RBCC Red Blood Cell Collection

AKR1D1 (SRD5B1) [Confidence: low (only semi-automatic identification from reviews)]
3-oxo-5-beta-steroid 4-dehydrogenase; 1.3.1.3 (Aldo-keto reductase family 1 member D1; Delta(4)-3-ketosteroid 5-beta-reductase; Delta(4)-3-oxosteroid 5-beta-reductase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P51857
ID AK1D1_HUMAN Reviewed; 326 AA.
AC P51857; A1L4P6; A8K060; B4DPN3; B4DPN8;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 120.
DE RecName: Full=3-oxo-5-beta-steroid 4-dehydrogenase;
DE EC=1.3.1.3;
DE AltName: Full=Aldo-keto reductase family 1 member D1;
DE AltName: Full=Delta(4)-3-ketosteroid 5-beta-reductase;
DE AltName: Full=Delta(4)-3-oxosteroid 5-beta-reductase;
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] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=7508385; 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 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] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Liver, and 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 PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX 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 [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) IN COMPLEXES WITH NADP;
RP TESTOSTERONE; 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 [10]
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 [11]
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 -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P51857-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P51857-2; Sequence=VSP_042901;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P51857-3; Sequence=VSP_042913;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Highly expressed in liver. Expressed in testis
CC and weakly in colon.
CC -!- DISEASE: Congenital bile acid synthesis defect 2 (CBAS2)
CC [MIM:235555]: A condition characterized by jaundice, intrahepatic
CC cholestasis and hepatic failure. Patients with this liver disease
CC show absence or low levels of chenodeoxycholic acid and cholic
CC acid in plasma and urine. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family.
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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; AK298421; BAG60645.1; -; mRNA.
DR EMBL; AK298428; BAG60650.1; -; mRNA.
DR EMBL; AC009263; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC024082; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC083867; -; NOT_ANNOTATED_CDS; Genomic_DNA.
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_001177835.1; NM_001190906.1.
DR RefSeq; NP_001177836.1; NM_001190907.1.
DR RefSeq; NP_005980.1; NM_005989.3.
DR UniGene; Hs.201667; -.
DR UniGene; Hs.740214; -.
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; 3CAQ; X-ray; 2.20 A; A/B=1-326.
DR PDB; 3CAS; X-ray; 2.00 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 PDB; 3DOP; X-ray; 2.00 A; A/B=1-326.
