755 | ACCEPT | Summary: The steroid reduction reaction places AKR1D1 in cytosol. Reason: The indexed human event recovered during this audit places AKR1D1 in cytosol. Its steroid substrate can originate in the endoplasmic reticulum membrane; that substrate compartment does not make AKR1D1 a membrane enzyme or establish a transport function. Independent curated localization corroborates cytosol. Supporting Evidence: file:human/AKR1D1/AKR1D1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:7508385}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-193821 | ACCEPT | Summary: The steroid reduction reaction places AKR1D1 in cytosol. Reason: The cached Reactome event places AKR1D1 in cytosol. Its steroid substrate can originate in the endoplasmic reticulum membrane; that substrate compartment does not make AKR1D1 a membrane enzyme or establish a transport function. Independent curated localization corroborates cytosol. Supporting Evidence: Reactome:R-HSA-193821 AKR1D1 is localized to the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-193824 | ACCEPT | Summary: The steroid reduction reaction places AKR1D1 in cytosol. Reason: The cached Reactome event places AKR1D1 in cytosol. Its steroid substrate can originate in the endoplasmic reticulum membrane; that substrate compartment does not make AKR1D1 a membrane enzyme or establish a transport function. Independent curated localization corroborates cytosol. Supporting Evidence: Reactome:R-HSA-193824 AKR1D1 is localized to the cytosol |
| GO:0005496 steroid binding | TAS PMID:7508385 Cloning and expression of cDNA of human delta 4-3-oxosteroid... | ACCEPT | Summary: Steroid recognition is integral to AKR1D1 catalysis. Reason: The original substrate-turnover study establishes steroid recognition indirectly, and independent human NADP+/cortisone/progesterone/testosterone structures in PMID:18407998 directly resolve steroid binding. Productive and inhibitory binding modes are parts of the same catalytic system, not separate unrelated functions. Supporting Evidence: PMID:18407998 Each steroid carbonyl accepts hydrogen bonds from catalytic residues Tyr 58 and Glu 120 . |
| GO:0005829 cytosol | IDA PMID:7508385 Cloning and expression of cDNA of human delta 4-3-oxosteroid... | ACCEPT | Summary: The experimental cytosol assertion is consistent with independent compartment evidence. Reason: The source abstract does not expose its localization method, but the curated IDA and UniProt experimental attribution agree with the soluble enzyme and cytosolic reaction records. Retain the asserted location without inventing a specific fractionation or imaging assay. Supporting Evidence: file:human/AKR1D1/AKR1D1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:7508385}. |
| GO:0006699 bile acid biosynthetic process | IDA PMID:7508385 Cloning and expression of cDNA of human delta 4-3-oxosteroid... | ACCEPT | Summary: Human AKR1D1 directly reduces bile-acid intermediates. Reason: PMID:7508385 expresses human cDNA in COS cells and reports high activity toward 7alpha-hydroxy- and 7alpha,12alpha-dihydroxy-4-cholesten-3-one. Purified human enzyme independently confirms broad 5beta-reduction. These are catalytic steps in bile acid biosynthesis. Supporting Evidence: PMID:7508385 Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one. PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0006707 cholesterol catabolic process | IDA PMID:7508385 Cloning and expression of cDNA of human delta 4-3-oxosteroid... | ACCEPT | Summary: AKR1D1 directly catalyzes an intermediate step in cholesterol catabolism. Reason: Conversion of cholesterol into bile acids includes AKR1D1-mediated reduction of steroid-ring intermediates. GO:0006707 covers the reactions and pathways of cholesterol breakdown, so it does not require AKR1D1 to consume cholesterol as its immediate substrate. Supporting Evidence: PMID:7508385 Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one. |
| GO:0007586 digestion | IDA PMID:7508385 Cloning and expression of cDNA of human delta 4-3-oxosteroid... | UNDECIDED | Summary: The original digestion assertion remains unresolved at its full source scope. Reason: GO:0007586 concerns breakdown of ingested nutrients into absorbable components. AKR1D1 makes bile acids that support digestion, while the accessible PMID:7508385 abstract directly assays precursor reduction. The full source context establishing the broader IDA was not recovered. Retain UNDECIDED rather than asserting that the experimental annotation is wrong or that every upstream bile-acid enzyme executes digestion. Supporting Evidence: PMID:7508385 Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one. |
