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- Name help_outline 20α-hydroxy-5β-pregnan-3-one Identifier CHEBI:78666 Charge 0 Formula C21H34O2 InChIKeyhelp_outline DYVGYXXLXQESJE-WTVMURBBSA-N SMILEShelp_outline C1[C@@]2([C@]3(CC[C@]4([C@]([C@@]3(CC[C@@]2(CC(C1)=O)[H])[H])(CC[C@]4([H])[C@@H](O)C)[H])C)[H])C 2D coordinates Mol file for the small molecule Search links Involved in 1 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline NADP+ Identifier CHEBI:58349 Charge -3 Formula C21H25N7O17P3 InChIKeyhelp_outline XJLXINKUBYWONI-NNYOXOHSSA-K SMILEShelp_outline NC(=O)c1ccc[n+](c1)[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OC[C@H]2O[C@H]([C@H](OP([O-])([O-])=O)[C@@H]2O)n2cnc3c(N)ncnc23)[C@@H](O)[C@H]1O 2D coordinates Mol file for the small molecule Search links Involved in 1,335 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline 5β-pregnan-3,20-dione Identifier CHEBI:30154 (CAS: 128-23-4) help_outline Charge 0 Formula C21H32O2 InChIKeyhelp_outline XMRPGKVKISIQBV-XWOJZHJZSA-N SMILEShelp_outline [H][C@]12CC[C@@]3([H])[C@]4([H])CC[C@H](C(C)=O)[C@@]4(C)CC[C@]3([H])[C@@]1(C)CCC(=O)C2 2D coordinates Mol file for the small molecule Search links Involved in 4 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline NADPH Identifier CHEBI:57783 (Beilstein: 10411862) help_outline Charge -4 Formula C21H26N7O17P3 InChIKeyhelp_outline ACFIXJIJDZMPPO-NNYOXOHSSA-J SMILEShelp_outline NC(=O)C1=CN(C=CC1)[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OC[C@H]2O[C@H]([C@H](OP([O-])([O-])=O)[C@@H]2O)n2cnc3c(N)ncnc23)[C@@H](O)[C@H]1O 2D coordinates Mol file for the small molecule Search links Involved in 1,329 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H+ Identifier CHEBI:15378 Charge 1 Formula H InChIKeyhelp_outline GPRLSGONYQIRFK-UHFFFAOYSA-N SMILEShelp_outline [H+] 2D coordinates Mol file for the small molecule Search links Involved in 9,932 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
Cross-references
| RHEA:42168 | RHEA:42169 | RHEA:42170 | RHEA:42171 | |
|---|---|---|---|---|
| Reaction direction help_outline | undefined | left-to-right | right-to-left | bidirectional |
| UniProtKB help_outline |
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Publications
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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.
Penning T.M., Burczynski M.E., Jez J.M., Hung C.F., Lin H.K., Ma H., Moore M., Palackal N., Ratnam K.