DR PDB; 3G1R; X-ray; 1.70 A; A/B=1-326.
DR PDB; 3UZW; X-ray; 1.89 A; A/B=1-326.
DR PDB; 3UZX; X-ray; 1.64 A; A/B=1-326.
DR PDB; 3UZY; X-ray; 1.83 A; A/B=1-326.
DR PDB; 3UZZ; X-ray; 1.82 A; A/B=1-326.
DR PDBsum; 3BUR; -.
DR PDBsum; 3BUV; -.
DR PDBsum; 3BV7; -.
DR PDBsum; 3CAQ; -.
DR PDBsum; 3CAS; -.
DR PDBsum; 3CAV; -.
DR PDBsum; 3CMF; -.
DR PDBsum; 3COT; -.
DR PDBsum; 3DOP; -.
DR PDBsum; 3G1R; -.
DR PDBsum; 3UZW; -.
DR PDBsum; 3UZX; -.
DR PDBsum; 3UZY; -.
DR PDBsum; 3UZZ; -.
DR ProteinModelPortal; P51857; -.
DR SMR; P51857; 2-326.
DR STRING; 9606.ENSP00000242375; -.
DR PhosphoSite; P51857; -.
DR DMDM; 1703007; -.
DR PaxDb; P51857; -.
DR PRIDE; P51857; -.
DR DNASU; 6718; -.
DR Ensembl; ENST00000242375; ENSP00000242375; ENSG00000122787.
DR Ensembl; ENST00000411726; ENSP00000402374; ENSG00000122787.
DR Ensembl; ENST00000432161; ENSP00000389197; ENSG00000122787.
DR GeneID; 6718; -.
DR KEGG; hsa:6718; -.
DR UCSC; uc003vtz.3; human.
DR CTD; 6718; -.
DR GeneCards; GC07P137687; -.
DR HGNC; HGNC:388; AKR1D1.
DR MIM; 235555; phenotype.
DR MIM; 604741; gene.
DR neXtProt; NX_P51857; -.
DR Orphanet; 79303; Congenital bile acid synthesis defect type 2.
DR PharmGKB; PA24681; -.
DR eggNOG; COG0656; -.
DR HOGENOM; HOG000250272; -.
DR HOVERGEN; HBG000020; -.
DR InParanoid; P51857; -.
DR KO; K00251; -.
DR OMA; VAYNDAH; -.
DR OrthoDB; EOG70KGQF; -.
DR PhylomeDB; P51857; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P51857; -.
DR EvolutionaryTrace; P51857; -.
DR GenomeRNAi; 6718; -.
DR NextBio; 26206; -.
DR PRO; PR:P51857; -.
DR ArrayExpress; P51857; -.
DR Bgee; P51857; -.
DR CleanEx; HS_AKR1D1; -.
DR Genevestigator; P51857; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0047787; F:delta4-3-oxosteroid 5beta-reductase activity; IEA:UniProtKB-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 process; IDA:UniProtKB.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR001395; Aldo/ket_red.
DR InterPro; IPR018170; Aldo/ket_reductase_CS.
DR InterPro; IPR020471; Aldo/keto_reductase_subgr.
DR InterPro; IPR023210; NADP_OxRdtase_dom.
DR PANTHER; PTHR11732; PTHR11732; 1.
DR Pfam; PF00248; Aldo_ket_red; 1.
DR PIRSF; PIRSF000097; AKR; 1.
DR PRINTS; PR00069; ALDKETRDTASE.
DR SUPFAM; SSF51430; SSF51430; 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; Alternative splicing; Bile acid catabolism;
KW Complete proteome; Cytoplasm; Disease mutation;
KW Intrahepatic cholestasis; Lipid degradation; Lipid metabolism; NADP;
KW Oxidoreductase; Reference proteome; 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 VAR_SEQ 153 193 Missing (in isoform 3).
FT /FTId=VSP_042913.
FT VAR_SEQ 286 326 IFDFSLTEEEMKDIEALNKNVRFVELLMWRDHPEYPFHDEY
FT -> VARSS (in isoform 2).
FT /FTId=VSP_042901.
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 TURN 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 242 250
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
//

