ID AK1D1_HUMAN Reviewed; 326 AA. AC P51857; A1L4P6; A8K060; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 16-DEC-2008, entry version 69. DE RecName: Full=3-oxo-5-beta-steroid 4-dehydrogenase; DE EC=1.3.1.3; DE AltName: Full=Delta(4)-3-ketosteroid 5-beta-reductase; DE AltName: Full=Delta(4)-3-oxosteroid 5-beta-reductase; DE AltName: Full=Aldo-keto reductase family 1 member D1; GN Name=AKR1D1; Synonyms=SRD5B1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Liver; RX MEDLINE=94139710; PubMed=7508385; RX DOI=10.1111/j.1432-1033.1994.tb19947.x; RA Kondo K.-H., Kai M.-H., Setoguchi Y., Eggertsen G., Sjoeblom P., RA Setoguchi T., Okuda K., Bjoerkhem I.; RT "Cloning and expression of cDNA of human delta 4-3-oxosteroid 5 beta- RT reductase and substrate specificity of the expressed enzyme."; RL Eur. J. Biochem. 219:357-363(1994). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], CHARACTERIZATION, AND TISSUE RP SPECIFICITY. RX MEDLINE=21240205; PubMed=11342103; DOI=10.1016/S0167-4781(00)00278-5; RA Charbonneau A., The V.L.; RT "Genomic organization of a human 5beta-reductase and its pseudogene RT and substrate selectivity of the expressed enzyme."; RL Biochim. Biophys. Acta 1517:228-235(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Mammary gland; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX MEDLINE=22616434; PubMed=12690205; DOI=10.1126/science.1083423; RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F., RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H., RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G., RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P., RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J., RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F., RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B., RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., RA Mural R.J., Adams M.D., Tsui L.-C.; RT "Human chromosome 7: DNA sequence and biology."; RL Science 300:767-772(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) IN COMPLEXES WITH NADP; RP TESTOSTRONE; PROGESTERONE AND CORTISONE, MUTAGENESIS OF TYR-58 AND RP GLU-120, ENZYME REGULATION, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=18407998; DOI=10.1074/jbc.M801778200; RA Di Costanzo L., Drury J.E., Penning T.M., Christianson D.W.; RT "Crystal structure of human liver delta(4)-3-ketosteroid 5beta- RT reductase (AKR1D1) and implications for substrate binding and RT catalysis."; RL J. Biol. Chem. 283:16830-16839(2008). RN [8] RP VARIANTS CBAS2 PHE-106 AND LEU-198. RX PubMed=12970144; DOI=10.1136/gut.52.10.1494; RA Lemonde H.A., Custard E.J., Bouquet J., Duran M., Overmars H., RA Scambler P.J., Clayton P.T.; RT "Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid RT 5beta-reductase, in hepatitis and liver failure in infancy."; RL Gut 52:1494-1499(2003). RN [9] RP VARIANTS CBAS2 ARG-133 AND CYS-261. RX PubMed=15030995; DOI=10.1016/j.jhep.2003.12.024; RA Gonzales E., Cresteil D., Baussan C., Dabadie A., Gerhardt M.F., RA Jacquemin E.; RT "SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid 5beta- RT reductase deficiency: evidence for primary genetic defect."; RL J. Hepatol. 