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Reviewed, UniProtKB/Swiss-Prot P54868 (HMCS2_HUMAN)

Last modified February 9, 2010. Version 99. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Hydroxymethylglutaryl-CoA synthase, mitochondrial
      Short name=HMG-CoA synthase
    EC=2.3.3.10
Alternative name(s):
    3-hydroxy-3-methylglutaryl coenzyme A synthase
Gene names
Name: HMGCS2
OrganismHomo sapiens (Human) [Complete proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length508 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

This enzyme condenses acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is the substrate for HMG-CoA reductase.

Catalytic activity

Acetyl-CoA + H2O + acetoacetyl-CoA = (S)-3-hydroxy-3-methylglutaryl-CoA + CoA.

Pathway

Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 2/3.

Subcellular location

Mitochondrion.

Tissue specificity

High expression in liver and colon. Low expression in testis, heart, skeletal muscle and kidney. Ref.1 Ref.7

Involvement in disease

Defects in HMGCS2 are the cause of HMG-CoA synthase deficiency [MIM:605911]; also known as deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2. Affected individuals present with severe hypoketotic hypoglycemia, mild hepatomegaly, or fatty liver, and a nondiagnostic pattern of urinary organic acids with increase of medium and short chain dicarboxylic acids. Ref.8 Ref.9 Ref.10

Sequence similarities

Belongs to the HMG-CoA synthase family.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 3737Mitochondrion Probable
Chain38 – 508471Hydroxymethylglutaryl-CoA synthase, mitochondrial
PRO_0000013483

Sites

Active site1661 Potential

Amino acid modifications

Modified residue831N6-acetyllysine By similarity
Modified residue4331Phosphoserine By similarity
Modified residue4371N6-acetyllysine By similarity

Natural variations

Natural variant541V → M in HMG-CoA synthase deficiency. dbSNP rs28937320. Ref.10
VAR_032757
Natural variant1671Y → C in HMG-CoA synthase deficiency. Ref.10
VAR_032758
Natural variant1741F → L in HMG-CoA synthase deficiency; reduced peptide level; no enzymatic activity. Ref.9
VAR_032711
Natural variant2121G → R in HMG-CoA synthase deficiency. Ref.8
VAR_032759
Natural variant5001R → H in HMG-CoA synthase deficiency. Ref.8
VAR_032760

Secondary structure

..................................................................... 508
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P54868-1 [UniParc].

Last modified October 1, 1996. Version 1.
Checksum: BD362D631F7C3C80

FASTA50856,635
        10         20         30         40         50         60 
MQRLLTPVKR ILQLTRAVQE TSLTPARLLP VAHQRFSTAS AVPLAKTDTW PKDVGILALE 

        70         80         90        100        110        120 
VYFPAQYVDQ TDLEKYNNVE AGKYTVGLGQ TRMGFCSVQE DINSLCLTVV QRLMERIQLP 

       130        140        150        160        170        180 
WDSVGRLEVG TETIIDKSKA VKTVLMELFQ DSGNTDIEGI DTTNACYGGT ASLFNAANWM 

       190        200        210        220        230        240 
ESSSWDGRYA MVVCGDIAVY PSGNARPTGG AGAVAMLIGP KAPLALERGL RGTHMENVYD 

       250        260        270        280        290        300 
FYKPNLASEY PIVDGKLSIQ CYLRALDRCY TSYRKKIQNQ WKQAGSDRPF TLDDLQYMIF 

       310        320        330        340        350        360 
HTPFCKMVQK SLARLMFNDF LSASSDTQTS LYKGLEAFGG LKLEDTYTNK DLDKALLKAS 

       370        380        390        400        410        420 
QDMFDKKTKA SLYLSTHNGN MYTSSLYGCL ASLLSHHSAQ ELAGSRIGAF SYGSGLAASF 

       430        440        450        460        470        480 
FSFRVSQDAA PGSPLDKLVS STSDLPKRLA SRKCVSPEEF TEIMNQREQF YHKVNFSPPG 