MIM 235555
*RECORD*
*FIELD* NO
235555
*FIELD* TI
#235555 BILE ACID SYNTHESIS DEFECT, CONGENITAL, 2; CBAS2
;;CHOLESTASIS WITH DELTA(4)-3-OXOSTEROID 5-BETA-REDUCTASE DEFICIENCY
read more*FIELD* TX
A number sign (#) is used with this entry because this form of
congenital defect in bile acid synthesis with delta(4)-3-oxosteroid
5-beta-reductase deficiency, referred to here as CBAS2, is caused by
homozygous or compound heterozygous mutation in the AKR1D1 gene
(604741).

For a general description and a discussion of genetic heterogeneity of
congenital bile acid synthesis defects (CBAS), see 607765.

CLINICAL FEATURES

Setchell et al. (1988) reported monozygotic male twins who presented at
birth with cholestatic jaundice due to severe intrahepatic cholestasis.
A previously born sib had died at the age of 4 months of hepatic failure
following an identical course. Using fast atom bombardment
ionization-mass spectrometry, the authors found increased urinary
excretion and predominance of taurine-conjugated unsaturated
hydroxy-oxo-bile acids. The biochemical findings indicated a defect in
bile acid synthesis involving the delta(4)-3-oxosteroid 5-beta-reductase
enzyme which converts delta(4)-3-oxo-C27 bile acid intermediates into
the corresponding 3-alpha-hydroxy-5-beta(H) structures. The inheritance
suggested an autosomal recessive disorder. On follow-up studies of the
patients reported by Setchell et al. (1988), Daugherty et al. (1993)
found defective primary bile acid synthesis and markedly increased
levels of atypical oxo and allo bile acids in urine and serum. Liver
biopsy showed hepatocellular cholestasis and giant-cell transformation
which resolved in parallel with clinical and biochemical recovery during
oral bile acid administration. In the twins, 5 years old at the time of
report, portal fibrosis stabilized at a mild level. Follow-up biopsy in
another brother at 8 months was normal, and he was doing well at 3 years
of age. Daugherty et al. (1993) identified 8 additional patients by
urine screening; all were boys.

Shneider et al. (1994) and Siafakas et al. (1997) reported a total of 5
infants with delta(4)-3-oxosteroid 5-beta-reductase deficiency who also
had neonatal hemochromatosis (231100).

Kimura et al. (1998) studied a 5-month-old Japanese boy with severe
neonatal cholestasis associated with hypertyrosinemia. A liver sample
was examined by immunoblot analysis using monoclonal antibodies against
5-beta-reductase. Although an indistinct band of 5-beta-reductase was
seen in the analysis, it remained uncertain as to whether this
represented a primary or inherited 5-beta-reductase deficiency. It may
have been a secondary deficiency due to severe liver damage, even though
3-oxo-delta(4) bile acids constituted more than 70% of the total urinary
bile acids.

Clayton et al. (1996) and Lemonde et al. (2003) reported a Sardinian
girl who presented at age 3 weeks with hyperbilirubinemia, elevated
liver enzymes, and prolonged prothrombin time consistent with
cholestasis. She also had steatorrhea, failure to thrive, and rickets.
Liver biopsy showed extensive giant cell transformation and steatosis.
Gamma-GGT (see 612346) was normal. By age 9 years, she was doing well on
bile replacement therapy with chenodeoxycholic acid and cholic acid.

Lemonde et al. (2003) described 2 additional unrelated patients with
neonatal cholestatic jaundice. Both patients were born of consanguineous
parents. Other clinical features included coagulopathy, giant cell
hepatitis, and almost complete absence of chenodeoxycholic and cholic
acids. Both patients developed liver failure necessitating liver
transplantation.

MOLECULAR GENETICS

In an infant with clinical and biochemical features of 5-beta-reductase
deficiency, including urinary bile salts with a 3-oxo-delta(4) content
greater than 94%, Sumazaki et al. (1997) excluded a pathogenic mutation
in the AKR1D1 gene.

In 3 unrelated patients with progressive familial intrahepatic
cholestasis due to delta(4)-3-oxosteroid 5-beta-reductase deficiency
Lemonde et al. (2003) identified 3 different homozygous mutations in the
AKR1D1 gene (604741.0001-604741.0003). Urinary profile of all 3 patients
showed almost complete absence of chenodeoxycholic and cholic acids. One
of the patients had been reported by Clayton et al. (1996).

GENOTYPE/PHENOTYPE CORRELATIONS

Drury et al. (2010) noted that a patient with a homozygous truncating
mutation in the ARK1D1 gene (604741.0002; Lemonde et al., 2003) had a
more severe phenotype necessitating liver transplantation compared to 2
sibs with compound heterozygous missense mutations resulting in some
residual protein function (605741.0004 and 604741.0005; Gonzales et al.,
2004) who responded well to oral cholic acid supplementation and did not
need liver transplantation.

*FIELD* RF
1. Clayton, P. T.; Mills, K. A.; Johnson, A. W.; Barabino, A.; Marazzi,
M. G.: Delta 4-3-oxosteroid 5 beta-reductase deficiency: failure
of ursodeoxycholic acid treatment and response to chenodeoxycholic
acid plus cholic acid. Gut 38: 623-628, 1996.

