Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic Gene Ontology annotation based on Rhea mapping
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Characterization of a novel variant (S145C/L311V) of 3alpha-hydroxysteroid/dihydrodiol dehydrogenase in human liver.
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Human liver 3alpha-hydroxysteroid/dihydrodiol dehydrogenase (AKR1C4) is involved in the metabolism of steroid hormones and polycyclic aromatic hydrocarbons and reduces ketone-containing drugs; the S145C/L311V variant has 3-5-fold reduced activity.
"Human liver 3alpha-hydroxysteroid/dihydrodiol dehydrogenase (DD) is involved in
the metabolism of steroid hormones and polycyclic aromatic hydrocarbons"
Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones.
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AKR1C4 is the type 1 3alpha-HSD, the most catalytically efficient AKR1C isoform, virtually liver-specific, and inactivates 5alpha-DHT to 3alpha-androstanediol; the isoforms modulate levels of active androgens, estrogens and progestins.
"AKR1C4 was virtually liver-specific
and its high k(cat)/K(m) allows this enzyme to form
5alpha/5beta-tetrahydrosteroids robustly"
Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution.
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Human type 1 3alpha-HSD (AKR1C4) efficiently converts dihydrotestosterone to 3alpha-diol and is expressed exclusively in the liver; 3alpha-HSDs act on glucocorticoids, progestins, prostaglandins, bile acid precursors and xenobiotics.
"3 alpha-HSDs are involved in the
metabolism of glucocorticoids, progestins, prostaglandins, bile acid precursors"
Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3beta-hydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action.
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AKR1C enzymes (including AKR1C4) catalyze reduction of DHT into both 3alpha- and 3beta-androstanediol and act as non-positional-specific 3alpha-/17beta-/20alpha-HSDs; in vivo they work preferentially as reductases because NADPH inhibits the oxidase direction.
"in vivo all AKR1Cs will preferentially
work as reductases"
Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism.
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AKR1C4 reduces conjugated (sulfate/glucuronide) DHT with superior catalytic efficiency unaffected by conjugation, and drives the hepatic "conjugation pathway" (UGT2B17 then AKR1C4) for DHT metabolism.
"AKR1C4 is set to be the most important 3-keto reductase for Dht metabolism"
AKR1C isoforms represent a novel cellular target for jasmonates alongside their mitochondrial-mediated effects.
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Jasmonic acid and methyl jasmonate inhibit all four human AKR1C isoforms; AKR1C enzymes are a pharmacological target of jasmonates in cancer cells.
"jasmonic acid (JA) and methyl jasmonate
(MeJ) are capable of inhibiting all four human AKR1C isoforms"
Naturally occurring variants of human aldo-keto reductases with reduced in vitro metabolism of daunorubicin and doxorubicin.
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The L311V variant of AKR1C4 significantly reduces in-vitro daunorubicin metabolism; ns-SNPs in AKR1C4 decrease in-vitro metabolism of doxorubicin and daunorubicin to their alcohol metabolites.
"the L311V variant of AKR1C4 significantly decreased V(max)"
Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation.
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A splicing mutation causing loss of AKR1C4 exon 2 co-occurs with causative AKR1C2 mutations in 46,XY DSD individuals, worsening the phenotype; AKR1C4 acts as a disease modifier in the alternative (backdoor) androgen pathway required for male sexual differentiation.
"The 46,XY DSD individuals also
carry a mutation causing aberrant splicing in AKR1C4"
Retinaldehyde is a substrate for human aldo-keto reductases of the 1C subfamily.
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Human AKR1C enzymes (all except AKR1C2, so including AKR1C4) show retinaldehyde reductase activity with low Km (~1 uM), linking AKR1C to retinoid metabolism.
"retinaldehyde reductase activity with low Km values"
Isolation and characterization of cloned cDNAs encoding human liver chlordecone reductase.
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Chlordecone (Kepone) is bioreduced to chlordecone alcohol in human liver by the cytosolic enzyme chlordecone reductase (CDR), later identified as AKR1C4.