The kinetic parameters, steroid substrate specificity and identities of reaction products were determined for four homogeneous recombinant human 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) isoforms of the aldo-keto reductase (AKR) superfamily. The enzymes correspond to type 1 3alpha-HSD (AKR1 ... >> More
The kinetic parameters, steroid substrate specificity and identities of reaction products were determined for four homogeneous recombinant human 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) isoforms of the aldo-keto reductase (AKR) superfamily. The enzymes correspond to type 1 3alpha-HSD (AKR1C4), type 2 3alpha(17beta)-HSD (AKR1C3), type 3 3alpha-HSD (AKR1C2) and 20alpha(3alpha)-HSD (AKR1C1), and share at least 84% amino acid sequence identity. All enzymes acted as NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductases and as 3alpha-, 17beta- and 20alpha-hydroxysteroid oxidases. The functional plasticity of these isoforms highlights their ability to modulate the levels of active androgens, oestrogens and progestins. Salient features were that AKR1C4 was the most catalytically efficient, with k(cat)/K(m) values for substrates that exceeded those obtained with other isoforms by 10-30-fold. In the reduction direction, all isoforms inactivated 5alpha-dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one; 5alpha-DHT) to yield 5alpha-androstane-3alpha,17beta-diol (3alpha-androstanediol). However, only AKR1C3 reduced Delta(4)-androstene-3,17-dione to produce significant amounts of testosterone. All isoforms reduced oestrone to 17beta-oestradiol, and progesterone to 20alpha-hydroxy-pregn-4-ene-3,20-dione (20alpha-hydroxyprogesterone). In the oxidation direction, only AKR1C2 converted 3alpha-androstanediol to the active hormone 5alpha-DHT. AKR1C3 and AKR1C4 oxidized testosterone to Delta(4)-androstene-3,17-dione. All isoforms oxidized 17beta-oestradiol to oestrone, and 20alpha-hydroxyprogesterone to progesterone. Discrete tissue distribution of these AKR1C enzymes was observed using isoform-specific reverse transcriptase-PCR. AKR1C4 was virtually liver-specific and its high k(cat)/K(m) allows this enzyme to form 5alpha/5beta-tetrahydrosteroids robustly. AKR1C3 was most prominent in the prostate and mammary glands. The ability of AKR1C3 to interconvert testosterone with Delta(4)-androstene-3,17-dione, but to inactivate 5alpha-DHT, is consistent with this enzyme eliminating active androgens from the prostate. In the mammary gland, AKR1C3 will convert Delta(4)-androstene-3,17-dione to testosterone (a substrate aromatizable to 17beta-oestradiol), oestrone to 17beta-oestradiol, and progesterone to 20alpha-hydroxyprogesterone, and this concerted reductive activity may yield a pro-oesterogenic state. AKR1C3 is also the dominant form in the uterus and is responsible for the synthesis of 3alpha-androstanediol which has been implicated as a parturition hormone. The major isoforms in the brain, capable of synthesizing anxiolytic steroids, are AKR1C1 and AKR1C2. These studies are in stark contrast with those in rat where only a single AKR with positional- and stereo-specificity for 3alpha-hydroxysteroids exists. << Less
Biochem. J. 351:67-77(2000) [PubMed] [EuropePMC]
This publication is cited by 15 other entries.
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Selective and potent inhibitors of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone.
Higaki Y., Usami N., Shintani S., Ishikura S., El-Kabbani O., Hara A.
Neuroactive steroids, such as 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP) and 3alpha,5alpha-tetrahydrodeoxycorticosterone have been shown to be synthesized from progesterone in animal brains. Comparison of kinetic constants for the neuroactive steroids and their precursors among four ... >> More
Neuroactive steroids, such as 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP) and 3alpha,5alpha-tetrahydrodeoxycorticosterone have been shown to be synthesized from progesterone in animal brains. Comparison of kinetic constants for the neuroactive steroids and their precursors among four human 3(20)alpha-hydroxysteroid dehydrogenases (AKR1C1-AKR1C4) suggests that AKR1C1 and AKR1C2 are involved in the catabolism and synthesis, respectively, of the neuroactive steroids in the human brain. In our efforts to identify agents that would specifically inhibit the two enzymes, benzbromarone and 3',3",5',5"-tetrabromophenolphthalein were found to be relatively selective and potent inhibitors of AKR1C1. Kinetic analyses in the oxidoreduction catalyzed by AKR1C1 in the presence of the inhibitors suggest that the inhibitors bind to the enzyme-NADP(H) complex (K(i)=0.7 nM) in the ordered bi-bi pathway, including an isomerization step. The inhibitors effectively also decreased the reduction of 3alpha,5alpha-THP to its 20alpha-hydroxy metabolite in HepG2 cells treated with ethacrynic acid. << Less
Chem Biol Interact 143-144:503-513(2003) [PubMed] [EuropePMC]
This publication is cited by 2 other entries.