2. Daugherty, C. C.; Setchell, K. D. R.; Heubi, J. E.; Balistreri,
W. F.: Resolution of liver biopsy alterations in three siblings with
bile acid treatment of an inborn error of bile acid metabolism (delta(4)-3-oxosteroid
5-beta-reductase deficiency). Hepatology 18: 1096-1101, 1993.

3. Drury, J. E.; Mindnich, R.; Penning, T. M.: Characterization of
disease-related 5-beta-reductase (AKR1D1) mutations reveals their
potential to cause bile acid deficiency. J. Biol. Chem. 285: 24529-24537,
2010.

4. Gonzales, E.; Cresteil, D.; Baussan, C.; Dabadie, A.; Gerhardt,
M.-F.; Jacquemin, E.: SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid
5beta-reductase deficiency: evidence for primary genetic defect. (Letter) J.
Hepatol. 40: 716-718, 2004.

5. Kimura, A.; Kondo, K.-H.; Okuda, K.-I.; Higashi, S.; Suzuki, M.;
Kurosawa, T.; Tohma, M.; Inoue, T.; Nishiyori, A.; Yoshino, M.; Kato,
H.; Setoguchi, T.: Diagnosis of the first Japanese patient with 3-oxo-delta(4)-steroid
5-beta-reductase deficiency by use of immunoblot analysis. Europ.
J. Pediat. 157: 386-390, 1998.

6. Lemonde, H. A.; Custard, E. J.; Bouquet, J.; Duran, M.; Overmars,
H.; Scambler, P. J.; Clayton, P. T.: Mutations in SRD5B1 (AKR1D1),
the gene encoding delta-4-3-oxosteroid 5-beta-reductase, in hepatitis
and liver failure in infancy. Gut 52: 1494-1499, 2003.

7. Setchell, K. D. R.; Suchy, F. J.; Welsh, M. B.; Zimmer-Nechemias,
L.; Heubi, J.; Balistreri, W. F.: Delta(4)-3-oxosteroid 5-beta-reductase
deficiency described in identical twins with neonatal hepatitis: a
new inborn error in bile acid synthesis. J. Clin. Invest. 82: 2148-2157,
1988.

8. Shneider, B. L.; Setchell, K. D. R.; Whitington, P. F.; Neilson,
K. A.; Suchy, F. J.: Delta-4-3-oxosteroid 5 beta-reductase deficiency
causing neonatal liver failure and hemochromatosis. J. Pediat. 124:
234-238, 1994.

9. Siafakas, C. G.; Jonas, M. M.; Perez-Atayde, A. R.: Abnormal bile
acid metabolism and neonatal hemochromatosis: a subset with poor prognosis. J.
Pediat. Gastroent. Nutr. 25: 321-326, 1997.

10. Sumazaki, R.; Nakamura, N.; Shoda, J.; Kurosawa, T.; Tohma, M.
: Gene analysis in delta-4-3-oxosteroid 5-beta-reductase deficiency. Lancet 349:
329 only, 1997.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Failure to thrive

ABDOMEN:
[Liver];
Intrahepatic cholestasis;
Jaundice;
Hepatomegaly;
Giant cell transformation on biopsy;
Canalicular cholestasis;
Hepatocyte necrosis;
Liver failure before adulthood;
Septal fibrosis;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Diarrhea;
Steatorrhea;
Malabsorption of fat and fat-soluble vitamins

SKIN, NAILS, HAIR:
[Skin];
Jaundice

HEMATOLOGY:
Coagulopathy secondary to liver disease

LABORATORY ABNORMALITIES:
Hyperbilirubinemia;
Abnormal liver function tests;
Increased serum alkaline phosphatase;
Normal serum levels of gamma-GGT (231950);
Decreased or absent serum and urinary chenodeoxycholic acid and cholic
acid

MISCELLANEOUS:
Neonatal onset;
Caused by inborn error in bile acid synthesis;
Favorable response to oral bile acid therapy

