AKR1C4 (P17516) — gene review notes

Identity

• UniProt: P17516 (AK1C4_HUMAN), 323 aa, gene AKR1C4 (synonym CHDR), human (NCBITaxon:9606).
• Names: Aldo-keto reductase family 1 member C4; 3-alpha-hydroxysteroid 3-dehydrogenase type I (3-alpha-HSD1); Chlordecone reductase (CDR); Dihydrodiol dehydrogenase 4 (DD-4/DD4); HAKRA. [file:human/AKR1C4/AKR1C4-uniprot.txt, "RecName: Full=Aldo-keto reductase family 1 member C4"]
• Member of the aldo/keto reductase family. [file:human/AKR1C4/AKR1C4-uniprot.txt, "Belongs to the aldo/keto reductase family."]

Core molecular function

• Cytosolic NADPH-dependent aldo-keto reductase catalyzing reduction of ketosteroids to hydroxysteroids, with broad substrate specificity producing 3alpha/beta-, 17beta- and 20alpha-hydroxysteroids. [file:human/AKR1C4/AKR1C4-uniprot.txt, "Cytosolic aldo-keto reductase that catalyzes NADPH-dependent"]
• The general catalyzed reaction: a 3alpha-hydroxysteroid + NADP(+) = a 3-oxosteroid + NADPH + H(+) (EC 1.1.1.357; GO:0140169 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity). Physiological direction is right-to-left (reductase). [file:human/AKR1C4/AKR1C4-uniprot.txt, "Reaction=a 3alpha-hydroxysteroid + NADP(+) = a 3-oxosteroid + NADPH +"]
• Named as type 1 3alpha-HSD; the expressed enzyme interconverts 5alpha-dihydrotestosterone and 5alpha-androstane-3alpha,17beta-diol, and is virtually liver-specific. PMID:7650035, PMID:7650035
• Most catalytically efficient of the four human AKR1C 3alpha-HSD isoforms; virtually liver-specific; forms 5alpha/5beta-tetrahydrosteroids robustly. PMID:10998348, PMID:10998348
• Also displays significant 3beta-HSD activity (reduces DHT to both 3alpha- and 3beta-diol); in vivo works preferentially as a reductase because the oxidase activity is inhibited by low micromolar NADPH. PMID:14672942, PMID:14672942
• NADP(H)-dependent; cofactor binding residues span 20-24, 50, 166-167, 190, 216-221, 270-280 (crystal 2FVL, NADP+ complex). [file:human/AKR1C4/AKR1C4-uniprot.txt, "COMPLEX WITH NADP(+)"]

Additional (broad, promiscuous) activities — mostly in-vitro substrate range

• Estradiol 17-beta-dehydrogenase (reduces estrone to 17beta-estradiol, low efficiency). [file:human/AKR1C4/AKR1C4-uniprot.txt, "Catalyzes the reduction of estrone into 17beta-"], EXP PMID:10998348.
• Androsterone dehydrogenase [NAD(P)+] (GO:0047023): reduction of 5alpha-androstan-3,17-dione ⇌ androsterone. EXP PMID:10998348, PMID:7650035; IDA PMID:21851338.
• Testosterone dehydrogenase (NAD+/NADP+) (GO:0047035 / GO:0047045): oxidizes testosterone to androst-4-ene-3,17-dione (EC 1.1.1.51). EXP PMID:10998348.
• 5-alpha-androstane-3-beta,17-beta-diol dehydrogenase (NADP+) (GO:0047024, EC 1.1.1.210): the 3beta-HSD reaction. EXP PMID:14672942.
• Chlordecone reductase (GO:0047743, EC 1.1.1.225): biotransforms the pesticide chlordecone (Kepone) to its alcohol, increasing biliary excretion and reducing neurotoxicity. Historically purified/cloned as "chlordecone reductase". PMID:2427522, PMID:2187532. IDA PMID:2427522, EXP PMID:2187532.
• Reduces conjugated (sulfate/glucuronide) DHT; AKR1C4 shows superior catalytic efficiency versus the other isoforms, unaffected by conjugation → hepatic "conjugation pathway" for Dht metabolism (UGT2B17 then AKR1C4). PMID:19218247, PMID:19218247.
• Retinaldehyde reductase: reduces retinaldehyde with low Km (~1 uM). PMID:21851338. IDA (retinal dehydrogenase GO:0001758) PMID:21851338.

