Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q16836 (HCDH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 163. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial

Short name=HCDH
EC=1.1.1.35
Alternative name(s):
Medium and short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase
Short-chain 3-hydroxyacyl-CoA dehydrogenase
Gene names
Name:HADH
Synonyms:HAD, HADHSC, SCHAD
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length314 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Plays an essential role in the mitochondrial beta-oxidation of short chain fatty acids. Exerts it highest activity toward 3-hydroxybutyryl-CoA.

Catalytic activity

(S)-3-hydroxyacyl-CoA + NAD+ = 3-oxoacyl-CoA + NADH.

Pathway

Lipid metabolism; fatty acid beta-oxidation.

Subunit structure

Homodimer.

Subcellular location

Mitochondrion matrix.

Tissue specificity

Expressed in liver, kidney, pancreas, heart and skeletal muscle.

Post-translational modification

Succinylation at Lys-81, adjacent to a coenzyme A binding site. Desuccinylated by SIRT5 By similarity.

Involvement in disease

3-alpha-hydroxyacyl-CoA dehydrogenase deficiency (HADH deficiency) [MIM:231530]: A metabolic disorder with various clinical presentations including hypoglycemia, hepatoencephalopathy, myopathy or cardiomyopathy, and in some cases sudden death.
Note: The disease is caused by mutations affecting the gene represented in this entry.

Familial hyperinsulinemic hypoglycemia 4 (HHF4) [MIM:609975]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. HHF4 should be easily recognizable by analysis of acylcarnitine species and that this disorder responds well to treatment with diazoxide. It provides the first 'experiment of nature' that links impaired fatty acid oxidation to hyperinsulinism and that provides support for the concept that a lipid signaling pathway is implicated in the control of insulin secretion.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.12

Sequence similarities

Belongs to the 3-hydroxyacyl-CoA dehydrogenase family.

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q16836-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q16836-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MGRAGLEAPPPPCGVTGTPGARGLQGRVGPRPQSLAFRGCLPRASSLPGSPRCRRRCHTM
     236-236: R → RDFQTCGDSNSGLGFSLK
Isoform 3 (identifier: Q16836-3)

The sequence of this isoform differs from the canonical sequence as follows:
     236-236: R → RDFQTCGDSNSGLGFSLK
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 1212Mitochondrion
Chain13 – 314302Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial
PRO_0000007406

Regions

Nucleotide binding34 – 396NAD

Sites

Binding site571NAD
Binding site731Coenzyme A
Binding site801Coenzyme A
Binding site1221NAD
Binding site1271NAD
Binding site1491Coenzyme A
Binding site1491NAD
Binding site1731NAD
Binding site3051NAD
Site1701Important for catalytic activity Probable

Amino acid modifications

Modified residue801N6-succinyllysine By similarity
Modified residue811N6-acetyllysine; alternate By similarity
Modified residue811N6-succinyllysine; alternate By similarity
Modified residue871N6-acetyllysine; alternate By similarity
Modified residue871N6-succinyllysine; alternate By similarity
Modified residue1251N6-acetyllysine By similarity
Modified residue1361N6-acetyllysine; alternate By similarity
Modified residue1361N6-succinyllysine; alternate By similarity
Modified residue1791N6-acetyllysine By similarity
Modified residue1851N6-acetyllysine; alternate Ref.6
Modified residue1851N6-succinyllysine; alternate By similarity
Modified residue1921N6-acetyllysine; alternate By similarity
Modified residue1921N6-succinyllysine; alternate By similarity
Modified residue2021N6-acetyllysine; alternate Ref.6
Modified residue2021N6-succinyllysine; alternate By similarity
Modified residue2061N6-succinyllysine By similarity
Modified residue2121N6-acetyllysine; alternate By similarity
Modified residue2121N6-succinyllysine; alternate By similarity
Modified residue2411N6-acetyllysine; alternate Ref.6
Modified residue2411N6-succinyllysine; alternate By similarity
Modified residue3121N6-acetyllysine; alternate Ref.6
Modified residue3121N6-succinyllysine; alternate By similarity

Natural variations

Alternative sequence11M → MGRAGLEAPPPPCGVTGTPG ARGLQGRVGPRPQSLAFRGC LPRASSLPGSPRCRRRCHTM in isoform 2.
VSP_016551
Alternative sequence2361R → RDFQTCGDSNSGLGFSLK in isoform 2 and isoform 3.
VSP_016552
Natural variant401A → T in HADH deficiency. Ref.11
VAR_024079
Natural variant571D → E in HADH deficiency. Ref.11
VAR_024080
Natural variant861L → P. Ref.1 Ref.2 Ref.3 Ref.5
Corresponds to variant rs4956145 [ dbSNP | Ensembl ].
VAR_026764
Natural variant1521Q → H. Ref.1
Corresponds to variant rs1051519 [ dbSNP | Ensembl ].
VAR_055701
Natural variant2581P → L in HHF4; loss of activity. Ref.12
VAR_024081