| GO:0008207 C21-steroid hormone metabolic process | IDA PMID:7508385 Cloning and expression of cDNA of human delta 4-3-oxosteroid... | ACCEPT | Summary: AKR1D1 directly metabolizes cortisol and other C21 steroid hormones. Reason: PMID:7508385 reports positive cortisol and testosterone reduction by expressed human AKR1D1 in COS cells. Its single-condition progesterone/androstenedione negatives do not negate those positive reactions. Independent purified-enzyme analysis in PMID:21255593 expands the verified substrate range and identifies substrate inhibition as a contributor to earlier discrepancies. Supporting Evidence: PMID:7508385 In addition, the expressed enzyme showed a small but significant 5 beta-reduction activity toward 11 beta,17 alpha,21-trihydroxy-delta 4-pregnene-3,20-dione (cortisol) and 17 beta-hydroxy-delta 4-androsten-3-one (testosterone) whereas no activity was observed toward delta 4-pregnene-3,20-dione (progesterone) or delta 4-androstene-3-17-dione (androstenedione). PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0008209 androgen metabolic process | IDA PMID:7508385 Cloning and expression of cDNA of human delta 4-3-oxosteroid... | ACCEPT | Summary: AKR1D1 directly metabolizes testosterone and other androgens. Reason: PMID:7508385 reports positive cortisol and testosterone reduction by expressed human AKR1D1 in COS cells. Its single-condition progesterone/androstenedione negatives do not negate those positive reactions. Independent purified-enzyme analysis in PMID:21255593 expands the verified substrate range and identifies substrate inhibition as a contributor to earlier discrepancies. Supporting Evidence: PMID:7508385 In addition, the expressed enzyme showed a small but significant 5 beta-reduction activity toward 11 beta,17 alpha,21-trihydroxy-delta 4-pregnene-3,20-dione (cortisol) and 17 beta-hydroxy-delta 4-androsten-3-one (testosterone) whereas no activity was observed toward delta 4-pregnene-3,20-dione (progesterone) or delta 4-androstene-3-17-dione (androstenedione). PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
| GO:0006699 bile acid biosynthetic process | IDA PMID:7508385 Cloning and expression of cDNA of human delta 4-3-oxosteroid... | ACCEPT | Summary: Human AKR1D1 directly reduces bile-acid intermediates. Reason: PMID:7508385 expresses human cDNA in COS cells and reports high activity toward 7alpha-hydroxy- and 7alpha,12alpha-dihydroxy-4-cholesten-3-one. Purified human enzyme independently confirms broad 5beta-reduction. These are catalytic steps in bile acid biosynthesis. Supporting Evidence: PMID:7508385 Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one. PMID:21255593 5Ξ²-Reduced products were identified directly with all the C18-C27 steroid substrates except for aldosterone. |
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Download this section (compressed HTML)Q: Does purified wild-type human AKR1D1 retain the ancestral aldose-reductase or ketosteroid-monooxygenase activities, and which original assays ground the PAINT donor nodes?
Q: What exact substrate, C17 product identification and controls in PMID:11342103 support RHEA:53484, independently of endogenous HEK293 steroid enzymes?
Q: Can Reactome correct GO:0008106 to GO:0047787 for the six displayed steroid C4-C5 reduction events while preserving their substrate-specific reaction identities?
Q: What experimental scope in the complete PMID:7508385 source supports the digestion annotation beyond bile-acid biosynthesis?
Experiment: Compare purified human AKR1D1 with appropriate sugar-reductase and monooxygenase controls using product-resolving assays; explicitly test aldose-to-alditol, oxygen-insertion and steroid-double-bond products rather than NADPH consumption alone.
Experiment: Test androst-4-ene-3,11,17-trione with purified AKR1D1 and authentic C17-hydroxy versus 5beta standards, including enzyme-free and cofactor controls, to resolve RHEA:53484.
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