HCDH_HUMAN
ID HCDH_HUMAN Reviewed; 314 AA.
AC Q16836; J3KQ17; O00324; O00397; O00753; Q4W5B4;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2010, sequence version 3.
DT 03-AUG-2022, entry version 219.
DE RecName: Full=Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial;
DE Short=HCDH;
DE EC=1.1.1.35 {ECO:0000269|PubMed:10231530, ECO:0000269|PubMed:11489939, ECO:0000269|PubMed:16725361};
DE AltName: Full=Medium and short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase;
DE AltName: Full=Short-chain 3-hydroxyacyl-CoA dehydrogenase {ECO:0000303|PubMed:8687463};
DE Flags: Precursor;
GN Name=HADH;
GN Synonyms=HAD {ECO:0000303|PubMed:10231530},
GN HAD1 {ECO:0000303|PubMed:16725361}, HADHSC,
GN SCHAD {ECO:0000303|PubMed:8687463};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS PRO-86 AND HIS-152, TISSUE
RP SPECIFICITY, AND SUBCELLULAR LOCATION.
RC TISSUE=Liver;
RX PubMed=8687463; DOI=10.1006/bbrc.1996.0961;
RA Vredendaal P.J.C.M., van den Berg I.E.T., Malingre H.E.M., Stroobants A.K.,
RA 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), NUCLEOTIDE SEQUENCE
RP [MRNA] OF 7-314 (ISOFORM 1), AND VARIANT PRO-86.
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 glucose
RT transporter cytoplasmic C-terminus: possible crosstalk between glucose
RT transport and fatty acid metabolism.";
RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT PRO-86.
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 GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT PRO-86.
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-185; LYS-202; LYS-241 AND
RP LYS-312, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [7]
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., Buerckstuemmer T.,
RA 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 [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [10]
RP HYDROXYBUTYRYLATION AT LYS-127.
RX PubMed=29192674; DOI=10.1038/cr.2017.149;
RA Huang H., Luo Z., Qi S., Huang J., Xu P., Wang X., Gao L., Li F., Wang J.,
RA Zhao W., Gu W., Chen Z., Dai L., Dai J., Zhao Y.;
RT "Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation
RT pathway.";
RL Cell Res. 28:111-125(2018).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 13-314 IN COMPLEX WITH SUBSTRATE
RP AND NAD, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, FUNCTION, AND
RP SUBUNIT.
RX 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 human
RT heart short chain L-3-hydroxyacyl-CoA dehydrogenase provide insights into
RT catalytic mechanism.";
RL Biochemistry 38:5786-5798(1999).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 13-314 IN COMPLEX WITH SUBSTRATE
RP AND NAD, AND SUBUNIT.
RX 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. Crystallographic
RT and spectroscopic evidence for distinct conformations of L-3-hydroxyacyl-
RT CoA dehydrogenase.";
RL J. Biol. Chem. 275:27186-27196(2000).
RN [13]
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 [14]
RP VARIANTS HADH DEFICIENCY THR-40 AND GLU-57.
RA O'Brien L.K., Rinaldo P., Sims H.F., Alonso E.M., Charrow J., Jones P.M.,
RA 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 [15]
RP VARIANT HHF4 LEU-258, CHARACTERIZATION OF VARIANT HHF4 LEU-258, CATALYTIC
RP ACTIVITY, FUNCTION, AND PATHWAY.
RX PubMed=11489939; DOI=10.1172/jci200111294;
RA Clayton P.T., Eaton S., Aynsley-Green A., Edginton M., Hussain K.,
RA Krywawych S., Datta V., Malingre H.E.M., Berger R., 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 secretion.";
RL J. Clin. Invest. 108:457-465(2001).
RN [16]
RP VARIANTS GLY-57 AND HIS-226, CATALYTIC ACTIVITY, FUNCTION, CHARACTERIZATION
RP OF VARIANTS GLY-57 AND HIS-226, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND
RP PATHWAY.
RX PubMed=16725361; DOI=10.1016/j.ymgme.2006.04.004;
RA Bennett M.J., Russell L.K., Tokunaga C., Narayan S.B., Tan L.,
RA Seegmiller A., Boriack R.L., Strauss A.W.;
RT "Reye-like syndrome resulting from novel missense mutations in
RT mitochondrial medium- and short-chain l-3-hydroxy-acyl-CoA dehydrogenase.";
RL Mol. Genet. Metab. 89:74-79(2006).
