AKR1C4 (3-alpha-hydroxysteroid 3-dehydrogenase type 1; historically chlordecone reductase / dihydrodiol dehydrogenase 4) is a cytosolic, NADPH-dependent aldo-keto reductase of the AKR1C subfamily. It is strongly enriched in adult liver, with expression and activity also documented in fetal testis and adrenal. It is among the most catalytically efficient of the four human AKR1C 3-alpha-hydroxysteroid dehydrogenase isoforms. It catalyzes NADPH-dependent reduction of the 3-oxo group of steroids to the corresponding 3-alpha- (and 3-beta-) hydroxysteroid, and more broadly reduces ketosteroids to hydroxysteroids with positional/stereochemical plasticity, generating 3-alpha/beta-, 17-beta- and 20-alpha-hydroxysteroids. In bile-acid biosynthesis it provides the hepatic 3-alpha-hydroxysteroid dehydrogenase step, reducing the 3-oxo group of the 5-beta-reduced bile-acid intermediates downstream of the AKR1D1 5-beta-reductase. In steroid-hormone metabolism it acts mainly as a pre-receptor reductase, inactivating 5-alpha-dihydrotestosterone to 3-alpha/3-beta-androstanediols and reducing progestins to their 20-alpha/3-alpha-hydroxy products (including neuroactive allopregnanolone-type steroids), and it can reduce sulfate- and glucuronide-conjugated androgens. It also biotransforms the pesticide chlordecone to chlordecone alcohol, promoting biliary excretion. The enzyme is a monomer with a canonical (alpha/beta)8-barrel aldo-keto reductase fold that binds NADP(H).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004032 aldose reductase (NADPH) activity | IBA GO_REF:0000033 | UNDECIDED | Summary: Aldose reduction is a specific ancestral catalytic assertion, not a generic label for all AKR chemistry. Reason: The verified PTHR11732 target lineage descends from aldose-reductase IBD PTN000198921. Steroid preference does not establish loss of sugar-carbonyl reduction, and absence of a target experiment is not a reason to reject inheritance. Conversely, retinal/ketosteroid reduction does not itself demonstrate the aldose/alditol reaction. The prior description of an IBA guess is withdrawn; the focused OpenScientist report supported skepticism but found no direct AKR1C4 aldose assay that closes the substrate question. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000198921 Β· PTN000198921 UNRESOLVED Actual ancestral node recovered on the target path, with no matching loss. Target substrate scope remains unresolved rather than disproved by steroid specialization. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosolic localization is well supported: UniProt records the subcellular location as cytoplasm/cytosol, consistent with a soluble monomeric aldo-keto reductase. Reason: Cytosol is the established compartment of the soluble enzyme; the individual Reactome reactions and primary liver-enzyme characterization support this same location. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0047023 androsterone dehydrogenase [NAD(P)+] activity | IBA GO_REF:0000033 | ACCEPT | Summary: Androsterone dehydrogenase activity (reduction of 5alpha-androstan-3,17-dione to androsterone / oxidation of androsterone) is a genuine AKR1C4 activity, also supported experimentally (EXP PMID:10998348, PMID:7650035; IDA PMID:21851338). It is one of the many specific 3-keto/3-alpha-hydroxysteroid activities and is retained as a non-core supporting activity rather than the single best-supported MF. Reason: Androsterone/3-alpha-androstanediol interconversion is part of the established 3-alpha-hydroxysteroid dehydrogenase substrate range, not a different paralog-exclusive function. Direct steroid assays and the inherited androsterone IBD at PTN000199031 support this catalytic component of AKR1C4 steroid metabolism. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt androsterone + NADP(+) = 5alpha-androstan-3,17-dione + NADPH + |
| GO:0032052 bile acid binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain the inherited bile-acid-binding capacity without conflating historical DD clone identities. Reason: The actual binding IBD is PTN000199031 and lies on the C4 target path. PMID:8172617 distinguishes C9/bile-acid binder from C11/DD4/chlordecone reductase, so the old assertion that C4 itself was identified as that binder was too strong; PMID:8573067 further revises DD nomenclature. This source-name issue does not refute inherited binding in C4. Keep the curated ancestral binding as non-core while separating it from the independently unresolved transport claims. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000199031 Β· PTN000199031 SUPPORTS TRANSFER Bile-acid-binding IBD recovered on the verified target lineage; no target-specific binding loss established. Historical binder clone identity is not used as direct C4 proof. |
| GO:0044598 doxorubicin metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA family propagation of anthracycline (doxorubicin) metabolism. AKR1C4 can reduce doxorubicin in vitro (experimentally confirmed by IMP PMID:20837989 below), but this is a xenobiotic drug-metabolism side activity rather than a core physiological process. Kept as non-core to stay consistent with the experimental annotation for the same term. Reason: Anthracycline reduction is a genuine but minor in-vitro/pharmacological activity, not a core biological role; retained as non-core. |