Experimental info

Isoform 2:
Sequence conflict411L → P in AAB58153. Ref.2
Sequence conflict561R → H in AAB58153. Ref.2

Secondary structure

......................................................... 314
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 2, 2010. Version 3.
Checksum: 0C6F7C01BBCE646A

FASTA31434,294
        10         20         30         40         50         60 
MAFVTRQFMR SVSSSSTASA SAKKIIVKHV TVIGGGLMGA GIAQVAAATG HTVVLVDQTE 

        70         80         90        100        110        120 
DILAKSKKGI EESLRKVAKK KFAENLKAGD EFVEKTLSTI ATSTDAASVV HSTDLVVEAI 

       130        140        150        160        170        180 
VENLKVKNEL FKRLDKFAAE HTIFASNTSS LQITSIANAT TRQDRFAGLH FFNPVPVMKL 

       190        200        210        220        230        240 
VEVIKTPMTS QKTFESLVDF SKALGKHPVS CKDTPGFIVN RLLVPYLMEA IRLYERGDAS 

       250        260        270        280        290        300 
KEDIDTAMKL GAGYPMGPFE LLDYVGLDTT KFIVDGWHEM DAENPLHQPS PSLNKLVAEN 

       310 
KFGKKTGEGF YKYK 

« Hide

Isoform 2 [UniParc].

Checksum: 3C20D80AAC4EB142
Show »

FASTA39042,140
Isoform 3 [UniParc].

Checksum: 11B5646AD077A666
Show »

FASTA33136,051

References

« Hide 'large scale' references
[1]"Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence."
Vredendaal P.J.C.M., van den Berg I.E.T., Malingre H.E.M., Stroobants A.K., Oldeweghuis D.E.M., Berger R.
Biochem. Biophys. Res. Commun. 223:718-723(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS PRO-86 AND HIS-152.
Tissue: Liver.
[2]"Cloning of a L-3-hydroxyacyl CoA dehydrogenase that binds to GLUT4 glucose transporter cytoplasmic C-terminus: possible crosstalk between glucose transport and fatty acid metabolism."
Shi Y., Samuel S.J., Lee W., Yu C.H., Zhang W., Lachaal M., Jung C.Y.
Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [MRNA] OF 7-314 (ISOFORM 1), VARIANT PRO-86.
Tissue: Skeletal muscle.
[3]"Human short chain L-3-hydroxyacyl-CoA dehydrogenase."
O'Brien L.K., Sims H.F., Strauss A.W.
Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT PRO-86.
[4]"Generation and annotation of the DNA sequences of human chromosomes 2 and 4."
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. expand/collapse author list , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.
Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT PRO-86.
Tissue: Lung.
[6]"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-185; LYS-202; LYS-241 AND LYS-312, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[7]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[8]"Biochemical characterization and crystal structure determination of human heart short chain L-3-hydroxyacyl-CoA dehydrogenase provide insights into catalytic mechanism."
Barycki J.J., O'Brien L.K., Bratt J.M., Zhang R., Sanishvili R., Strauss A.W., Banaszak L.J.
Biochemistry 38:5786-5798(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 13-314 IN COMPLEX WITH SUBSTRATE AND NAD.
[9]"Sequestration of the active site by interdomain shifting. Crystallographic and spectroscopic evidence for distinct conformations of L-3-hydroxyacyl-CoA dehydrogenase."
Barycki J.J., O'Brien L.K., Strauss A.W., Banaszak L.J.
J. Biol. Chem. 275:27186-27196(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 13-314 IN COMPLEX WITH SUBSTRATE AND NAD.
[10]"3-hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease."
Yang S.-Y., He X.-Y., Schulz H.
FEBS J. 272:4874-4883(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[11]"Fulminant hepatic failure associated with mutations in the medium and short chain L-3-hydroxyacyl-CoA dehydrogenase gene."
O'Brien L.K., Rinaldo P., Sims H.F., Alonso E.M., Charrow J., Jones P.M., Bennett M.J., Barycki J.J., Banaszak L.J., Strauss A.W.
J. Inherit. Metab. Dis. 23 Suppl. 1:127-127(2000)
Cited for: VARIANTS HADH DEFICIENCY THR-40 AND GLU-57.
[12]"Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion."
Clayton P.T., Eaton S., Aynsley-Green A., Edginton M., Hussain K., Krywawych S., Datta V., Malingre H.E.M., Berger R., van den Berg I.E.T.
J. Clin. Invest. 108:457-465(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HHF4 LEU-258, CHARACTERIZATION OF VARIANT HHF4 LEU-258.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X96752 mRNA. Translation: CAA65528.1.
AF001902 mRNA. Translation: AAB54008.1.
AF001903 mRNA. Translation: AAB54009.1.
AF001904 Genomic DNA. Translation: AAB58153.1.
AF095703 Genomic DNA. Translation: AAD13581.1.
AC114733 Genomic DNA. Translation: AAY41050.1.
AC118062 Genomic DNA. No translation available.
BC000306 mRNA. Translation: AAH00306.1.
CCDSCCDS3678.1. [Q16836-1]
CCDS54790.1. [Q16836-3]
PIRJC4879.
RefSeqNP_001171634.2. NM_001184705.2.
NP_005318.3. NM_005327.4.
UniGeneHs.438289.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1F0YX-ray1.80A/B13-314[»]
1F12X-ray2.40A/B13-314[»]
1F14X-ray2.30A/B13-314[»]
1F17X-ray2.30A/B13-314[»]
1IL0X-ray2.20A/B13-314[»]
1LSJX-ray2.50A/B13-314[»]
1LSOX-ray2.60A/B13-314[»]
1M75X-ray2.30A/B13-314[»]
1M76X-ray2.15A/B13-314[»]
2HDHX-ray2.20A/B24-314[»]
3HADX-ray2.00A/B13-314[»]
3RQSX-ray2.00A/B1-314[»]
ProteinModelPortalQ16836.
SMRQ16836. Positions 1-314.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109283. 6 interactions.
IntActQ16836. 3 interactions.
MINTMINT-5004681.
STRING9606.ENSP00000312288.

