ID HCDH_HUMAN STANDARD; PRT; 314 AA. AC Q16836; O00324; O00397; O00753; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 27-MAR-2002, sequence version 2. DT 07-FEB-2006, entry version 58. DE Short chain 3-hydroxyacyl-CoA dehydrogenase, mitochondrial precursor DE (EC 1.1.1.35) (HCDH) (Medium and short chain L-3-hydroxyacyl-coenzyme DE A dehydrogenase). GN Name=HADHSC; Synonyms=HAD, SCHAD; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Liver; RX MEDLINE=96268746; PubMed=8687463; DOI=10.1006/bbrc.1996.0961; RA Vredendaal P.J.C.M., van den Berg I.E.T., Malingre H.E.M., RA Stroobants A.K., Oldeweghuis D.E.M., Berger R.; RT "Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and RT characterization of the coding sequence."; RL Biochem. Biophys. Res. Commun. 223:718-723(1996). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 2), AND NUCLEOTIDE RP SEQUENCE [MRNA] OF 7-314 (ISOFORM 1). RC TISSUE=Skeletal muscle; RA Shi Y., Samuel S.J., Lee W., Yu C.H., Zhang W., Lachaal M., Jung C.Y.; RT "Cloning of a L-3-hydroxyacyl CoA dehydrogenase that binds to GLUT4 RT glucose transporter cytoplasmic C-terminus: possible crosstalk between RT glucose transport and fatty acid metabolism."; RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA O'Brien L.K., Sims H.F., Strauss A.W.; RT "Human short chain L-3-hydroxyacyl-CoA dehydrogenase."; RL Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Lung; RX MEDLINE=22388257; PubMed=12477932; DOI=10.1073/pnas.242603899; RA Strausberg R.L., Feingold E.A., Grouse L.H., Derge J.G., RA Klausner R.D., Collins F.S., Wagner L., Shenmen C.M., Schuler G.D., RA Altschul S.F., Zeeberg B., Buetow K.H., Schaefer C.F., Bhat N.K., RA Hopkins R.F., Jordan H., Moore T., Max S.I., Wang J., Hsieh F., RA Diatchenko L., Marusina K., Farmer A.A., Rubin G.M., Hong L., RA Stapleton M., Soares M.B., Bonaldo M.F., Casavant T.L., Scheetz T.E., RA Brownstein M.J., Usdin T.B., Toshiyuki S., Carninci P., Prange C., RA Raha S.S., Loquellano N.A., Peters G.J., Abramson R.D., Mullahy S.J., RA Bosak S.A., McEwan P.J., McKernan K.J., Malek J.A., Gunaratne P.H., RA Richards S., Worley K.C., Hale S., Garcia A.M., Gay L.J., Hulyk S.W., RA Villalon D.K., Muzny D.M., Sodergren E.J., Lu X., Gibbs R.A., RA Fahey J., Helton E., Ketteman M., Madan A., Rodrigues S., Sanchez A., RA Whiting M., Madan A., Young A.C., Shevchenko Y., Bouffard G.G., RA Blakesley R.W., Touchman J.W., Green E.D., Dickson M.C., RA Rodriguez A.C., Grimwood J., Schmutz J., Myers R.M., RA Butterfield Y.S.N., Krzywinski M.I., Skalska U., Smailus D.E., RA Schnerch A., Schein J.E., Jones S.J.M., Marra M.A.; RT "Generation and initial analysis of more than 15,000 full-length human RT and mouse cDNA sequences."; RL Proc. Natl. Acad. Sci. U.S.A. 99:16899-16903(2002). RN [5] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 13-314 IN COMPLEX WITH RP SUBSTRATE AND NAD. RX MEDLINE=99249789; PubMed=10231530; DOI=10.1021/bi9829027; RA Barycki J.J., O'Brien L.K., Bratt J.M., Zhang R., Sanishvili R., RA Strauss A.W., Banaszak L.J.; RT "Biochemical characterization and crystal structure determination of RT human heart short chain