| GO:0006693 prostaglandin metabolic process | IBA GO_REF:0000033 | UNDECIDED | Summary: Prostaglandin metabolism requires assessment of the actual substrate range and ancestral process grounding. Reason: PTN000199031 is on the verified C4 lineage; its process grounding includes C2 and C3, not only C3. Full PMID:20003443 tested recombinant human enzymes and distinguishes PGD2/PGE2 activities, but does not establish absence of every C4 prostaglandin transformation. PMID:8573067 also revises the historical DD identities. A steroid preference is not a loss test. Leave the broad inherited process unresolved pending reconciliation of the source assays and target substrate panel. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000199031 Β· PTN000199031 UNRESOLVED C2 and C3 experimental grounding and exact target-path descent verified. Broad prostaglandin metabolism cannot be dismissed solely as a C3-specific activity. |
| GO:0042448 progesterone metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: AKR1C4 directly metabolizes progesterone and related progestins. Reason: PMID:10998348 reports progesterone reduction and full PMID:21802064 demonstrates conversion of dihydroprogesterone to allopregnanolone in the fetal androgen-pathway context. The actual progesterone-process IBD at PTN000199031 lies on the verified target lineage. This is a catalytic steroid-hormone function, not merely a distal phenotype. Supporting Evidence: PMID:10998348 progesterone to 20alpha-hydroxy-pregn-4-ene-3,20-dione |
| GO:0044597 daunorubicin metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA family propagation of anthracycline (daunorubicin) metabolism. As for doxorubicin, this is a pharmacological reductase side activity (experimentally confirmed by IMP PMID:20837989) rather than a core physiological process. Kept as non-core to stay consistent with the experimental annotation for the same term. Reason: Daunorubicin reduction is a genuine but minor drug-metabolism activity; retained as non-core. |
| GO:0047086 ketosteroid monooxygenase activity | IBA GO_REF:0000033 | REMOVE | Summary: The monooxygenase assertion specifies chemistry different from the established AKR1C4 ketosteroid reduction. Reason: GO:0047086 requires progesterone plus oxygen and NADPH to yield testosterone acetate, water and NADP+. NADPH-dependent AKR chemistry transfers hydride equivalents and offers no oxygen-insertion mechanism, so the target-side retention of this Baeyer-Villiger-like monooxygenase term is chemically strained. The verified IBD is PTN000199026, and live source annotations on C1/C2/C3 cite IDA PMID:21232532. Its cached abstract is expression/IHC-focused and cannot establish the exact donor assay either way; full source review is still needed. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000199026 Β· PTN000199026 UNRESOLVED Actual common steroid-enzyme ancestor recovered; source IDAs cite PMID:21232532. Exact source oxygen-insertion evidence requires full-source review, while the target side has a reaction-class mismatch. |
| GO:0000253 3-beta-hydroxysteroid 3-dehydrogenase (NADP+) activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Rhea-mapped 3-beta-hydroxysteroid 3-dehydrogenase (NADP+) activity. AKR1C4 demonstrably reduces DHT to 3beta-androstanediol and 11-keto-androstanes to 3beta-hydroxy products, so this 3beta-HSD activity is genuine. It is a real supporting activity; kept as non-core. Reason: Direct steroid assays in PMID:14672942 and the product-identification experiments in PMID:19218247 establish 3beta as well as 3alpha products. Retain this secondary stereochemical capacity; 3alpha preference does not imply absolute exclusion of 3beta turnover. Supporting Evidence: PMID:14672942 AKR1Cs catalyze the reduction of DHT into both 3alpha- and 3beta-Diol |
| GO:0004303 estradiol 17-beta-dehydrogenase [NAD(P)+] activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: 17-beta estradiol/estrone interconversion is documented experimentally for AKR1C4 (EC 1.1.1.62), though the reductive estrone->estradiol reaction is low efficiency. The IEA duplicates the experimental annotation below; a genuine but low-efficiency supporting activity, kept as non-core. Reason: PMID:10998348 explicitly reports estrone/estradiol interconversion by all four human isoforms. PMID:20003443 discusses the limited sensitivity of its negative spectrophotometric result and does not overturn slower activity measured with other methods. Retain the measured secondary capacity. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt Catalyzes the reduction of estrone into 17beta- |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt-SubCell IEA for cytosol, consistent with the manually curated subcellular location. Reason: Cytosol is the established compartment of the soluble enzyme; the individual Reactome reactions and primary liver-enzyme characterization support this same location. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | IEA GO_REF:0000117 | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0008202 steroid metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: Steroid metabolic process is the central, well-supported biological process for AKR1C4, which inter-converts androgens, estrogens and progestins and functions in bile-acid (a steroid-derived) synthesis. Accepted as a core process. Reason: The enzyme directly transforms steroid substrates, including androgens, in the cited characterization studies. These are catalytic contributions to the named processes rather than a phenotype caused only by altered expression. Supporting Evidence: PMID:10998348 ability to modulate the levels of active androgens, oestrogens and progestins |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0032787 monocarboxylic acid metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0042445 hormone metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0044594 17-beta-hydroxysteroid dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Rhea-mapped 17beta-HSD (NAD+) activity, based on the 5alpha-androstane-3alpha,17beta-diol/androsterone NAD+ reaction. AKR1C4 has 17beta-HSD activity as part of its non-positional-specific hydroxysteroid dehydrogenase repertoire. Genuine supporting activity; kept as non-core. Reason: The original steroid enzymology describes oxidation as well as reduction of 17beta-hydroxysteroids. Reductive preference in cells does not erase experimentally measured oxidative capacity; retain this secondary reaction scope. Supporting Evidence: PMID:10998348 17beta- and 20alpha-hydroxysteroid oxidases |
