2fvl is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
AK1C4_HUMAN 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency. The gene represented in this entry may act as a disease modifier. A splicing mutation resulting in loss of AKR1C4 exon 2 has been found in affected individuals carrying a causative mutation in AKR1C2 (PubMed:21802064). These patients manifest a more severe disease phenotype than individuals only carrying mutations in AKR1C2.[1]
Function
AK1C4_HUMAN Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids. Liver specific enzyme that acts as NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductase on the steroid nucleus and side chain (PubMed:14672942, PubMed:10998348, PubMed:7650035, PubMed:1530633, PubMed:11158055, PubMed:10634139, PubMed:19218247). Displays the ability to catalyze both oxidation and reduction in vitro, but most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentration of NADPH (PubMed:14672942). Acts preferentially as a 3-alpha-hydroxysteroid dehydrogenase (HSD) with a subsidiary 3-beta-HSD activity (PubMed:14672942). Catalyzes efficiently the transformation of the potent androgen 5-alpha-dihydrotestosterone (5alpha-DHT or 17beta-hydroxy-5alpha-androstan-3-one) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol) (PubMed:11158055, PubMed:10998348, PubMed:14672942). Catalyzes the reduction of estrone into 17beta-estradiol but with low efficiency (PubMed:14672942). Metabolizes a broad spectrum of natural and synthetic therapeutic steroid and plays an important role in metabolism of androgens, estrogens, progestereone and conjugated steroids (PubMed:10998348, PubMed:14672942, PubMed:19218247). Catalyzes the biotransformation of the pesticide chlordecone (kepone) to its corresponding alcohol leading to increased biliary excretion of the pesticide and concomitant reduction of its neurotoxicity since bile is the major excretory route (PubMed:2427522).[2][3][4][5][6][7][8][9]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
↑Fluck CE, Meyer-Boni M, Pandey AV, Kempna P, Miller WL, Schoenle EJ, Biason-Lauber A. Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation. Am J Hum Genet. 2011 Aug 12;89(2):201-18. doi: 10.1016/j.ajhg.2011.06.009. Epub, 2011 Jul 28. PMID:21802064 doi:10.1016/j.ajhg.2011.06.009
↑Kume T, Iwasa H, Shiraishi H, Yokoi T, Nagashima K, Otsuka M, Terada T, Takagi T, Hara A, Kamataki T. Characterization of a novel variant (S145C/L311V) of 3alpha-hydroxysteroid/dihydrodiol dehydrogenase in human liver. Pharmacogenetics. 1999 Dec;9(6):763-71 PMID:10634139
↑Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, Moore M, Palackal N, Ratnam K. 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. Biochem J. 2000 Oct 1;351(Pt 1):67-77. PMID:10998348 doi:10.1042/0264-6021:3510067
↑Dufort I, Labrie F, Luu-The V. Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution. J Clin Endocrinol Metab. 2001 Feb;86(2):841-6. PMID:11158055 doi:10.1210/jcem.86.2.7216
↑Steckelbroeck S, Jin Y, Gopishetty S, Oyesanmi B, Penning TM. Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3beta-hydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action. J Biol Chem. 2004 Mar 12;279(11):10784-95. PMID:14672942 doi:10.1074/jbc.M313308200
↑Binstock JM, Iyer RB, Hamby CV, Fried VA, Schwartz IS, Weinstein BI, Southren AL. Human hepatic 3 alpha-hydroxysteroid dehydrogenase: possible identity with human hepatic chlordecone reductase. Biochem Biophys Res Commun. 1992 Sep 16;187(2):760-6. PMID:1530633 doi:10.1016/0006-291x(92)91260-w
↑Jin Y, Duan L, Lee SH, Kloosterboer HJ, Blair IA, Penning TM. Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism. J Biol Chem. 2009 Apr 10;284(15):10013-22. PMID:19218247 doi:10.1074/jbc.M809465200
↑Molowa DT, Shayne AG, Guzelian PS. Purification and characterization of chlordecone reductase from human liver. J Biol Chem. 1986 Sep 25;261(27):12624-7 PMID:2427522
↑Khanna M, Qin KN, Wang RW, Cheng KC. Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases. J Biol Chem. 1995 Aug 25;270(34):20162-8. PMID:7650035 doi:10.1074/jbc.270.34.20162