CC -!- FUNCTION: Mitochondrial fatty acid beta-oxidation enzyme that catalyzes
CC the third step of the beta-oxidation cycle for medium and short-chain
CC 3-hydroxy fatty acyl-CoAs (C4 to C10) (PubMed:10231530,
CC PubMed:11489939, PubMed:16725361). Plays a role in the control of
CC insulin secretion by inhibiting the activation of glutamate
CC dehydrogenase 1 (GLUD1), an enzyme that has an important role in
CC regulating amino acid-induced insulin secretion (By similarity).
CC {ECO:0000250|UniProtKB:Q61425, ECO:0000269|PubMed:10231530,
CC ECO:0000269|PubMed:11489939, ECO:0000269|PubMed:16725361}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a (3S)-3-hydroxyacyl-CoA + NAD(+) = a 3-oxoacyl-CoA + H(+) +
CC NADH; Xref=Rhea:RHEA:22432, ChEBI:CHEBI:15378, ChEBI:CHEBI:57318,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:90726; EC=1.1.1.35;
CC Evidence={ECO:0000269|PubMed:10231530, ECO:0000269|PubMed:11489939,
CC ECO:0000269|PubMed:16725361};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(3S)-3-hydroxybutanoyl-CoA + NAD(+) = acetoacetyl-CoA + H(+) +
CC NADH; Xref=Rhea:RHEA:30799, ChEBI:CHEBI:15378, ChEBI:CHEBI:57286,
CC ChEBI:CHEBI:57316, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC Evidence={ECO:0000269|PubMed:10231530, ECO:0000269|PubMed:16725361};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(3S)-hydroxydecanoyl-CoA + NAD(+) = 3-oxodecanoyl-CoA + H(+) +
CC NADH; Xref=Rhea:RHEA:31187, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:62548, ChEBI:CHEBI:62616;
CC Evidence={ECO:0000250|UniProtKB:P00348};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(3S)-hydroxyhexadecanoyl-CoA + NAD(+) = 3-oxohexadecanoyl-CoA
CC + H(+) + NADH; Xref=Rhea:RHEA:31159, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57349, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945,
CC ChEBI:CHEBI:62613; Evidence={ECO:0000250|UniProtKB:P00348};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=34.5 uM for acetoacetyl-CoA at pH 5.0
CC {ECO:0000269|PubMed:10231530};
CC KM=45.0 uM for acetoacetyl-CoA at pH 6.0
CC {ECO:0000269|PubMed:10231530};
CC KM=18.7 uM for acetoacetyl-CoA at pH 7.0
CC {ECO:0000269|PubMed:10231530};
CC KM=13.8 uM for acetoacetyl-CoA at pH 8.0
CC {ECO:0000269|PubMed:10231530};
CC KM=11.9 uM for acetoacetyl-CoA {ECO:0000269|PubMed:16725361};
CC KM=24.2 uM for NADH {ECO:0000269|PubMed:16725361};
CC Vmax=281 umol/min/mg enzyme with acetoacetyl-CoA as substrate at PH
CC 5.0 {ECO:0000269|PubMed:10231530};
CC Vmax=448 umol/min/mg enzyme with acetoacetyl-CoA as substrate at PH
CC 6.0 {ECO:0000269|PubMed:10231530};
CC Vmax=459 umol/min/mg enzyme with acetoacetyl-CoA as substrate at PH
CC 6.0 {ECO:0000269|PubMed:10231530};
CC Vmax=205 umol/min/mg enzyme with acetoacetyl-CoA as substrate at PH
CC 8.0 {ECO:0000269|PubMed:10231530};
CC pH dependence:
CC Optimum at neutral pH. {ECO:0000269|PubMed:10231530};
CC -!- PATHWAY: Lipid metabolism; fatty acid beta-oxidation.
CC {ECO:0000269|PubMed:11489939, ECO:0000269|PubMed:16725361}.
CC -!- SUBUNIT: Homodimer (PubMed:10231530, PubMed:10840044, PubMed:16725361).