| GO:0047023 androsterone dehydrogenase [NAD(P)+] activity | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of the experimentally-supported androsterone dehydrogenase activity (see EXP PMID:10998348 / PMID:7650035 and IDA PMID:21851338). Genuine specific activity; kept as non-core. Reason: Androsterone/3-alpha-androstanediol interconversion is part of the established 3-alpha-hydroxysteroid dehydrogenase substrate range, not a different paralog-exclusive function. Direct steroid assays and the inherited androsterone IBD at PTN000199031 support this catalytic component of AKR1C4 steroid metabolism. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt androsterone + NADP(+) = 5alpha-androstan-3,17-dione + NADPH + |
| GO:0047024 5-alpha-androstane-3-beta,17-beta-diol dehydrogenase (NADP+) activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Rhea/EC (1.1.1.210) mapping of the 3beta-diol dehydrogenase reaction, experimentally established for AKR1C4 (EXP PMID:14672942, duplicated below). Genuine specific 3beta-HSD activity; kept as non-core. Reason: Direct steroid assays in PMID:14672942 and the product-identification experiments in PMID:19218247 establish 3beta as well as 3alpha products. Retain this secondary stereochemical capacity; 3alpha preference does not imply absolute exclusion of 3beta turnover. Supporting Evidence: PMID:14672942 AKR1Cs catalyze the reduction of DHT into both 3alpha- and 3beta-Diol |
| GO:0047035 testosterone dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Rhea-mapped testosterone dehydrogenase (NAD+) activity; AKR1C4 oxidizes testosterone to androst-4-ene-3,17-dione (EC 1.1.1.51, EXP PMID:10998348). Genuine but non-core (in vivo the enzyme favors reduction); kept as non-core. Reason: The original steroid enzymology describes oxidation as well as reduction of 17beta-hydroxysteroids. Reductive preference in cells does not erase experimentally measured oxidative capacity; retain this secondary reaction scope. Supporting Evidence: PMID:10998348 AKR1C3 and AKR1C4 oxidized testosterone to Delta(4)-androstene-3,17-dione |
| GO:0047044 androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Rhea/EC (1.1.1.53) mapping of 5alpha-androstane-3alpha,17beta-diol / 17beta-hydroxy-5alpha-androstan-3-one interconversion (NAD+). This is the canonical 3alpha-HSD reaction (the DHT / 3alpha-diol interconversion), a genuine AKR1C4 activity; kept as non-core (specific instance of the core 3alpha-HSD function). Reason: Androsterone/3-alpha-androstanediol interconversion is part of the established 3-alpha-hydroxysteroid dehydrogenase substrate range, not a different paralog-exclusive function. Direct steroid assays and the inherited androsterone IBD at PTN000199031 support this catalytic component of AKR1C4 steroid metabolism. Supporting Evidence: PMID:7650035 interconversion between 5 alpha-dihydrotestosterone and 5 alpha-androstane-3 alpha,17 beta-diol |
| GO:0047045 testosterone dehydrogenase (NADP+) activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Rhea-mapped testosterone dehydrogenase (NADP+) activity; duplicate of the experimental annotation (EXP PMID:10998348). Genuine but non-core. Reason: The original steroid enzymology describes oxidation as well as reduction of 17beta-hydroxysteroids. Reductive preference in cells does not erase experimentally measured oxidative capacity; retain this secondary reaction scope. Supporting Evidence: PMID:10998348 AKR1C3 and AKR1C4 oxidized testosterone to Delta(4)-androstene-3,17-dione |
| GO:0047743 chlordecone reductase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Rhea/EC (1.1.1.225) mapping of chlordecone reductase activity, the historical activity by which this protein was first purified and named. Experimentally established (IDA PMID:2427522; EXP PMID:2187532). Genuine xenobiotic-reduction activity; kept as non-core. Reason: The cited purification and cloning studies establish human liver chlordecone reduction to its alcohol metabolite. This is a real xenobiotic substrate capability, retained as non-core relative to endogenous steroid metabolism. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt chlordecone alcohol + NADP(+) = chlordecone + NADPH + H(+) |
| GO:0140169 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity | IEA GO_REF:0000120 | ACCEPT | Summary: Rhea/EC (1.1.1.357) mapping of the general 3-alpha-hydroxysteroid 3-dehydrogenase reaction. This is the core molecular function of AKR1C4 (extensively supported experimentally, see the EXP block below). Duplicate electronic support for the core MF. Reason: The source-specific enzyme studies and independent steroid product assays support 3alpha-hydroxysteroid dehydrogenase activity as core catalysis. Variant, conjugate and tissue contexts provide complementary evidence rather than making a duplicated activity assertion excessive. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt a 3alpha-hydroxysteroid + NADP(+) = a 3-oxosteroid + NADPH + |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: High-throughput affinity-capture/BioPlex interactome screen (Huttlin et al. 2017) reporting AKR1C4 protein-protein interactions (e.g. with paralog AKR1C3 and PLXDC2). Bare "protein binding" is uninformative of AKR1C4 function and derives from a proteome-scale network; flagged as over-annotated rather than removed, per policy for IPI protein-binding. Reason: The reported physical interaction is not denied. Generic protein binding provides no informative molecular-function description, and interaction-screen evidence alone does not justify a more specific replacement. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput BioPlex 3.0 interactome screen (Huttlin et al. 2021). As above, bare "protein binding" from a proteome-scale network is uninformative; flagged as over-annotated. Reason: The reported physical interaction is not denied. Generic protein binding provides no informative molecular-function description, and interaction-screen evidence alone does not justify a more specific replacement. |
| GO:0001523 retinoid metabolic process | TAS Reactome:R-HSA-975634 | KEEP AS NON CORE | Summary: Reactome TAS placing AKR1C4 in retinoid metabolism, consistent with its documented retinaldehyde reductase activity (reduces retinaldehyde to retinol, IDA PMID:21851338). A real but minor, non-core metabolic role for this liver enzyme. Reason: Full PMID:21851338 directly demonstrates retinaldehyde-to-retinol catalysis and tests retinoic-acid reporter consequences in transfected cells. Retain this secondary metabolic process while correcting the separately annotated reaction chemistry. Supporting Evidence: PMID:21851338 retinaldehyde reductase activity with low Km values |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-193368 | ACCEPT | Summary: Reactome TAS (bile-acid synthesis via 7alpha-hydroxycholesterol). This is a core biological process for AKR1C4: as the hepatic 3-alpha-hydroxysteroid dehydrogenase it reduces the 3-oxo group of the 5beta-reduced bile-acid intermediates (downstream of the AKR1D1 5beta-reductase). Reason: AKR1C4 directly reduces the 3-oxo group of 5beta-reduced bile-acid intermediates in the cited Reactome pathway variants. Catalysis of that step is a core biosynthetic contribution. Supporting Evidence: PMID:11158055 3 alpha-HSDs are involved in the metabolism of glucocorticoids, progestins, prostaglandins, bile acid precursors |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-193775 | ACCEPT | Summary: Reactome TAS (bile-acid synthesis via 24-hydroxycholesterol). Same core bile-acid biosynthetic role; redundant Reactome pathway variant. Reason: AKR1C4 directly reduces the 3-oxo group of 5beta-reduced bile-acid intermediates in the cited Reactome pathway variants. Catalysis of that step is a core biosynthetic contribution. Supporting Evidence: PMID:11158055 3 alpha-HSDs are involved in the metabolism of glucocorticoids, progestins, prostaglandins, bile acid precursors |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-193807 | ACCEPT | Summary: Reactome TAS (bile-acid synthesis via 27-hydroxycholesterol). Same core bile-acid biosynthetic role; redundant Reactome pathway variant. Reason: AKR1C4 directly reduces the 3-oxo group of 5beta-reduced bile-acid intermediates in the cited Reactome pathway variants. Catalysis of that step is a core biosynthetic contribution. Supporting Evidence: PMID:11158055 3 alpha-HSDs are involved in the metabolism of glucocorticoids, progestins, prostaglandins, bile acid precursors |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-192036 | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-192160 | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-193758 | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-193781 | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-193800 | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-193841 | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-2855252 | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0004303 estradiol 17-beta-dehydrogenase [NAD(P)+] activity | EXP PMID:10998348 Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-A... | KEEP AS NON CORE | Summary: Experimental (Penning et al. 2000): all AKR1C isoforms including AKR1C4 reduce estrone to 17beta-estradiol and oxidize 17beta-estradiol to estrone. A genuine, experimentally-supported but low-efficiency 17beta-HSD activity on estrogens; kept as non-core. Reason: PMID:10998348 explicitly reports estrone/estradiol interconversion by all four human isoforms. PMID:20003443 discusses the limited sensitivity of its negative spectrophotometric result and does not overturn slower activity measured with other methods. Retain the measured secondary capacity. Supporting Evidence: PMID:10998348 All isoforms reduced oestrone to 17beta-oestradiol |
| GO:0047023 androsterone dehydrogenase [NAD(P)+] activity | EXP PMID:10998348 Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-A... | ACCEPT | Summary: Experimental androsterone dehydrogenase activity (reduction of 5alpha-androstan-3,17-dione / oxidation of androsterone), a specific instance of AKR1C4's 3-alpha-hydroxysteroid dehydrogenase repertoire. Genuine; kept as non-core. Reason: Androsterone/3-alpha-androstanediol interconversion is part of the established 3-alpha-hydroxysteroid dehydrogenase substrate range, not a different paralog-exclusive function. Direct steroid assays and the inherited androsterone IBD at PTN000199031 support this catalytic component of AKR1C4 steroid metabolism. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt androsterone + NADP(+) = 5alpha-androstan-3,17-dione + NADPH + |