       490        500 
DTNSLFPGTW YLERVDEQHR RKYARRPV 

« Hide

References

« Hide 'large scale' references
[1]"Molecular cloning and tissue expression of human mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase."
Mascaro C., Buesa C., Ortiz J.A., Haro D., Hegardt F.G.
Arch. Biochem. Biophys. 317:385-390(1995) [PubMed: 7893153] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
[2]"Cloning and characterization of the human mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase gene."
Boukaftane Y., Mitchell G.A.
Gene 195:121-126(1997) [PubMed: 9305755] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Tissue: Liver.
[3]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed: 16710414] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
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: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain.
[6]"Human mitochondrial HMG CoA synthase: liver cDNA and partial genomic cloning, chromosome mapping to 1p12-p13, and possible role in vertebrate evolution."
Boukaftane Y., Duncan A., Wang S., Labuda D., Robert M.-F., Sarrazin J., Schappert K.T., Mitchell G.A.
Genomics 23:552-559(1994) [PubMed: 7851882] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 36-508.
Tissue: Liver.
[7]"Ketogenic HMGCS2 Is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer."
Camarero N., Mascaro C., Mayordomo C., Vilardell F., Haro D., Marrero P.F.
Mol. Cancer Res. 4:645-653(2006) [PubMed: 16940161] [Abstract]
Cited for: TISSUE SPECIFICITY.
[8]"Genetic basis of mitochondrial HMG-CoA synthase deficiency."
Aledo R., Zschocke J., Pie J., Mir C., Fiesel S., Mayatepek E., Hoffmann G.F., Casals N., Hegardt F.G.
Hum. Genet. 109:19-23(2001) [PubMed: 11479731] [Abstract]
Cited for: VARIANTS HMG-COA SYNTHASE DEFICIENCY ARG-212 AND HIS-500.
[9]"Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: clinical course and description of causal mutations in two patients."
Bouchard L., Robert M.-F., Vinarov D., Stanley C.A., Thompson G.N., Morris A., Leonard J.V., Quant P., Hsu B.Y.L., Boneh A., Boukaftane Y., Ashmarina L., Wang S., Miziorko H., Mitchell G.A.
Pediatr. Res. 49:326-331(2001) [PubMed: 11228257] [Abstract]
Cited for: VARIANT HMG-COA SYNTHASE DEFICIENCY LEU-174, CHARACTERIZATION OF VARIANT HMG-COA SYNTHASE DEFICIENCY LEU-174.
[10]"Mitochondrial HMG-CoA synthase deficiency: identification of two further patients carrying two novel mutations."
Wolf N.I., Rahman S., Clayton P.T., Zschocke J.
Eur. J. Pediatr. 162:279-280(2003) [PubMed: 12647205] [Abstract]
Cited for: VARIANTS HMG-COA SYNTHASE DEFICIENCY MET-54 AND CYS-167.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X83618 mRNA. Translation: CAA58593.1.
U81859 expand/collapse EMBL AC list , U81851, U81852, U81853, U81854, U81855, U81856, U81857, U81858 Genomic DNA. Translation: AAB72036.1.
AL589734 Genomic DNA. Translation: CAI22408.1.
CH471122 Genomic DNA. Translation: EAW56709.1.
BC044217 mRNA. Translation: AAH44217.1.
U12788 mRNA. Translation: AAA92673.1.
U12789 mRNA. Translation: AAA92674.1.
IPIIPI00008934.
PIRS71623.
RefSeqNP_001159579.1.
NP_005509.1.
UniGeneHs.59889
Hs.603127

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2WYAX-ray1.70A/B/C/D51-508[»]
ModBaseSearch...

Protein-protein interaction databases

STRINGP54868.

PTM databases

PhosphoSiteP54868.

2-D gel databases

REPRODUCTION-2DPAGEIPI00008934.

Proteomic databases

PeptideAtlasP54868.
PRIDEP54868.

Genome annotation databases

EnsemblENST00000369406; ENSP00000358414; ENSG00000134240; Homo sapiens. [Genome view]
GeneID3158.
UCSCuc001eid.1. human.

Organism-specific databases

CTD3158.
GeneCardsGC01M120003.
H-InvDBHIX0023645.
HGNCHGNC:5008. HMGCS2.
MIM600234. gene.
605911. phenotype.
Orphanet35701. 3-hydroxy 3-methylglutaryl-CoA (HMG) synthase deficiency.
PharmGKBPA29338.
GenAtlasSearch...

Phylogenomic databases

eggNOGprNOG16021.
HOGENOMHBG578402.
HOVERGENP54868.
InParanoidP54868.
OMAGKYSTEQ.
OrthoDBEOG9S4S1K.
PhylomeDBP54868.

Enzyme and pathway databases

BioCycMetaCyc:ENSG00000134240-MONOMER.
BRENDA2.3.3.10. 247.
ReactomeREACT_602. Metabolism of lipids and lipoproteins.

Gene expression databases

ArrayExpressP54868.
BgeeP54868.
CleanExHS_HMGCS2.
GenevestigatorP54868.
GermOnlineENSG00000134240. Homo sapiens.

Family and domain databases

InterProIPR000590. HMG_CoA_synt_AS.
IPR013746. HMG_CoA_synt_C.
IPR013528. HMG_CoA_synth_N.
IPR010122. HMG_CoA_synthase_euk.
IPR016039. Thiolase-like.
[Graphical view]
PfamPF08540. HMG_CoA_synt_C. 1 hit.
PF01154. HMG_CoA_synt_N. 1 hit.
[Graphical view]
TIGRFAMsTIGR01833. HMG-CoA-S_euk. 1 hit.
PROSITEPS01226. HMG_COA_SYNTHASE. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

NextBio12510.
SOURCESearch...

Entry information

Entry nameHMCS2_HUMAN
AccessionPrimary (citable) accession number: P54868
Secondary accession number(s): Q5SZU2
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: February 9, 2010
This is version 99 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)
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

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

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

PATHWAY comments

Index of metabolic and biosynthesis pathways

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents