AKR1C1
aldo-keto reductase family 1 member C1
Theoretical — per Powers
Gene summary
A protein-coding gene on chromosome 10 (steroid hormone synthesis, steroid conjugation and clearance). Encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors.
Source: NCBI Gene, accessed 2026-10-07.
Protein reference (UniProt)
- Protein
Aldo-keto reductase family 1 member C1
- Function (excerpt)
Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids. Displays broad substrate specificity with distinct positional and stereochemistry, primarily generating 20alpha-hydroxysteroids, but also 3alpha/beta- and 17beta-hydroxysteroids. Involved in neurosteroid metabolism. Reduces 5alpha-dihydrodeoxycorticosterone (5-alpha-DHDOC) to neuroactive steroid 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) known to alter neural excitability via allosteric activation of gamma-aminobutyric acid type A (GABAAR) receptors. Inactivates 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) into less potent neurosteroid 3alpha,20alpha-dihydroxy-5alpha-pregnane. Catalyzes the reduction of progesterone to less potent progestogen (20S)-hydroxypregn-4-en-3-one likely regulating ligand availability for progesterone receptors.
- Pathway
Steroid metabolism.
- Subcellular location
Cytoplasm, cytosol.
- Tissue specificity
Expressed in all tissues tested including liver, prostate, testis, adrenal gland, brain, uterus, mammary gland and keratinocytes. Highest levels found in liver, mammary gland and brain.
Source: UniProtKB/Swiss-Prot Q04828, release 2026_03, licensed CC BY 4.0. This is the protein’s normal biology, not evidence about post-drug syndromes; associated conditions are inherited disorders of the gene, not PFS, PSSD or PRSD.
Why its pathway is in the library
Steroid-synthesis enzymes sit directly on the pathways perturbed by 5-alpha-reductase inhibitors and SSRIs; inherited variation here is a candidate susceptibility factor for persistent post-drug phenotypes. Steroid clearance is the exit route for androgens and their metabolites — the pathway at the center of Powers' PFS model (defective glucuronidation/sulfation trapping androgens intracellularly). Gut bacterial enzymes can undo this clearance, linking it to the microbiome thread.
Written for the whole steroid synthesis / conjugation & clearance family, not for AKR1C1 specifically.
Powers’ note (his unpublished theorizing)
Named by Powers (DWP-001 2020 model; DWP-003, unpublished): decreased-function AKR1C variants were his original proposed susceptibility factor — impaired neurosteroid (allopregnanolone) synthesis when 5AR is blocked. In his 2026 revision, AKR1C products feed the glucuronidation exit, making UGT defects the more fundamental lesion; AKR1C enzymes are also described as epigenetically silenceable.
Narrative library record
Function
Cytosolic NAD(P)H-dependent oxidoreductase with mainly 20-alpha-hydroxysteroid dehydrogenase activity; converts progesterone to the inactive 20-alpha-hydroxyprogesterone and also reduces a range of aldehydes, ketones, and xenobiotics. One of four closely related AKR1C enzymes clustered together on chromosome 10 with overlapping but distinct substrate preferences.
Corpus relevance
Member of the AKR1C family at the center of Powers' original PFS theory (DWP-001), which proposed that decreased-function variants in AKR1C enzymes impair downstream neurosteroid synthesis when 5-alpha-reductase is blocked, explaining why only a susceptible subset develops PFS. AKR1C1's 20-alpha-HSD activity sits on the progesterone/allopregnanolone axis Powers discusses. Attribution: theoretical-per-Powers (unpublished Reddit theorizing); no PFS patient variant data in corpus.
Powers’ claims naming AKR1C1
- Powers gene claim
AKR1C1; AKR1C2; AKR1C3; AKR1C4 — defects (unspecified)
Confidence: direct
Defects in AKR1C enzymes can contribute, but their products are mostly cleared via glucuronidation — so a bad glucuronidation enzyme (UGT2B1X) is the more fundamental defect. AKR1C enzymes and SRD5A1 are also epigenetically silenceable, and valproic acid may…
AKR1C1AKR1C2AKR1C3AKR1C4SRD5A1PGL-AKR1C1-AKR1C2-AKR1C3-AKR1C4circa May 2026PFS
Mentioned in 5 corpus records
- Powers · Reddit post
I think I have figured out at least one specific phenotype of PFS, and it is different from the "allopregnanolone" theory
u/drwillpowers · r/DrWillPowers
Powers' key genetics-first post: he proposed a specific PFS phenotype whose "base, core defect" is defective UGT2B17, disabling testosterone's main glucuronidation exit pathway. Carriers show shockingly low 3α-androstanediol glucuronide and near-zero urinary…
AKR1C1AKR1C2AKR1C3AKR1C4HSD17B2+3DWP-0032026PFSCore corpus - Gene recordPowers’ theory
AKR1C2 — aldo-keto reductase family 1 member C2
10p15-p14 (AKR1C gene cluster, chromosome 10)
3-alpha-hydroxysteroid dehydrogenase type 3; interconverts DHT and the much weaker 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol), effectively switching DHT's androgenic signal off, and participates in synthesis of neurosteroids such as…
AKR1C1AKR1C2AKR1C3AKR1C4AR+1GENE-AKR1C2PFSCore corpus - Gene recordPowers’ theory
AKR1C3 — aldo-keto reductase family 1 member C3
10p15-p14 (AKR1C gene cluster, chromosome 10)
3-alpha-hydroxysteroid dehydrogenase type 2 (also 17-beta-hydroxysteroid dehydrogenase type 5); metabolizes prostaglandins, estrogens, and progesterone in addition to androgens, and is overexpressed in prostate cancer. Broadest substrate range of the four…
AKR1C1AKR1C2AKR1C3AKR1C4CYP19A1GENE-AKR1C3Core corpus - Gene recordPowers’ theory
AKR1C4 — aldo-keto reductase family 1 member C4
10p15-p14 (AKR1C gene cluster, chromosome 10)
3-alpha-hydroxysteroid dehydrogenase type 1; liver-restricted isoform that reduces 3-keto-5-dihydrosteroids to tetrahydro products and participates in neurosteroid synthesis. Loss of AKR1C4 alone does not cause developmental phenotypes but can worsen the…
AKR1C1AKR1C2AKR1C3AKR1C4UGT1A1+1GENE-AKR1C4Core corpus - Gene record
Bifunctional enzyme oxidizing delta-5-3-beta-hydroxysteroids and isomerizing them to delta-4-ketosteroids - an essential step in making all classes of active steroid hormones. HSD3B1 is expressed in placenta and peripheral tissues (critical for placental…
AKR1C1CYP17A1HSD3B1HSD3B2SRD5A1GENE-HSD3B1PFSPSSDCore corpus
Also in steroid hormone synthesis
All 38 genes- SRD5A2
steroid 5 alpha-reductase 2
chr 2· Steroid synthesis· 19 records - SRD5A1Powers
steroid 5 alpha-reductase 1
chr 5· Steroid synthesis· 17 records - AKR1C2Powers
aldo-keto reductase family 1 member C2
chr 10· Steroid synthesis· 12 records - AKR1C3Powers
aldo-keto reductase family 1 member C3
chr 10· Steroid synthesis· 9 records - CYP17A1
cytochrome P450 family 17 subfamily A member 1
chr 10· Steroid synthesis· 9 records - AKR1C4Powers
aldo-keto reductase family 1 member C4
chr 10· Steroid synthesis· 8 records - HSD3B2
hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2
chr 1· Steroid synthesis· 7 records - SRD5A3
steroid 5 alpha-reductase 3
chr 4· Steroid synthesis· 6 records
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