| GO:0047023 androsterone dehydrogenase [NAD(P)+] activity | EXP PMID:7650035 Substrate specificity, gene structure, and tissue-specific d... | ACCEPT | Summary: Experimental support (Khanna et al. 1995) for the 3-alpha-hydroxysteroid dehydrogenase / androsterone interconversion activity of the liver type-1 enzyme. Genuine specific activity; kept as non-core. Reason: Androsterone/3-alpha-androstanediol interconversion is part of the established 3-alpha-hydroxysteroid dehydrogenase substrate range, not a different paralog-exclusive function. Direct steroid assays and the inherited androsterone IBD at PTN000199031 support this catalytic component of AKR1C4 steroid metabolism. Supporting Evidence: PMID:7650035 interconversion between 5 alpha-dihydrotestosterone and 5 alpha-androstane-3 alpha,17 beta-diol |
| GO:0047024 5-alpha-androstane-3-beta,17-beta-diol dehydrogenase (NADP+) activity | EXP PMID:14672942 Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the ... | KEEP AS NON CORE | Summary: Experimental (Steckelbroeck et al. 2004): AKR1C enzymes including AKR1C4 have significant 3beta-HSD activity, reducing DHT to 3beta-androstanediol. Genuine specific 3beta-HSD activity; kept as non-core. Reason: Direct steroid assays in PMID:14672942 and the product-identification experiments in PMID:19218247 establish 3beta as well as 3alpha products. Retain this secondary stereochemical capacity; 3alpha preference does not imply absolute exclusion of 3beta turnover. Supporting Evidence: PMID:14672942 AKR1Cs catalyze the reduction of DHT into both 3alpha- and 3beta-Diol |
| GO:0047035 testosterone dehydrogenase (NAD+) activity | EXP PMID:10998348 Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-A... | KEEP AS NON CORE | Summary: Experimental: AKR1C4 oxidizes testosterone to androst-4-ene-3,17-dione (NAD+-linked, EC 1.1.1.51). Genuine 17beta-HSD/testosterone dehydrogenase activity; kept as non-core (reductive direction dominates in vivo). Reason: The original steroid enzymology describes oxidation as well as reduction of 17beta-hydroxysteroids. Reductive preference in cells does not erase experimentally measured oxidative capacity; retain this secondary reaction scope. Supporting Evidence: PMID:10998348 AKR1C3 and AKR1C4 oxidized testosterone to Delta(4)-androstene-3,17-dione |
| GO:0047045 testosterone dehydrogenase (NADP+) activity | EXP PMID:10998348 Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-A... | KEEP AS NON CORE | Summary: Experimental testosterone dehydrogenase (NADP+) activity for AKR1C4. Genuine specific activity; kept as non-core. Reason: The original steroid enzymology describes oxidation as well as reduction of 17beta-hydroxysteroids. Reductive preference in cells does not erase experimentally measured oxidative capacity; retain this secondary reaction scope. Supporting Evidence: PMID:10998348 AKR1C3 and AKR1C4 oxidized testosterone to Delta(4)-androstene-3,17-dione |
| GO:0047743 chlordecone reductase activity | EXP PMID:2187532 Isolation and characterization of cloned cDNAs encoding huma... | KEEP AS NON CORE | Summary: Experimental support (Winters et al. 1990) from cloning of human liver chlordecone reductase (AKR1C4). Chlordecone -> chlordecone alcohol reduction is a bona fide xenobiotic-detoxification activity; kept as non-core. Reason: The cited purification and cloning studies establish human liver chlordecone reduction to its alcohol metabolite. This is a real xenobiotic substrate capability, retained as non-core relative to endogenous steroid metabolism. Supporting Evidence: PMID:2187532 Chlordecone (Kepone), a toxic organochlorine pesticide, undergoes bioreduction to chlordecone alcohol in human liver |
| GO:0140169 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity | EXP PMID:10634139 Characterization of a novel variant (S145C/L311V) of 3alpha-... | ACCEPT | Summary: Experimental support for the 3-alpha-hydroxysteroid/dihydrodiol dehydrogenase activity of the human liver enzyme (variant characterization). Part of the strong experimental basis for the core MF. Reason: The source-specific enzyme studies and independent steroid product assays support 3alpha-hydroxysteroid dehydrogenase activity as core catalysis. Variant, conjugate and tissue contexts provide complementary evidence rather than making a duplicated activity assertion excessive. Supporting Evidence: PMID:10634139 Human liver 3alpha-hydroxysteroid/dihydrodiol dehydrogenase (DD) is involved in the metabolism of steroid hormones |
| GO:0140169 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity | EXP PMID:10998348 Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-A... | ACCEPT | Summary: Experimental (Penning et al. 2000): AKR1C4 is the type-1 3alpha-HSD and is the most catalytically efficient of the AKR1C isoforms. Core molecular function. Reason: The source-specific enzyme studies and independent steroid product assays support 3alpha-hydroxysteroid dehydrogenase activity as core catalysis. Variant, conjugate and tissue contexts provide complementary evidence rather than making a duplicated activity assertion excessive. Supporting Evidence: PMID:10998348 type 1 3alpha-HSD (AKR1C4) |
| GO:0140169 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity | EXP PMID:11158055 Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: d... | ACCEPT | Summary: Human type 1 3alpha-HSD (AKR1C4) efficiently catalyzes DHT-to-3alpha-diol conversion. Adult liver enrichment does not exclude the fetal testis/adrenal expression demonstrated in PMID:21802064. Reason: The source-specific enzyme studies and independent steroid product assays support 3alpha-hydroxysteroid dehydrogenase activity as core catalysis. Variant, conjugate and tissue contexts provide complementary evidence rather than making a duplicated activity assertion excessive. Supporting Evidence: PMID:11158055 3 alpha-Hydroxysteroid dehydrogenases (3 alpha-HSDs) catalyze the conversion of 3-ketosteroids to 3 alpha-hydroxy compounds |