MOLECULAR BASIS:
Caused by mutation in the delta-4-3-oxosteroid 5-beta-reductase gene
(AKR1D1, 604741.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 6/6/2006

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 10/05/2010
joanna: 12/2/2008
ckniffin: 6/15/2006
ckniffin: 6/6/2006

*FIELD* CN
Cassandra L. Kniffin - updated: 10/5/2010
Cassandra L. Kniffin - updated: 6/6/2006
Marla J. F. O'Neill - updated: 9/30/2005
Cassandra L. Kniffin - updated: 4/5/2004
Victor A. McKusick - updated: 8/24/1998

*FIELD* CD
Victor A. McKusick: 9/30/1991

*FIELD* ED
carol: 03/15/2011
wwang: 10/5/2010
ckniffin: 10/5/2010
mgross: 10/7/2008
carol: 6/14/2006
ckniffin: 6/6/2006
terry: 2/16/2006
wwang: 10/7/2005
terry: 9/30/2005
carol: 4/8/2004
ckniffin: 4/5/2004
alopez: 3/24/2000
carol: 8/25/1998
terry: 8/24/1998
mimadm: 2/19/1994
carol: 12/20/1993
supermim: 3/16/1992
carol: 2/29/1992
carol: 9/30/1991

MIM 604741
*RECORD*
*FIELD* NO
604741
*FIELD* TI
*604741 ALDO-KETO REDUCTASE FAMILY 1, MEMBER D1; AKR1D1
;;DELTA(4)-3-OXOSTEROID 5-BETA-REDUCTASE;;
read moreSTEROID 5-BETA-REDUCTASE; SRD5B1;;
5-@BETA-REDUCTASE
*FIELD* TX

DESCRIPTION

Human delta(4)-3-oxosteroid 5-beta-reductase (steroid 5-beta-reductase;
EC 1.3.1.23) catalyzes 5-beta-reduction of bile acid intermediates and
steroid hormones carrying a delta(4)-3-one structure (Kondo et al.,
1994).

CLONING

Kondo et al. (1994) screened a human liver cDNA library with a rat
5-beta-reductase cDNA to isolate the cDNA encoding human
5-beta-reductase. The full-length cDNA encodes a peptide of 326 amino
acids with a relative mass of 37,380 Da. Northern blot analysis of human
liver RNA identified a 2.7-kb transcript.

Using Northern blot analysis, Charbonneau and The (2001) detected very
high expression of a 2.7-kb 5-beta reductase transcript in liver only.
Weaker expression of a 2.2-kb transcript was detected in testis only. A
1.3-kb transcript was highly expressed in liver and weakly expressed in
all other tissues examined.

GENE STRUCTURE

Charbonneau and The (2001) determined that the AKR1D1 gene contains 9
exons and spans about 42 kb.

MAPPING

Charbonneau and Luu-The (1999) used FISH analysis to map the AKR1D1 gene
to chromosome 7q32-q33. They mapped an AKR1D1 pseudogene to chromosome
1q23-q25.

GENE FUNCTION

Kondo et al. (1994) found that recombinant human 5-beta-reductase showed
5-beta-reductase activity against several substrates, as detected by
high-performance liquid chromatography, in transfected COS cells.

Charbonneau and The (2001) assayed the enzymatic activity of intact
HEK293 cells stably expressing human 5-beta reductase. The enzyme
efficiently catalyzed the reduction of progesterone, androstenedione,
17-alpha-hydroxyprogesterone, and testosterone to 5-beta-reduced
metabolites. It less efficiently catalyzed the reduction of aldosterone
and corticosterone, and cortisol was a poor substrate.

MOLECULAR GENETICS

In 3 unrelated patients with neonatal cholestasis due to
delta(4)-3-oxosteroid 5-beta-reductase deficiency (CBAS2; 235555),
Lemonde et al. (2003) identified 3 different homozygous mutations in the
AKR1D1 gene (604741.0001-604741.0003). Urinary profile of all 3 patients
showed almost complete absence of chenodeoxycholic and cholic acids.