"Chlordecone (Kepone), a toxic organochlorine pesticide, undergoes bioreduction
to chlordecone alcohol in human liver"
In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
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Large-scale shotgun proteomics of urinary prostatic-secretion exosomes detected ~900 proteins; AKR1C4 was among proteins catalogued (basis for the HDA extracellular-exosome annotation).
"In pooled EPS-urine exosome
samples, ~900 proteins were detected"
Purification and characterization of chlordecone reductase from human liver.
Architecture of the human interactome defines protein communities and disease networks.
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Proteome-scale affinity-purification (BioPlex) interactome study; source of high-throughput AKR1C4 protein-protein interaction (protein binding) annotations.
"Architecture of the human interactome defines protein communities and disease networks"
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
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BioPlex 3.0 proteome-scale interactome study; source of additional high-throughput AKR1C4 protein-protein interaction (protein binding) annotations.
"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome"
Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases.
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The expressed liver type 1 3alpha-HSD (AKR1C4) interconverts 5alpha-dihydrotestosterone and 5alpha-androstane-3alpha,17beta-diol and its mRNA is found only in the liver.
"interconversion between 5 alpha-dihydrotestosterone and 5
alpha-androstane-3 alpha,17 beta-diol"
Molecular cloning of two human liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile-acid binder.
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DD4 (= AKR1C4) is a human liver 3alpha-hydroxysteroid/dihydrodiol dehydrogenase whose cDNA is virtually identical with human chlordecone reductase; the related DD2 corresponds to the "bile-acid binder".
"virtually identical with those of human bile-acid
binder and human chlordecone reductase cDNAs"
Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase.
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Cloning of multiple human cDNAs encoding enzymes structurally related to 3alpha-hydroxysteroid dehydrogenase, the family that includes AKR1C4, supporting a role in steroid metabolism.
"3 alpha-hydroxysteroid dehydrogenase"
5Beta-cholesten-7alpha, 12alpha-diol-3-one is reduced to 5beta-cholestan-3alpha, 7alpha, 12alpha-triol
5beta-cholestan-7alpha-ol-3-one is reduced to 5beta-cholestan-3alpha, 7alpha-diol
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
5beta-cholestan-7alpha,24(S)-diol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,24(S)-triol
Synthesis of bile acids and bile salts via 24-hydroxycholesterol
5Beta-cholestan-7alpha,12alpha,27-triol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,12alpha,27-tetrol
Synthesis of bile acids and bile salts via 27-hydroxycholesterol
5beta-cholestan-7alpha,27-diol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,27-triol
AKRs reduce RBP2:atRAL to RBP2:atROL
Retinoid metabolism and transport
Lack of functional and expression homology between human and mouse aldo-keto reductase 1C enzymes: implications for modelling human cancers.
Relationship of human liver dihydrodiol dehydrogenases to hepatic bile-acid-binding protein and an oxidoreductase of human colon cells.
Aldo-keto reductases AKR1C1, AKR1C2 and AKR1C3 may enhance progesterone metabolism in ovarian endometriosis.
AKR1C4 primary-source and PAINT checks, 2026-09-20
OpenScientist focused review of AKR1C4 aldose, prostaglandin, monooxygenase and bile-acid transport scope, 2026-09-21
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The report concluded that AKR1C4's disputed aldose reductase, prostaglandin, ketosteroid monooxygenase and bile-acid transport assertions are not directly supported.
"none of the four contested functions of human AKR1C4 (aldose reductase, prostaglandin metabolism, ketosteroid monooxygenase, bile-acid transmembrane transport) survives as a directly supported, curatable function"
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The report nevertheless left narrow residual uncertainty only around possible weak in-vitro aldose or prostaglandin turnover that would not justify core GO terms.
"narrow residual uncertainty only around unmeasured weak in-vitro aldose/prostaglandin activity that, even if real, would not warrant core GO terms"