ID HCDH_HUMAN Reviewed; 314 AA. AC Q16836; O00324; O00397; O00753; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 27-MAR-2002, sequence version 2. DT 23-OCT-2007, entry version 90. DE Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial precursor DE (EC 1.1.1.35) (Short chain 3-hydroxyacyl-CoA dehydrogenase) (HCDH) DE (Medium and short chain L-3-hydroxyacyl-coenzyme A dehydrogenase). GN Name=HADH; Synonyms=HAD, HADHSC, SCHAD; 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 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 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 [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 HADH 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 HHF4 LEU-258, AND CHARACTERIZATION OF VARIANT HHF4 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 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 HADH are the cause of 3-alpha-hydroxyacyl-CoA CC dehydrogenase deficiency (HADH deficiency) [MIM:231530]. HADH 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 -!- DISEASE: Defects in HADH are the cause of familial CC hyperinsulinemic hypoglycemia 4 (HHF4) [MIM:609975]. CC Inappropriately elevated insulin secretion is the hallmark of CC persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also CC denoted congenital hyperinsulinism. PHHI is due to defective CC negative feedback regulation of insulin secretion by low glucose CC levels. Unless early and aggressive intervention is undertaken, CC brain damage from recurrent episodes of hypoglycemia may occur. CC HHF4 should be easily recognizable by analysis of acylcarnitine CC species and that this disorder responds well to treatment with CC diazoxide. It provides the first "experiment of nature" that links CC impaired fatty acid oxidation to hyperinsulinism and that provides CC support for the concept that a lipid signaling pathway is CC implicated in the control of insulin secretion. CC -!- SIMILARITY: Belongs to the 3-hydroxyacyl-CoA dehydrogenase family. CC -!- WEB RESOURCE: Name=GeneReviews; CC URL="http://www.genetests.org/query?gene=HADH"; 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 UniGene; Hs.438289; -. 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 KEGG; hsa:3033; -. DR H-InvDB; HIX0004429; -. DR HGNC; HGNC:4799; HADH. DR MIM; 231530; phenotype. DR MIM; 601609; gene. DR MIM; 609975; phenotype. DR Orphanet; 71212; 3-hydroxylacyl-CoA dehydrogenase deficiency. DR PharmGKB; PA27682; -. DR Reactome; REACT_13; Metabolism of amino acids. DR Reactome; REACT_602; Lipid and lipoprotein metabolism. DR LinkHub; Q16836; -. DR ArrayExpress; Q16836; -. DR GermOnline; ENSG00000138796; Homo sapiens. DR GO; GO:0005739; C:mitochondrion; TAS:ProtInc. DR GO; GO:0003857; F:3-hydroxyacyl-CoA dehydrogenase activity; TAS:ProtInc. DR InterPro; IPR006108; 3HC_DH_C. DR InterPro; IPR006180; 3HCDH. DR InterPro; IPR006176; 3HCDH_NAD_bd. DR InterPro; IPR013328; DH_multihelical. DR Gene3D; G3DSA:1.10.1040.10; Opine_DH; 1. DR Pfam; PF00725; 3HCDH; 1. DR Pfam; PF02737; 3HCDH_N; 1. DR PROSITE; PS00067; 3HCDH; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Disease mutation; KW Fatty acid metabolism; Lipid metabolism; Mitochondrion; NAD; KW Oxidoreductase; Polymorphism; Transit peptide. FT TRANSIT 1 12 Mitochondrion. FT CHAIN 13 314 Hydroxyacyl-coenzyme A 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 MOD_RES 202 202 N6-acetyllysine (By similarity). FT VAR_SEQ 1 1 M -> MGRAGLEAPPPPCGVTGTPGARGLQGRVGPRPQSLA FT FRGCLPRASSLPGSPRCRRRCHTM (in isoform 2). FT /FTId=VSP_016551. FT VAR_SEQ 236 236 R -> RDFQTCGDSNSGLGFSLK (in isoform 2). FT /FTId=VSP_016552. FT VARIANT 40 40 A -> T (in HADH deficiency). FT /FTId=VAR_024079. FT VARIANT 57 57 D -> E (in HADH deficiency). FT /FTId=VAR_024080. FT VARIANT 86 86 P -> L (in dbSNP:rs4956145). FT /FTId=VAR_026764. FT VARIANT 258 258 P -> L (in HHF4; loss of activity). FT /FTId=VAR_024081. FT CONFLICT 152 152 Q -> H (in Ref. 1; CAA65528). FT STRAND 29 33 FT HELIX 37 48 FT STRAND 52 56 FT HELIX 60 79 FT STRAND 82 84 FT HELIX 86 98 FT STRAND 100 104 FT HELIX 106 109 FT STRAND 114 118 FT HELIX 124 134 FT TURN 135 137 FT STRAND 143 146 FT STRAND 149 151 FT HELIX 153 157 FT HELIX 163 165 FT STRAND 166 171 FT TURN 175 177 FT STRAND 180 184 FT HELIX 191 203 FT STRAND 207 211 FT TURN 215 218 FT HELIX 219 235 FT HELIX 241 252 FT HELIX 258 265 FT HELIX 267 279 FT TURN 280 283 FT HELIX 285 287 FT HELIX 291 298 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 //