By Western blot analysis, Drury et al. (2010) showed that
disease-related ARK1D1 mutants, including P198L (604741.0001), L106F
(604741.0003), and P133R (604741.0004), and R261C (604741.0005) were
associated with poor protein expression and/or stability when expressed
in HEK293 cells. Spectrofluormetric assay showed that mutant proteins
had overall decreased enzymatic activity compared to wildtype. These
findings were consistent with the observed bile acid metabolic profile
seen in patients.

GENOTYPE/PHENOTYPE CORRELATIONS

Drury et al. (2010) noted that a patient with a homozygous truncating
mutation in the ARK1D1 gene (604741.0002; Lemonde et al., 2003) had a
more severe phenotype necessitating liver transplantation compared to 2
sibs with compound heterozygous missense mutations resulting in some
residual protein function (605741.0004 and 604741.0005; Gonzales et al.,
2004) who responded well to oral cholic acid supplementation and did not
need liver transplantation.

*FIELD* AV
.0001
BILE ACID SYNTHESIS DEFECT, CONGENITAL, 2
AKR1D1, PRO198LEU

In a patient with intrahepatic cholestasis due to delta(4)-3-oxosteroid
5-beta-reductase deficiency (235555) first reported by Clayton et al.
(1996), Lemonde et al. (2003) identified a homozygous 662C-T mutation in
the AKR1D1 gene, resulting in a pro198-to-leu (P198L) substitution. The
mutation was not identified in 100 control chromosomes. The mutation is
predicted to interfere with normal NADPH binding, rendering the mutant
enzyme inactive.

.0002
BILE ACID SYNTHESIS DEFECT, CONGENITAL, 2
AKR1D1, 1-BP DEL, 511T

In a Pakistani patient with CBAS2 (235555), born of consanguineous
parents, Lemonde et al. (2003) identified a homozygous 1-bp deletion
(511delT) in the AKR1D1 gene, resulting in a frameshift and premature
truncation of the protein in exon 5. The mutation was not identified in
100 control chromosomes. The patient had a severe form of the disorder
and required liver transplantation, as oral cholic therapy was
insufficient to treat the disorder.

.0003
BILE ACID SYNTHESIS DEFECT, CONGENITAL, 2
AKR1D1, LEU106PHE

In a patient from Sri Lanka with CBAS2 (235555), whose parents were
consanguineous, Lemonde et al. (2003) identified a homozygous 385C-T
transition in the AKR1D1 gene, resulting in a leu106-to-phe (L106F)
substitution within the alpha-3 helix of the enzyme. The mutation was
not identified in 100 control chromosomes.

.0004
BILE ACID SYNTHESIS DEFECT, CONGENITAL, 2
AKR1D1, PRO133ARG

In a pair of twin sisters with CBAS2 (235555), who developed progressive
cholestasis and liver failure by age 8 months, Gonzales et al. (2004)
identified compound heterozygosity for mutation in the AKR1D1 gene: a
467C-G transversion in exon 4, resulting in a pro133-to-arg (P133R)
substitution, and an 850C-T transition in exon 7, resulting in an
arg261-to-cys (R261C; 604741.0005) substitution. Neither mutation was
found in 100 control individuals, and each unaffected parent was
heterozygous for 1 of the mutations. The girls had neonatal cholestasis,
steatorrhea, and laboratory evidence of a defect in bile acid synthesis,
including liver biopsy showing canalicular cholestasis and giant
hepatocytes. Both patients responded well to cholic acid therapy, with
almost complete disappearance of bile acid precursors and improved
hepatic function, thus avoiding liver transplantation.