| GO:0140169 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity | EXP PMID:14672942 Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the ... | ACCEPT | Summary: Experimental (Steckelbroeck et al. 2004): AKR1C4 acts as a (non-positional-specific) 3alpha-/3beta-HSD. Core molecular function. Reason: The source-specific enzyme studies and independent steroid product assays support 3alpha-hydroxysteroid dehydrogenase activity as core catalysis. Variant, conjugate and tissue contexts provide complementary evidence rather than making a duplicated activity assertion excessive. Supporting Evidence: PMID:14672942 known to act as non-positional-specific 3alpha-/17beta-/20alpha-HSDs |
| GO:0140169 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity | EXP PMID:19218247 Human cytosolic hydroxysteroid dehydrogenases of the aldo-ke... | ACCEPT | Summary: Experimental (Jin et al. 2009): AKR1C4 is the most efficient 3-keto reductase for DHT and its conjugates, acting mainly as a reductive 3alpha-HSD in liver. Core molecular function. Reason: The source-specific enzyme studies and independent steroid product assays support 3alpha-hydroxysteroid dehydrogenase activity as core catalysis. Variant, conjugate and tissue contexts provide complementary evidence rather than making a duplicated activity assertion excessive. Supporting Evidence: PMID:19218247 AKR1C4 is very efficient at 3-keto reduction and acts mainly as a reductive 3Ξ±-HSD |
| GO:0140169 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity | EXP PMID:21802064 Why boys will be boys: two pathways of fetal testicular andr... | ACCEPT | Summary: Experimental support in the context of the "backdoor" androgen pathway / 46,XY DSD study; AKR1C4 has 3alpha-HSD activity relevant to pregnane reduction. Core molecular function. Reason: The source-specific enzyme studies and independent steroid product assays support 3alpha-hydroxysteroid dehydrogenase activity as core catalysis. Variant, conjugate and tissue contexts provide complementary evidence rather than making a duplicated activity assertion excessive. Supporting Evidence: PMID:21802064 AKR1C4, which encodes an enzyme with similar activity |
| GO:0140169 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity | EXP PMID:7650035 Substrate specificity, gene structure, and tissue-specific d... | ACCEPT | Summary: Experimental (Khanna et al. 1995): the liver type-1 enzyme (AKR1C4) interconverts DHT and 5alpha-androstane-3alpha,17beta-diol. Core molecular function. Reason: The source-specific enzyme studies and independent steroid product assays support 3alpha-hydroxysteroid dehydrogenase activity as core catalysis. Variant, conjugate and tissue contexts provide complementary evidence rather than making a duplicated activity assertion excessive. Supporting Evidence: PMID:7650035 interconversion between 5 alpha-dihydrotestosterone and 5 alpha-androstane-3 alpha,17 beta-diol |
| GO:0140169 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity | EXP PMID:8172617 Molecular cloning of two human liver 3 alpha-hydroxysteroid/... | ACCEPT | Summary: Experimental support (Deyashiki et al. 1994): DD4 (= AKR1C4 / chlordecone reductase) is a human liver 3alpha-hydroxysteroid/dihydrodiol dehydrogenase. Core molecular function. Reason: The source-specific enzyme studies and independent steroid product assays support 3alpha-hydroxysteroid dehydrogenase activity as core catalysis. Variant, conjugate and tissue contexts provide complementary evidence rather than making a duplicated activity assertion excessive. Supporting Evidence: PMID:8172617 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes |
| GO:0047743 chlordecone reductase activity | IDA PMID:2427522 Purification and characterization of chlordecone reductase f... | KEEP AS NON CORE | Summary: Direct assay (Molowa et al. 1986): purification and characterization of human liver chlordecone reductase, the enzyme later shown to be AKR1C4. Genuine xenobiotic-reduction activity; kept as non-core. Reason: The cited purification and cloning studies establish human liver chlordecone reduction to its alcohol metabolite. This is a real xenobiotic substrate capability, retained as non-core relative to endogenous steroid metabolism. Supporting Evidence: PMID:2427522 We purified this enzyme from human liver |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Retain the curated urinary-exosome proteomic detection as a secondary localization. Reason: PMID:23533145 isolates urinary extracellular vesicle preparations and characterizes their proteome. The HDA source is a compartment observation, not a claim that AKR1C4 has an extracellular catalytic role. Its established cytosolic pool does not exclude vesicle-associated detection; generic concerns about contamination are not target-specific contrary evidence. Retain with the limits of high-throughput proteomic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-192036 | ACCEPT | Summary: Reactome TAS cytosol localization, consistent with the curated subcellular location. Core localization. Reason: Cytosol is the established compartment of the soluble enzyme; the individual Reactome reactions and primary liver-enzyme characterization support this same location. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-192160 | ACCEPT | Summary: Reactome TAS cytosol localization (redundant pathway variant). Core localization. Reason: Cytosol is the established compartment of the soluble enzyme; the individual Reactome reactions and primary liver-enzyme characterization support this same location. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-193758 | ACCEPT | Summary: Reactome TAS cytosol localization (redundant pathway variant). Core localization. Reason: Cytosol is the established compartment of the soluble enzyme; the individual Reactome reactions and primary liver-enzyme characterization support this same location. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-193781 | ACCEPT | Summary: Reactome TAS cytosol localization (redundant pathway variant). Core localization. Reason: Cytosol is the established compartment of the soluble enzyme; the individual Reactome reactions and primary liver-enzyme characterization support this same location. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-193800 | ACCEPT | Summary: Reactome TAS cytosol localization (redundant pathway variant). Core localization. Reason: Cytosol is the established compartment of the soluble enzyme; the individual Reactome reactions and primary liver-enzyme characterization support this same location. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-193841 | ACCEPT | Summary: Reactome TAS cytosol localization (redundant pathway variant). Core localization. Reason: Cytosol is the established compartment of the soluble enzyme; the individual Reactome reactions and primary liver-enzyme characterization support this same location. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2855252 | ACCEPT | Summary: Reactome TAS cytosol localization (retinaldehyde-reduction pathway). Core localization. Reason: Cytosol is the established compartment of the soluble enzyme; the individual Reactome reactions and primary liver-enzyme characterization support this same location. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0044597 daunorubicin metabolic process | IMP PMID:20837989 Naturally occurring variants of human aldo-keto reductases w... | KEEP AS NON CORE | Summary: Experimental (Bains et al. 2010): the L311V AKR1C4 variant significantly reduces in-vitro daunorubicin metabolism, demonstrating AKR1C4 contributes to anthracycline (daunorubicin) reduction. This is a pharmacological/xenobiotic drug-metabolism activity rather than a core physiological process; kept as non-core. Reason: PMID:20837989 assays recombinant wild-type/variant drug reduction and reports decreased turnover by the L311V C4 variant. Retain the pharmacological metabolic capacity without making it the predominant endogenous role. Supporting Evidence: PMID:20837989 the L311V variant of AKR1C4 significantly decreased V(max) |
| GO:0044598 doxorubicin metabolic process | IMP PMID:20837989 Naturally occurring variants of human aldo-keto reductases w... | KEEP AS NON CORE | Summary: Experimental (Bains et al. 2010): AKR1C4 (and variants) affect in-vitro metabolism of doxorubicin/daunorubicin to their alcohol metabolites. Pharmacological drug-metabolism activity; kept as non-core. Reason: PMID:20837989 assays recombinant wild-type/variant drug reduction and reports decreased turnover by the L311V C4 variant. Retain the pharmacological metabolic capacity without making it the predominant endogenous role. Supporting Evidence: PMID:20837989 ns-SNPs in human AKR1C3, AKR1C4, and AKR7A2 significantly decrease the in vitro metabolism of DOX and DAUN |
| GO:0071395 cellular response to jasmonic acid stimulus | IDA PMID:19487289 AKR1C isoforms represent a novel cellular target for jasmona... | UNDECIDED | Summary: Jasmonic acid inhibits recombinant AKR1C4, but the C4-specific cellular-response interpretation is unresolved. Reason: Full PMID:19487289 shows inhibition of purified C4 in a quinone-reduction assay; the downstream cellular PGD2 experiments focus on C3. GO:0071395 is a cellular response term and does not require an endogenous plant signaling pathway. Biochemical inhibition alone does not settle whether C4 executes part of a cellular response, but neither human taxonomy nor steroid specialization proves the term wrong. Preserve uncertainty about the curated cellular interpretation. |
| GO:0001758 retinal dehydrogenase (NAD+) activity | IDA PMID:21851338 Retinaldehyde is a substrate for human aldo-keto reductases ... | MODIFY | Summary: The source demonstrates NADPH-dependent retinal reduction to retinol, not NAD+-dependent retinal oxidation to retinoate. Reason: Full PMID:21851338 uses purified C4, defined retinoid standards and HPLC to identify retinol formation from all-trans-retinaldehyde with NADPH. Live GO:0001758 describes retinal-to-retinoate oxidation; it is not the reverse of the demonstrated reaction. GO:0052650 captures all-trans-retinol/retinal interconversion with NADP(H), including the measured reductive direction. This is a secondary retinoid capability; the replacement does not assert efficient oxidative turnover in the tested assay. Proposed replacements: all-trans-retinol dehydrogenase (NADP+) activity Supporting Evidence: PMID:21851338 retinaldehyde reductase activity with low Km values |
| GO:0016655 oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor | IDA PMID:20837989 Naturally occurring variants of human aldo-keto reductases w... | KEEP AS NON CORE | Summary: AKR1C4 can reduce quinone substrates with NADPH. Reason: In addition to the anthracycline experiments in the original source PMID:20837989, full PMID:19487289 and PMID:20003443 directly assay recombinant C4 reduction of 9,10-phenanthrenequinone. This independently fits the NAD(P)H-donor/quinone-acceptor reaction class. The former exclusion assumed an overly narrow interpretation of anthracycline chemistry and overlooked the direct quinone assay. Retain this secondary substrate capability. Supporting Evidence: PMID:20003443 All purified proteins were able to reduce the pan-substrate 9, 10-phenanthrenequinone |