L-3-hydroxyacyl-CoA dehydrogenase provide RT insights into catalytic mechanism."; RL Biochemistry 38:5786-5798(1999). RN [6] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 13-314 IN COMPLEX WITH RP SUBSTRATE AND NAD. RX MEDLINE=20418095; PubMed=10840044; DOI=10.1074/jbc.M004669200; RA Barycki J.J., O'Brien L.K., Strauss A.W., Banaszak L.J.; RT "Sequestration of the active site by interdomain shifting. RT Crystallographic and spectroscopic evidence for distinct conformations RT of L-3-hydroxyacyl-CoA dehydrogenase."; RL J. Biol. Chem. 275:27186-27196(2000). RN [7] RP REVIEW. RX PubMed=16176262; DOI=10.1111/j.1742-4658.2005.04911.x; RA Yang S.-Y., He X.-Y., Schulz H.; RT "3-hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA RT dehydrogenase in human health and disease."; RL FEBS J. 272:4874-4883(2005). RN [8] RP VARIANTS HAD DEFICIENCY THR-40 AND GLU-57. RA O'Brien L.K., Rinaldo P., Sims H.F., Alonso E.M., Charrow J., RA Jones P.M., Bennett M.J., Barycki J.J., Banaszak L.J., Strauss A.W.; RT "Fulminant hepatic failure associated with mutations in the medium and RT short chain L-3-hydroxyacyl-CoA dehydrogenase gene."; RL J. Inherit. Metab. Dis. 23 Suppl. 1:127-127(2000). RN [9] RP VARIANT HAD DEFICIENCY LEU-258, AND CHARACTERIZATION OF VARIANT HAD RP DEFICIENCY LEU-258. RX PubMed=11489939; RA Clayton P.T., Eaton S., Aynsley-Green A., Edginton M., Hussain K., RA Krywawych S., Datta V., Malingre H.E.M., Berger R., RA van den Berg I.E.T.; RT "Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase RT deficiency reveals the importance of beta-oxidation in insulin RT secretion."; RL J. Clin. Invest. 108:457-465(2001). CC -!- FUNCTION: Plays an essential role in the mitochondrial beta- CC oxidation of short chain fatty acids. Exerts it highest activity CC toward 3-hydroxybutyryl-CoA. CC -!- CATALYTIC ACTIVITY: (S)-3-hydroxyacyl-CoA + NAD(+) = 3-oxoacyl-CoA CC + NADH. CC -!- PATHWAY: Fatty acid beta-oxidation cycle; step 3. CC -!- SUBUNIT: Homodimer. CC -!- SUBCELLULAR LOCATION: Mitochondrion; mitochondrial matrix. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q16836-1; Sequence=Displayed; CC Name=2; CC IsoId=Q16836-2; Sequence=VSP_016551, VSP_016552; CC Note=Ref.2 (AAB58153) sequence is in conflict in positions: CC 41:L->P, 56:R->H; CC -!- TISSUE SPECIFICITY: Expressed in liver, kidney, pancreas, heart CC and skeletal muscle. CC -!- DISEASE: Defects in HADHSC are the cause of 3-alpha-hydroxyacyl- CC CoA dehydrogenase deficiency (HAD deficiency) [MIM:609609]. HAD CC deficiency is a metabolic disorder with various clinical CC presentations including hypoglycemia, hepatoencephalopathy, CC myopathy or cardiomyopathy, and in some cases sudden death. CC -!- SIMILARITY: Belongs to the 3-hydroxyacyl-CoA dehydrogenase family. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X96752; CAA65528.1; -; mRNA. DR EMBL; AF001902; AAB54008.1; -; mRNA. DR EMBL; AF001903; AAB54009.1; -; mRNA. DR EMBL; AF001904; AAB58153.1; -; Genomic_DNA. DR EMBL; AF095703; AAD13581.1; -; Genomic_DNA. DR EMBL; BC000306; AAH00306.1; -; mRNA. DR PIR; JC4879; JC4879. DR PDB; 1F0Y; X-ray; A/B=13-314. DR PDB; 1F12; X-ray; A/B=13-314. DR PDB; 1F14; X-ray; A/B=13-314. DR PDB; 1F17; X-ray; A/B=13-314. DR PDB; 1IL0; X-ray; A/B=13-314. DR PDB; 1LSJ; X-ray; A/B=13-314. DR PDB; 1LSO; X-ray; A/B=13-314. DR PDB; 1M75; X-ray; A/B=13-314. DR PDB; 1M76; X-ray; A/B=13-314. DR PDB; 2HDH; X-ray; A/B=24-314. DR PDB; 3HAD; X-ray; A/B=13-314. DR Ensembl; ENSG00000138796; Homo sapiens. DR H-InvDB; HIX0004429; -. DR HGNC; HGNC:4804; HADHSC. DR MIM; 601609; gene. DR MIM; 609609; phenotype. DR Reactome; Q16836; -. DR LinkHub; Q16836; -. DR GO; GO:0005739; C:mitochondrion; TAS. DR GO; GO:0003857; F:3-hydroxyacyl-CoA dehydrogenase activity; TAS. DR InterPro; IPR006180; 3HCDH. DR InterPro; IPR006108; 3HCDH_C. DR InterPro; IPR006176; 3HCDH_NAD_bd. DR InterPro; IPR000205; NAD_BS. DR Pfam; PF00725; 3HCDH; 1. DR Pfam; PF02737; 3HCDH_N; 1. DR PROSITE; PS00067; 3HCDH; 1. KW 3D-structure; Alternative splicing; Disease mutation; KW Fatty acid metabolism; Lipid metabolism; Mitochondrion; NAD; KW Oxidoreductase; Transit peptide. FT TRANSIT 1 12 Mitochondrion. FT CHAIN 13 314 Short chain 3-hydroxyacyl-CoA FT dehydrogenase. FT /FTId=PRO_0000007406. FT NP_BIND 34 39 NAD. FT ACT_SITE 170 170 Proton acceptor (Probable). FT BINDING 57 57 NAD. FT BINDING 73 73 Coenzyme A. FT BINDING 80 80 Coenzyme A. FT BINDING 122 122 NAD. FT BINDING 127 127 NAD. FT BINDING 149 149 Coenzyme A. FT BINDING 149 149 NAD. FT BINDING 173 173 NAD. FT BINDING 305 305 NAD. FT VARSPLIC 1 1 M -> MGRAGLEAPPPPCGVTGTPGARGLQGRVGPRPQSLA FT FRGCLPRASSLPGSPRCRRRCHTM (in isoform 2). FT /FTId=VSP_016551. FT VARSPLIC 236 236 R -> RDFQTCGDSNSGLGFSLK (in isoform 2). FT /FTId=VSP_016552. FT VARIANT 40 40 A -> T (in HAD deficiency). FT /FTId=VAR_024079. FT VARIANT 57 57 D -> E (in HAD deficiency). FT /FTId=VAR_024080. FT VARIANT 258 258 P -> L (in HAD deficiency; loss of FT activity). FT /FTId=VAR_024081. FT CONFLICT 152 152 Q -> H (in Ref. 1). FT STRAND 29 33 FT STRAND 36 36 FT HELIX 37 48 FT TURN 49 50 FT STRAND 52 56 FT STRAND 58 58 FT HELIX 60 79 FT TURN 80 81 FT STRAND 82 84 FT HELIX 86 98 FT TURN 99 99 FT STRAND 100 104 FT HELIX 106 109 FT TURN 110 111 FT STRAND 112 112 FT STRAND 114 118 FT STRAND 122 122 FT HELIX 124 134 FT TURN 135 137 FT STRAND 138 138 FT TURN 140 141 FT STRAND 143 146 FT STRAND 149 151 FT HELIX 153 157 FT TURN 158 159 FT STRAND 160 161 FT HELIX 163 165 FT STRAND 166 171 FT STRAND 173 174 FT TURN 175 177 FT STRAND 180 184 FT TURN 187 188 FT HELIX 191 203 FT TURN 204 205 FT STRAND 207 211 FT STRAND 213 213 FT TURN 215 218 FT HELIX 219 235 FT TURN 236 237 FT STRAND 238 239 FT HELIX 241 252 FT STRAND 255 256 FT HELIX 258 265 FT HELIX 267 279 FT TURN 280 283 FT HELIX 285 287 FT HELIX 291 298 FT TURN 299 300 FT STRAND 303 303 FT TURN 304 307 FT STRAND 308 312 SQ SEQUENCE 314 AA; 34278 MW; 82579F8F872CFF16 CRC64; MAFVTRQFMR SVSSSSTASA SAKKIIVKHV TVIGGGLMGA GIAQVAAATG HTVVLVDQTE DILAKSKKGI EESLRKVAKK KFAENPKAGD EFVEKTLSTI ATSTDAASVV HSTDLVVEAI VENLKVKNEL FKRLDKFAAE HTIFASNTSS LQITSIANAT TRQDRFAGLH FFNPVPVMKL VEVIKTPMTS QKTFESLVDF SKALGKHPVS CKDTPGFIVN RLLVPYLMEA IRLYERGDAS KEDIDTAMKL GAGYPMGPFE LLDYVGLDTT KFIVDGWHEM DAENPLHQPS PSLNKLVAEN KFGKKTGEGF YKYK //