CC Interacts with GLUD1; this interaction inhibits the activation of
CC glutamate dehydrogenase 1 (GLUD1) (By similarity).
CC {ECO:0000250|UniProtKB:Q61425, ECO:0000269|PubMed:10231530,
CC ECO:0000269|PubMed:10840044, ECO:0000269|PubMed:16725361}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000305|PubMed:8687463}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q16836-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q16836-2; Sequence=VSP_016551, VSP_016552;
CC Name=3;
CC IsoId=Q16836-3; Sequence=VSP_016552;
CC -!- TISSUE SPECIFICITY: Expressed in liver, kidney, pancreas, heart and
CC skeletal muscle. {ECO:0000269|PubMed:8687463}.
CC -!- PTM: Succinylation at Lys-81, adjacent to a coenzyme A binding site.
CC Desuccinylated by SIRT5. {ECO:0000250|UniProtKB:Q61425}.
CC -!- DISEASE: 3-alpha-hydroxyacyl-CoA dehydrogenase deficiency (HADH
CC deficiency) [MIM:231530]: An autosomal recessive, metabolic disorder
CC with various clinical presentations including hypoglycemia,
CC hepatoencephalopathy, myopathy or cardiomyopathy, and in some cases
CC sudden death. {ECO:0000269|Ref.14}. Note=The disease is caused by
CC variants affecting the gene represented in this entry.
CC -!- DISEASE: Familial hyperinsulinemic hypoglycemia 4 (HHF4) [MIM:609975]:
CC Most common cause of persistent hypoglycemia in infancy. Unless early
CC and aggressive intervention is undertaken, brain damage from recurrent
CC episodes of hypoglycemia may occur. HHF4 should be easily recognizable
CC by analysis of acylcarnitine species and that this disorder responds
CC well to treatment with diazoxide. It provides the first 'experiment of
CC nature' that links impaired fatty acid oxidation to hyperinsulinism and
CC that provides support for the concept that a lipid signaling pathway is
CC implicated in the control of insulin secretion.
CC {ECO:0000269|PubMed:11489939}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the 3-hydroxyacyl-CoA dehydrogenase family.
CC {ECO:0000305}.
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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; AC114733; AAY41050.1; -; Genomic_DNA.
DR EMBL; AC118062; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000306; AAH00306.1; -; mRNA.
DR CCDS; CCDS3678.1; -. [Q16836-1]
DR CCDS; CCDS54790.1; -. [Q16836-3]
DR PIR; JC4879; JC4879.
DR RefSeq; NP_001171634.2; NM_001184705.2. [Q16836-3]
DR RefSeq; NP_005318.3; NM_005327.4. [Q16836-1]
DR PDB; 1F0Y; X-ray; 1.80 A; A/B=13-314.
DR PDB; 1F12; X-ray; 2.40 A; A/B=13-314.
DR PDB; 1F14; X-ray; 2.30 A; A/B=13-314.
DR PDB; 1F17; X-ray; 2.30 A; A/B=13-314.
DR PDB; 1IL0; X-ray; 2.20 A; A/B=13-314.
DR PDB; 1LSJ; X-ray; 2.50 A; A/B=13-314.
DR PDB; 1LSO; X-ray; 2.60 A; A/B=13-314.
DR PDB; 1M75; X-ray; 2.30 A; A/B=13-314.
DR PDB; 1M76; X-ray; 2.15 A; A/B=13-314.
DR PDB; 2HDH; X-ray; 2.20 A; A/B=24-314.
DR PDB; 3HAD; X-ray; 2.00 A; A/B=13-314.
DR PDB; 3RQS; X-ray; 2.00 A; A/B=1-314.
DR PDBsum; 1F0Y; -.
DR PDBsum; 1F12; -.
DR PDBsum; 1F14; -.
DR PDBsum; 1F17; -.
DR PDBsum; 1IL0; -.
DR PDBsum; 1LSJ; -.
DR PDBsum; 1LSO; -.
DR PDBsum; 1M75; -.
DR PDBsum; 1M76; -.
DR PDBsum; 2HDH; -.
DR PDBsum; 3HAD; -.
DR PDBsum; 3RQS; -.
DR AlphaFoldDB; Q16836; -.