Drury et al. (2010) noted that the P133R mutation occurs in a highly
conserved residue in loop A of the enzyme, and is not directly involved
in forming the protein scaffold or catalytic triad. Unlike other AKR1D1
mutant proteins studied, the P133R-mutant protein was able to be
purified after transfection in E. coli. Kinetic studies showed that the
P133R-mutant protein had decreased affinity for and catalytic activity
toward testosterone compared to controls, but had increased affinity and
decreased catalytic activity toward cortisone, which is necessary for
bile acid synthesis, compared to wildtype. There was no change in
affinity for the cofactor NADPH, but the mutant enzyme was thermolabile
compared to wildtype. The R261C-mutant protein had lower expression and
overall decreased enzymatic activity compared to the wildtype protein,
but did retain some residual activity, which together with P133R may
have contributed to the somewhat milder phenotype in these sibs.
However, the results in general indicated decreased catalytic activity
of both mutant proteins, which would be causal in the development of
bile acid deficiency syndrome.

.0005
BILE ACID SYNTHESIS DEFECT, CONGENITAL, 2
AKR1D1, ARG261CYS

See 604741.0004 and Gonzales et al. (2004).

*FIELD* RF
1. Charbonneau, A.; Luu-The, V.: Assignment of steroid 5-beta-reductase
(SRD5B1) and its pseudogene (SRD5BP1) to human chromosome bands 7q32-q33
and 1q23-q25, respectively, by in situ hybridization. Cytogenet.
Cell Genet. 84: 105-106, 1999.

2. Charbonneau, A.; The, V.-L.: Genomic organization of a human 5-beta-reductase
and its pseudogene and substrate selectivity of the expressed enzyme. Biochim.
Biophys. Acta 1517: 228-235, 2001.

3. Clayton, P. T.; Mills, K. A.; Johnson, A. W.; Barabino, A.; Marazzi,
M. G.: Delta 4-3-oxosteroid 5 beta-reductase deficiency: failure
of ursodeoxycholic acid treatment and response to chenodeoxycholic
acid plus cholic acid. Gut 38: 623-628, 1996.

4. Drury, J. E.; Mindnich, R.; Penning, T. M.: Characterization of
disease-related 5-beta-reductase (AKR1D1) mutations reveals their
potential to cause bile acid deficiency. J. Biol. Chem. 285: 24529-24537,
2010.

5. Gonzales, E.; Cresteil, D.; Baussan, C.; Dabadie, A.; Gerhardt,
M.-F.; Jacquemin, E.: SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid
5beta-reductase deficiency: evidence for primary genetic defect. (Letter) J.
Hepatol. 40: 716-718, 2004.

6. Kondo, K.-H.; Kai, M.-H.; Setoguchi, Y.; Eggertsen, G.; Sjoblom,
P.; Setoguchi, T.; Okuda, K.-I.; Bjorkhem, I.: Cloning and expression
of cDNA of human delta(4)-3 oxosteroid 5-beta-reductase and substrate
specificity of the expressed enzyme. Europ. J. Biochem. 219: 357-363,
1994.

7. Lemonde, H. A.; Custard, E. J.; Bouquet, J.; Duran, M.; Overmars,
H.; Scambler, P. J.; Clayton, P. T.: Mutations in SRD5B1 (AKR1D1),
the gene encoding delta-4-3-oxosteroid 5-beta-reductase, in hepatitis
and liver failure in infancy. Gut 52: 1494-1499, 2003.

*FIELD* CN
Patricia A. Hartz - updated: 1/6/2011
Cassandra L. Kniffin - updated: 10/5/2010
Cassandra L. Kniffin - updated: 9/24/2010
Cassandra L. Kniffin - updated: 6/6/2006

*FIELD* CD
Stefanie A. Nelson: 3/24/2000

*FIELD* ED
mgross: 01/06/2011
mgross: 1/6/2011
terry: 1/6/2011
wwang: 10/5/2010
ckniffin: 10/5/2010
wwang: 10/5/2010
ckniffin: 9/24/2010
carol: 6/14/2006
ckniffin: 6/6/2006
alopez: 3/24/2000