Chemistry

DrugBankDB00157. NADH.

PTM databases

PhosphoSiteQ16836.

Polymorphism databases

DMDM311033442.

2D gel databases

REPRODUCTION-2DPAGEIPI00298406.
UCD-2DPAGEO00324.
Q16836.

Proteomic databases

MaxQBQ16836.
PaxDbQ16836.
PRIDEQ16836.

Protocols and materials databases

DNASU3033.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000309522; ENSP00000312288; ENSG00000138796. [Q16836-1]
ENST00000603302; ENSP00000474560; ENSG00000138796. [Q16836-3]
GeneID3033.
KEGGhsa:3033.
UCSCuc003hyq.3. human. [Q16836-1]

Organism-specific databases

CTD3033.
GeneCardsGC04P108910.
GeneReviewsHADH.
HGNCHGNC:4799. HADH.
HPAHPA039588.
HPA043888.
MIM231530. phenotype.
601609. gene.
609975. phenotype.
neXtProtNX_Q16836.
Orphanet71212. Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency.
PharmGKBPA29173.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG1250.
HOGENOMHOG000141498.
HOVERGENHBG000832.
KOK00022.
OrthoDBEOG7K3TMS.
PhylomeDBQ16836.
TreeFamTF300886.

Enzyme and pathway databases

BioCycMetaCyc:HS06563-MONOMER.
ReactomeREACT_111217. Metabolism.
SABIO-RKQ16836.
UniPathwayUPA00659.

Gene expression databases

ArrayExpressQ16836.
BgeeQ16836.
CleanExHS_HADH.
GenevestigatorQ16836.

Family and domain databases

Gene3D1.10.1040.10. 1 hit.
3.40.50.720. 1 hit.
InterProIPR022694. 3-OHacyl-CoA_DH.
IPR006180. 3-OHacyl-CoA_DH_CS.
IPR006176. 3-OHacyl-CoA_DH_NAD-bd.
IPR006108. 3HC_DH_C.
IPR008927. 6-PGluconate_DH_C-like.
IPR013328. DH_multihelical.
IPR016040. NAD(P)-bd_dom.
[Graphical view]
PfamPF00725. 3HCDH. 1 hit.
PF02737. 3HCDH_N. 1 hit.
[Graphical view]
PIRSFPIRSF000105. HCDH. 1 hit.
SUPFAMSSF48179. SSF48179. 1 hit.
PROSITEPS00067. 3HCDH. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSHADH. human.
EvolutionaryTraceQ16836.
GeneWikiHydroxyacyl-Coenzyme_A_dehydrogenase.
GenomeRNAi3033.
NextBio12006.
PROQ16836.
SOURCESearch...

Entry information

Entry nameHCDH_HUMAN
AccessionPrimary (citable) accession number: Q16836
Secondary accession number(s): J3KQ17 expand/collapse secondary AC list , O00324, O00397, O00753, Q4W5B4
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 2, 2010
Last modified: July 9, 2014
This is version 163 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 4

Human chromosome 4: entries, gene names and cross-references to MIM