DR SMR; Q16836; -.
DR BioGRID; 109283; 96.
DR IntAct; Q16836; 13.
DR MINT; Q16836; -.
DR STRING; 9606.ENSP00000474560; -.
DR DrugBank; DB03612; 3-Hydroxybutyryl-Coenzyme A.
DR DrugBank; DB03059; Acetoacetyl-CoA.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB09568; Omega-3-carboxylic acids.
DR SwissLipids; SLP:000001250; -.
DR GlyGen; Q16836; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q16836; -.
DR PhosphoSitePlus; Q16836; -.
DR SwissPalm; Q16836; -.
DR BioMuta; HADH; -.
DR DMDM; 311033442; -.
DR REPRODUCTION-2DPAGE; IPI00298406; -.
DR UCD-2DPAGE; Q16836; -.
DR EPD; Q16836; -.
DR jPOST; Q16836; -.
DR MassIVE; Q16836; -.
DR MaxQB; Q16836; -.
DR PeptideAtlas; Q16836; -.
DR PRIDE; Q16836; -.
DR ProteomicsDB; 61096; -. [Q16836-1]
DR ProteomicsDB; 61097; -. [Q16836-2]
DR TopDownProteomics; Q16836-1; -. [Q16836-1]
DR Antibodypedia; 26260; 575 antibodies from 34 providers.
DR DNASU; 3033; -.
DR Ensembl; ENST00000309522.8; ENSP00000312288.4; ENSG00000138796.18. [Q16836-1]
DR Ensembl; ENST00000603302.5; ENSP00000474560.1; ENSG00000138796.18. [Q16836-3]
DR GeneID; 3033; -.
DR KEGG; hsa:3033; -.
DR MANE-Select; ENST00000309522.8; ENSP00000312288.4; NM_005327.7; NP_005318.6.
DR UCSC; uc003hyq.4; human. [Q16836-1]
DR CTD; 3033; -.
DR DisGeNET; 3033; -.
DR GeneCards; HADH; -.
DR GeneReviews; HADH; -.
DR HGNC; HGNC:4799; HADH.
DR HPA; ENSG00000138796; Tissue enhanced (tongue).
DR MalaCards; HADH; -.
DR MIM; 231530; phenotype.
DR MIM; 601609; gene.
DR MIM; 609975; phenotype.
DR neXtProt; NX_Q16836; -.
DR OpenTargets; ENSG00000138796; -.
DR Orphanet; 71212; Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency.
DR PharmGKB; PA29173; -.
DR VEuPathDB; HostDB:ENSG00000138796; -.
DR eggNOG; KOG2304; Eukaryota.
DR GeneTree; ENSGT00940000159984; -.
DR HOGENOM; CLU_009834_2_0_1; -.
DR InParanoid; Q16836; -.
DR OMA; FYDYSES; -.
DR OrthoDB; 938257at2759; -.
DR PhylomeDB; Q16836; -.
DR TreeFam; TF300886; -.
DR BioCyc; MetaCyc:HS06563-MON; -.
DR BRENDA; 1.1.1.35; 2681.
DR PathwayCommons; Q16836; -.
DR Reactome; R-HSA-77310; Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA.
DR Reactome; R-HSA-77346; Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA.
DR Reactome; R-HSA-77348; Beta oxidation of octanoyl-CoA to hexanoyl-CoA.
DR Reactome; R-HSA-77350; Beta oxidation of hexanoyl-CoA to butanoyl-CoA.
DR Reactome; R-HSA-77352; Beta oxidation of butanoyl-CoA to acetyl-CoA.
DR SABIO-RK; Q16836; -.
DR SignaLink; Q16836; -.
DR UniPathway; UPA00659; -.
DR BioGRID-ORCS; 3033; 16 hits in 1089 CRISPR screens.
DR ChiTaRS; HADH; human.
DR EvolutionaryTrace; Q16836; -.
DR GeneWiki; Hydroxyacyl-Coenzyme_A_dehydrogenase; -.
DR GenomeRNAi; 3033; -.
DR Pharos; Q16836; Tbio.
DR PRO; PR:Q16836; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q16836; protein.
DR Bgee; ENSG00000138796; Expressed in islet of Langerhans and 206 other tissues.