| GO:0047023 androsterone dehydrogenase [NAD(P)+] activity | IDA PMID:21851338 Retinaldehyde is a substrate for human aldo-keto reductases ... | ACCEPT | Summary: Direct assay support for androsterone dehydrogenase activity for AKR1C4. Genuine specific instance of the core 3-alpha-hydroxysteroid dehydrogenase function; kept as non-core. Reason: Androsterone/3-alpha-androstanediol interconversion is part of the established 3-alpha-hydroxysteroid dehydrogenase substrate range, not a different paralog-exclusive function. Direct steroid assays and the inherited androsterone IBD at PTN000199031 support this catalytic component of AKR1C4 steroid metabolism. Supporting Evidence: file:human/AKR1C4/AKR1C4-uniprot.txt androsterone + NADP(+) = 5alpha-androstan-3,17-dione + NADPH + |
| GO:0009055 electron transfer activity | TAS PMID:8172617 Molecular cloning of two human liver 3 alpha-hydroxysteroid/... | ACCEPT | Summary: AKR1C4 catalyzes electron transfer during NADP(H)-dependent substrate reduction and oxidation. Reason: The live GO:0009055 definition includes enzymatic redox transformations, not only respiratory carriers. Hydride transfer between nicotinamide cofactor and carbonyl substrates is integral to the documented catalytic function. The previous removal imposed an unsupported restriction on this broad term. |
| GO:0005737 cytoplasm | TAS PMID:2187532 Isolation and characterization of cloned cDNAs encoding huma... | ACCEPT | Summary: TAS cytoplasm localization from the chlordecone reductase cloning paper (describes a cytosolic enzyme). Correct but less precise than the cytosol annotation; retained as non-core (the cytosol term is the core CC). Reason: Cytoplasm is a true broad compartment containing the established cytosolic enzyme. A narrower cytosol annotation does not make the parent location non-core. Supporting Evidence: PMID:2187532 This reaction is controlled by a cytosolic enzyme, chlordecone reductase (CDR) |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | TAS PMID:7650035 Substrate specificity, gene structure, and tissue-specific d... | ACCEPT | Summary: The broad redox or metabolic annotation accurately describes AKR1C4 catalytic function. Reason: AKR1C4 catalyzes carbonyl/alcohol interconversion with NADP(H) and directly performs steroid-hormone and bile-acid pathway steps. The broad alcohol-dehydrogenase chemistry is applicable to these ketosteroid/hydroxysteroid pairs; it is not restricted to ethanol. Hormone and monocarboxylic-acid metabolism include the corresponding steroid and bile-acid pathways, without requiring the immediate enzyme substrate to be the final acid. Greater specificity elsewhere does not make a true core parent term an over-annotation. |
| GO:0008202 steroid metabolic process | TAS PMID:8274401 Molecular cloning of multiple cDNAs encoding human enzymes s... | ACCEPT | Summary: TAS from the cDNA cloning paper describing enzymes structurally related to 3alpha-HSD. Steroid metabolic process is the central, well-supported biological process for AKR1C4. Accepted as core. Reason: The enzyme directly transforms steroid substrates, including androgens, in the cited characterization studies. These are catalytic contributions to the named processes rather than a phenotype caused only by altered expression. Supporting Evidence: PMID:8274401 3 alpha-hydroxysteroid dehydrogenase |
| GO:0008209 androgen metabolic process | TAS PMID:7650035 Substrate specificity, gene structure, and tissue-specific d... | ACCEPT | Summary: TAS androgen metabolic process, strongly supported: AKR1C4 inactivates 5alpha-DHT (to 3alpha/3beta-androstanediols) and interconverts testosterone/androstenedione, functioning in pre-receptor androgen regulation. A core biological process (a specific and well-supported subset of steroid metabolism). Reason: The enzyme directly transforms steroid substrates, including androgens, in the cited characterization studies. These are catalytic contributions to the named processes rather than a phenotype caused only by altered expression. Supporting Evidence: PMID:7650035 interconversion between 5 alpha-dihydrotestosterone and 5 alpha-androstane-3 alpha,17 beta-diol |
| GO:0015125 bile acid transmembrane transporter activity | TAS PMID:8172617 Molecular cloning of two human liver 3 alpha-hydroxysteroid/... | REMOVE | Summary: A soluble cytosolic AKR is not an intrinsic bile-acid transmembrane transporter. Reason: PMID:8172617 distinguishes the C9 bile-acid-binder clone from C11/DD4, but the accessible abstract is not sufficient to determine every transport experiment or interpretation in the full paper. The relevant scanned full text was not obtained. Unlike the broad bile-acid transport process, GO:0015125 asserts intrinsic transmembrane-transporter activity; AKR1C4 is a soluble cytosolic enzyme with no transmembrane feature, and neither free bile-acid binding nor a possible intracellular carrier role would support this molecular-function term. |
| GO:0015721 bile acid and bile salt transport | TAS PMID:8172617 Molecular cloning of two human liver 3 alpha-hydroxysteroid/... | UNDECIDED | Summary: The original bile-acid transport assertions require full-source assessment independently of the catalytic role. Reason: PMID:8172617 distinguishes the C9 bile-acid-binder clone from C11/DD4, but the accessible abstract is not sufficient to determine every transport experiment or interpretation in the full paper. The relevant scanned full text was not obtained. Soluble localization does not categorically preclude ligand transport, and the broad transport process is not equivalent to intrinsic transmembrane-transporter activity. Leave the broad process unresolved pending source adjudication without reviving the intrinsic transmembrane-transporter MF. |
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