Biological processes / physiology

• Bile-acid synthesis: as liver 3alpha-HSD it reduces the 3-oxo group of 5beta-reduced bile-acid intermediates to 3alpha-hydroxy (downstream of AKR1D1 5beta-reductase). Reactome places AKR1C4 in the reduction of 5beta-cholesten/cholestan-3-one intermediates (R-HSA-192036, -192160, -193758, -193781, -193800, -193841). DR Reactome bile-acid synthesis pathways R-HSA-193368/193775/193807.
• 3alpha-HSDs are known to be involved in the metabolism of glucocorticoids, progestins, prostaglandins, bile acid precursors, and xenobiotics. PMID:11158055
• Steroid hormone metabolism / pre-receptor regulation: modulates levels of active androgens, estrogens and progestins; inactivates 5alpha-DHT to 3alpha/3beta-androstanediols. PMID:10998348, [file:human/AKR1C4/AKR1C4-uniprot.txt, "Regulates ligand availability for steroid hormone receptors."]
• "Backdoor" androgen pathway / male sex determination: with AKR1C2 converts 5alpha-DHP toward allopregnanolone en route to 5alpha-DHT for gonad differentiation; AKR1C4 splicing mutation acts as disease modifier in 46,XY DSD (SRXY8) with causative AKR1C2 mutations. [file:human/AKR1C4/AKR1C4-uniprot.txt, "component of\n"], PMID:21802064.
• Neurosteroid production: reduces 5alpha-DHP and 5alpha-DHDOC to allopregnanolone (3alpha,5alpha-THP) and 3alpha,5alpha-THDOC, GABA-A modulators. [file:human/AKR1C4/AKR1C4-uniprot.txt, "alter neural excitability via allosteric activation of gamma-"]
• Doxorubicin/daunorubicin metabolism: an L311V AKR1C4 variant significantly reduces in-vitro DAUN metabolism. PMID:20837989.
• Jasmonate target: AKR1C isoforms (incl. AKR1C4) are inhibited by jasmonic acid / methyl jasmonate in cancer cells. PMID:19487289.

Localization

• Cytoplasm, cytosol. [file:human/AKR1C4/AKR1C4-uniprot.txt, "SUBCELLULAR LOCATION: Cytoplasm, cytosol"]
• Reported in urinary/prostatic-secretion exosome proteome (HDA, PMID:23533145) — a large-scale MS catalog, not evidence for a physiological extracellular-exosome function.

Interactions

• IntAct: binds AKR1C3 (P42330) and PLXDC2 (Q6UX71). [file:human/AKR1C4/AKR1C4-uniprot.txt, "P17516; P42330: AKR1C3"], [file:human/AKR1C4/AKR1C4-uniprot.txt, "P17516; Q6UX71: PLXDC2"]. IPI protein-binding annotations derive from high-throughput BioPlex interactome screens (PMID:28514442, PMID:33961781).

Curation reasoning summary

• Core MF: GO:0140169 (3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity) — best-supported (8 EXP), covers bile-acid 3-oxo reduction and steroid 3-keto reduction. Supporting broad-but-real specific activities kept as non-core: GO:0047023, GO:0047024, GO:0047743, GO:0004303, GO:0047035, GO:0047045. Plus NADP binding as core cofactor MF (GO:0050661 — not currently annotated but supported by structure).
• Core BP: GO:0006699 (bile acid biosynthetic process), GO:0008202 (steroid metabolic process). Androgen metabolic process (GO:0008209) as core/non-core.
• Over-annotation flags: GO:0004032 (aldose reductase, IBA), GO:0047086 (ketosteroid monooxygenase, IBA — wrong reaction class), GO:0006693/GO:0042448/GO:0044597/GO:0044598 (IBA family metabolic processes), GO:0016491 (bare oxidoreductase), GO:0009055 (electron transfer — miscast for a dehydrogenase), GO:0015125/GO:0015721 (bile-acid transporter/transport — misinterpretation of "bile-acid binder"), GO:0071395 (jasmonic acid response — it is a drug target, not a JA-signaling participant), GO:0070062 (exosome HDA), GO:0032787/GO:0042445 (very general ARBA IEA), GO:0016655 (quinone-acceptor oxidoreductase — doxorubicin quinone reduction is peripheral).
• No experimental annotation is proposed for REMOVE. Clearly-wrong purely-electronic (IEA) or MF-miscast annotations proposed for REMOVE where justified; otherwise MARK_AS_OVER_ANNOTATED / KEEP_AS_NON_CORE.
  
  

2026-09-20 full-gene re-review

Read every source annotation and relevant evidence, including primary full texts for disputed reactions and the exact PAINT target path. See AKR1C4-primary-source-checks.md for assay context, access limits, short exact excerpts, and pending focused adjudication. All original source fields are preserved; no NEW annotation is added. Broad true chemistry and localization are retained separately from exact substrate/reaction conflicts.

2026-10-05 - OpenScientist scope follow-up

Evaluated AKR1C4-hypotheses/aldose-prostaglandin-monooxygenase-and-bile-transport-scope/openscientist.md.
The report reinforced the existing concerns around ancestral aldose reduction,
inherited prostaglandin metabolism, GO:0047086 oxygen-insertion chemistry, and
historical bile-acid-binder/transport carry-over from DD2 versus DD4 clone
nomenclature.

I did not adopt its removal recommendations wholesale, but the report sharpened
two access-independent removals: GO:0047086 asserts oxygen-insertion chemistry
that an AKR hydride-transfer enzyme cannot support, and GO:0015125 asserts
intrinsic transmembrane-transporter activity for a soluble cytosolic bile-acid
binder. A direct AKR1C4 aldose-reduction null assay remains absent, PMID:21232532
still needs full-text review on the donor side, and the scanned full text of
PMID:8172617 is still required to judge the broad bile-acid transport process.