DR ExpressionAtlas; Q16836; baseline and differential.
DR Genevisible; Q16836; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:LIFEdb.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0003857; F:3-hydroxyacyl-CoA dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR GO; GO:0070403; F:NAD+ binding; IDA:UniProtKB.
DR GO; GO:0016740; F:transferase activity; IEA:UniProtKB-KW.
DR GO; GO:0006635; P:fatty acid beta-oxidation; IDA:UniProtKB.
DR GO; GO:0046676; P:negative regulation of insulin secretion; IEA:Ensembl.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0050796; P:regulation of insulin secretion; ISS:UniProtKB.
DR GO; GO:0014823; P:response to activity; IEA:Ensembl.
DR GO; GO:0032868; P:response to insulin; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR Gene3D; 1.10.1040.10; -; 1.
DR InterPro; IPR022694; 3-OHacyl-CoA_DH.
DR InterPro; IPR006180; 3-OHacyl-CoA_DH_CS.
DR InterPro; IPR006176; 3-OHacyl-CoA_DH_NAD-bd.
DR InterPro; IPR006108; 3HC_DH_C.
DR InterPro; IPR008927; 6-PGluconate_DH-like_C_sf.
DR InterPro; IPR013328; 6PGD_dom2.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR Pfam; PF00725; 3HCDH; 1.
DR Pfam; PF02737; 3HCDH_N; 1.
DR PIRSF; PIRSF000105; HCDH; 1.
DR SUPFAM; SSF48179; SSF48179; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
DR PROSITE; PS00067; 3HCDH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Disease variant;
KW Fatty acid metabolism; Hydroxylation; Lipid metabolism; Mitochondrion; NAD;
KW Oxidoreductase; Reference proteome; Transferase; Transit peptide.
FT TRANSIT 1..12
FT /note="Mitochondrion"
FT /evidence="ECO:0000305|PubMed:8687463"
FT CHAIN 13..314
FT /note="Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial"
FT /id="PRO_0000007406"
FT BINDING 34..39
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10231530,
FT ECO:0000269|PubMed:10840044"
FT BINDING 57
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10231530,
FT ECO:0000269|PubMed:10840044"
FT BINDING 73
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:10840044"
FT BINDING 80
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:10840044"
FT BINDING 122
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10231530,
FT ECO:0000269|PubMed:10840044"
FT BINDING 127
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10231530,
FT ECO:0000269|PubMed:10840044"
FT BINDING 149
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:10840044"
FT BINDING 149
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10231530,
FT ECO:0000269|PubMed:10840044"
FT BINDING 173
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10231530,
FT ECO:0000269|PubMed:10840044"
FT BINDING 305
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:10231530,
FT ECO:0000269|PubMed:10840044"
FT SITE 170
FT /note="Important for catalytic activity"
FT /evidence="ECO:0000305"
FT MOD_RES 80
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 81
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 81
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 87
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 87
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 125
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 127
FT /note="N6-(2-hydroxyisobutyryl)lysine"
FT /evidence="ECO:0000269|PubMed:29192674"
FT MOD_RES 136
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 136
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 179
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 185
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 185
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 192
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 192
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 202
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 202
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 206
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 212
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 212
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 241
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 241
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT MOD_RES 312
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 312
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q61425"
FT VAR_SEQ 1
FT /note="M -> MGRAGLEAPPPPCGVTGTPGARGLQGRVGPRPQSLAFRGCLPRASSL
FT PGSPRCRRRCHTM (in isoform 2)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_016551"
FT VAR_SEQ 236
FT /note="R -> RDFQTCGDSNSGLGFSLK (in isoform 2 and isoform
FT 3)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_016552"
FT VARIANT 40
FT /note="A -> T (in HADH deficiency; dbSNP:rs137853101)"
FT /evidence="ECO:0000269|Ref.14"
FT /id="VAR_024079"
FT VARIANT 57
FT /note="D -> E (in HADH deficiency; dbSNP:rs137853102)"
FT /evidence="ECO:0000269|Ref.14"
FT /id="VAR_024080"
FT VARIANT 57
FT /note="D -> G (found in a patient with Reye-like syndrome.
FT Does not affect 3-hydroxyacyl-CoA dehydrogenase activity.