40:716-718(2004). CC -!- FUNCTION: Efficiently catalyzes the reduction of progesterone, CC androstenedione, 17-alpha-hydroxyprogesterone and testosterone to CC 5-beta-reduced metabolites. The bile acid intermediates 7- CC alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4- CC cholesten-3-one can also act as substrates. CC -!- CATALYTIC ACTIVITY: 5-beta-cholestan-3-one + NADP(+) = cholest-4- CC en-3-one + NADPH. CC -!- CATALYTIC ACTIVITY: 17,21-dihydroxy-5-beta-pregnane-3,11,20-trione CC + NADP(+) = cortisone. CC -!- ENZYME REGULATION: Subject to inhibition by high substrate CC concentrations. Inhibited by testosterone concentrations above 10 CC uM. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=2.7 uM for testosterone; CC -!- SUBCELLULAR LOCATION: Cytoplasm. CC -!- TISSUE SPECIFICITY: Highly expressed in liver. Expressed in testis CC and weakly in colon. CC -!- DISEASE: Defects in AKR1D1 are the cause of congenital bile acid CC synthesis defect type 2 (CBAS2) [MIM:235555]; also known as CC cholestasis with delta(4)-3-oxosteroid 5-beta-reductase CC deficiency. Patients with this liver disease show absence or low CC levels of chenodeoxycholic acid and cholic acid in plasma and CC urine. CC -!- SIMILARITY: Belongs to the aldo/keto reductase family. CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution-NoDerivs License CC ----------------------------------------------------------------------- DR EMBL; Z28339; CAA82193.1; -; mRNA. DR EMBL; AF283659; AAG39381.1; -; Genomic_DNA. DR EMBL; AF283651; AAG39381.1; JOINED; Genomic_DNA. DR EMBL; AF283652; AAG39381.1; JOINED; Genomic_DNA. DR EMBL; AF283653; AAG39381.1; JOINED; Genomic_DNA. DR EMBL; AF283654; AAG39381.1; JOINED; Genomic_DNA. DR EMBL; AF283655; AAG39381.1; JOINED; Genomic_DNA. DR EMBL; AF283656; AAG39381.1; JOINED; Genomic_DNA. DR EMBL; AF283657; AAG39381.1; JOINED; Genomic_DNA. DR EMBL; AF283658; AAG39381.1; JOINED; Genomic_DNA. DR EMBL; AK289425; BAF82114.1; -; mRNA. DR EMBL; CH236950; EAL24049.1; -; Genomic_DNA. DR EMBL; CH471070; EAW83881.1; -; Genomic_DNA. DR EMBL; BC130625; AAI30626.1; -; mRNA. DR EMBL; BC130627; AAI30628.1; -; mRNA. DR PIR; S41120; S41120. DR RefSeq; NP_005980.1; -. DR UniGene; Hs.201667; -. DR PDB; 3BUR; X-ray; 1.62 A; A/B=1-326. DR PDB; 3BUV; X-ray; 1.35 A; A/B=1-326. DR PDB; 3BV7; X-ray; 1.79 A; A/B=1-326. DR PDB; 3CAV; X-ray; 1.90 A; A/B=1-326. DR PDB; 3CMF; X-ray; 1.90 A; A/B=1-326. DR PDB; 3COT; X-ray; 2.03 A; A/B=1-326. DR PDBsum; 3BUR; -. DR PDBsum; 3BUV; -. DR PDBsum; 3BV7; -. DR PDBsum; 3CAV; -. DR PDBsum; 3CMF; -. DR PDBsum; 3COT; -. DR PhosphoSite; P51857; -. DR PRIDE; P51857; -. DR Ensembl; ENSG00000122787; Homo sapiens. DR GeneID; 6718; -. DR KEGG; hsa:6718; -. DR GeneCards; GC07P137411; -. DR H-InvDB; HIX0018220; -. DR HGNC; HGNC:388; AKR1D1. DR MIM; 235555; phenotype. DR MIM; 604741; gene. DR Orphanet; 172; Cholestasis, progressive familial intrahepatic. DR PharmGKB; PA24681; -. DR HOGENOM; P51857; -. DR HOVERGEN; P51857; -. DR Reactome; REACT_602; Lipid and lipoprotein metabolism. DR LinkHub; P51857; -. DR NextBio; 26206; -. DR ArrayExpress; P51857; -. DR CleanEx; HS_AKR1D1; -. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0004033; F:aldo-keto reductase activity; EXP:Reactome. DR GO; GO:0047787; F:delta4-3-oxosteroid 5beta-reductase activity; IEA:EC. DR GO; GO:0005496; F:steroid binding; TAS:UniProtKB. DR GO; GO:0008209; P:androgen metabolic process; IDA:UniProtKB. DR GO; GO:0006699; P:bile acid biosynthetic process; IDA:UniProtKB. DR GO; GO:0030573; P:bile acid catabolic process; IEA:UniProtKB-KW. DR GO; GO:0008207; P:C21-steroid hormone metabolic process; IDA:UniProtKB. DR GO; GO:0006707; P:cholesterol catabolic process; IDA:UniProtKB. DR GO; GO:0007586; P:digestion; IDA:UniProtKB. DR GO; GO:0055114; P:oxidation reduction; IDA:UniProtKB. DR InterPro; IPR001395; Aldo/ket_red. DR Gene3D; G3DSA:3.20.20.100; Aldo/ket_red; 1. DR PANTHER; PTHR11732; Aldo/ket_red; 1. DR Pfam; PF00248; Aldo_ket_red; 1. DR PRINTS; PR00069; ALDKETRDTASE. DR ProDom; PD000288; Aldo/ket_red; 1. DR PROSITE; PS00798; ALDOKETO_REDUCTASE_1; 1. DR PROSITE; PS00062; ALDOKETO_REDUCTASE_2; 1. DR PROSITE; PS00063; ALDOKETO_REDUCTASE_3; 1. PE 1: Evidence at protein level; KW 3D-structure; Bile acid catabolism; Cytoplasm; Disease mutation; KW Intrahepatic cholestasis; Lipid metabolism; NADP; Oxidoreductase; KW Steroid metabolism. FT CHAIN 1 326 3-oxo-5-beta-steroid 4-dehydrogenase. FT /FTId=PRO_0000124669. FT NP_BIND 169 170 NADP. FT NP_BIND 220 224 NADP. FT NP_BIND 273 283 NADP. FT ACT_SITE 58 58 Proton donor. FT BINDING 53 53 NADP. FT BINDING 193 193 NADP. FT BINDING 230 230 Substrate. FT VARIANT 106 106 L -> F (in CBAS2). FT /FTId=VAR_033007. FT VARIANT 133 133 P -> R (in CBAS2). FT /FTId=VAR_044430. FT VARIANT 198 198 P -> L (in CBAS2). FT /FTId=VAR_033008. FT VARIANT 261 261 R -> C (in CBAS2). FT /FTId=VAR_044431. FT MUTAGEN 58 58 Y->A: Loss of activity. FT MUTAGEN 120 120 E->A: Loss of activity. FT CONFLICT 14 14 D -> V (in Ref. 3; BAF82114). FT STRAND 9 11 FT STRAND 17 21 FT HELIX 29 31 FT HELIX 36 47 FT STRAND 51 53 FT HELIX 56 58 FT HELIX 61 73 FT HELIX 79 81 FT STRAND 83 88 FT HELIX 90 92 FT HELIX 95 97 FT HELIX 98 109 FT STRAND 114 120 FT HELIX 147 159 FT STRAND 162 170 FT HELIX 173 180 FT STRAND 191 195 FT HELIX 203 211 FT STRAND 215 220 FT TURN 228 230 FT HELIX 238 240 FT HELIX 242 251 FT HELIX 255 265 FT HELIX 277 284 FT HELIX 293 300 FT HELIX 312 314 FT STRAND 321 324 SQ SEQUENCE 326 AA; 37377 MW; 1FE02B95398A0A6F CRC64; MDLSAASHRI PLSDGNSIPI IGLGTYSEPK STPKGACATS VKVAIDTGYR HIDGAYIYQN EHEVGEAIRE KIAEGKVRRE DIFYCGKLWA TNHVPEMVRP TLERTLRVLQ LDYVDLYIIE VPMAFKPGDE IYPRDENGKW LYHKSNLCAT WEAMEACKDA GLVKSLGVSN FNRRQLELIL NKPGLKHKPV SNQVECHPYF TQPKLLKFCQ QHDIVITAYS PLGTSRNPIW VNVSSPPLLK DALLNSLGKR YNKTAAQIVL RFNIQRGVVV IPKSFNLERI KENFQIFDFS LTEEEMKDIE ALNKNVRFVE LLMWRDHPEY PFHDEY //