FT Increases KM value for NADH. Does not affect dimerization)"
FT /evidence="ECO:0000269|PubMed:16725361"
FT /id="VAR_083648"
FT VARIANT 86
FT /note="L -> P (in dbSNP:rs4956145)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:8687463, ECO:0000269|Ref.2,
FT ECO:0000269|Ref.3"
FT /id="VAR_026764"
FT VARIANT 152
FT /note="Q -> H (in dbSNP:rs1051519)"
FT /evidence="ECO:0000269|PubMed:8687463"
FT /id="VAR_055701"
FT VARIANT 226
FT /note="Y -> H (found in a patient with Reye-like syndrome;
FT loss of 3-hydroxyacyl-CoA dehydrogenase activity. Does not
FT affect dimerization; dbSNP:rs146036912)"
FT /evidence="ECO:0000269|PubMed:16725361"
FT /id="VAR_083649"
FT VARIANT 258
FT /note="P -> L (in HHF4; loss of 3-hydroxyacyl-CoA
FT dehydrogenase activity; dbSNP:rs137853103)"
FT /evidence="ECO:0000269|PubMed:11489939"
FT /id="VAR_024081"
FT HELIX 1..11
FT /evidence="ECO:0007829|PDB:3RQS"
FT HELIX 14..22
FT /evidence="ECO:0007829|PDB:3RQS"
FT STRAND 29..33
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 37..48
FT /evidence="ECO:0007829|PDB:1F0Y"
FT STRAND 52..56
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 60..79
FT /evidence="ECO:0007829|PDB:1F0Y"
FT STRAND 82..84
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 86..98
FT /evidence="ECO:0007829|PDB:1F0Y"
FT STRAND 100..104
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 106..109
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 110..112
FT /evidence="ECO:0007829|PDB:3HAD"
FT STRAND 114..118
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 124..134
FT /evidence="ECO:0007829|PDB:1F0Y"
FT TURN 135..137
FT /evidence="ECO:0007829|PDB:1F0Y"
FT STRAND 143..146
FT /evidence="ECO:0007829|PDB:1F0Y"
FT STRAND 149..151
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 153..157
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 163..165
FT /evidence="ECO:0007829|PDB:1F0Y"
FT STRAND 166..171
FT /evidence="ECO:0007829|PDB:1F0Y"
FT TURN 175..177
FT /evidence="ECO:0007829|PDB:1F0Y"
FT STRAND 180..184
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 191..203
FT /evidence="ECO:0007829|PDB:1F0Y"
FT STRAND 207..211
FT /evidence="ECO:0007829|PDB:1F0Y"
FT TURN 215..218
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 219..235
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 241..252
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 258..265
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 267..279
FT /evidence="ECO:0007829|PDB:1F0Y"
FT TURN 280..283
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 285..287
FT /evidence="ECO:0007829|PDB:1F0Y"
FT HELIX 291..298
FT /evidence="ECO:0007829|PDB:1F0Y"
FT TURN 304..307
FT /evidence="ECO:0007829|PDB:1F0Y"
FT STRAND 308..312
FT /evidence="ECO:0007829|PDB:1F0Y"
FT CONFLICT Q16836-2:41
FT /note="L -> P (in Ref. 2; AAB58153)"
FT /evidence="ECO:0000305"
FT CONFLICT Q16836-2:56
FT /note="R -> H (in Ref. 2; AAB58153)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 314 AA; 34294 MW; 0C6F7C01BBCE646A CRC64;
MAFVTRQFMR SVSSSSTASA SAKKIIVKHV TVIGGGLMGA GIAQVAAATG HTVVLVDQTE
DILAKSKKGI EESLRKVAKK KFAENLKAGD EFVEKTLSTI ATSTDAASVV HSTDLVVEAI
VENLKVKNEL FKRLDKFAAE HTIFASNTSS LQITSIANAT TRQDRFAGLH FFNPVPVMKL
VEVIKTPMTS QKTFESLVDF SKALGKHPVS CKDTPGFIVN RLLVPYLMEA IRLYERGDAS
KEDIDTAMKL GAGYPMGPFE LLDYVGLDTT KFIVDGWHEM DAENPLHQPS PSLNKLVAEN
KFGKKTGEGF YKYK
