Hydroxymethylglutaryl-CoA synthase, mitochondrial precursor

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Reviewed, UniProtKB/Swiss-Prot P54868 (HMCS2_HUMAN)

Last modified November 3, 2009. Version 95. History...

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

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Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	508 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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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.5
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.6 Ref.7 Ref.8
Sequence similarities	Belongs to the HMG-CoA synthase family.

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Ontologies

Keywords
Biological process	Cholesterol biosynthesis Lipid synthesis Steroid biosynthesis Sterol biosynthesis
Cellular component	Mitochondrion
Disease	Disease mutation
Domain	Transit peptide
Molecular function	Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	cholesterol biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW isoprenoid biosynthetic process Inferred from electronic annotation. Source: InterPro
Cellular component	mitochondrial matrix Ref.6 Inferred from Experiment. Source: Reactome
Molecular function	hydroxymethylglutaryl-CoA synthase activity Ref.6 Inferred from Experiment. Source: Reactome
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 37

Mitochondrion Probable

Chain

38 – 508

471

Hydroxymethylglutaryl-CoA synthase, mitochondrial

PRO_0000013483

Sites

Active site

166

Potential

Amino acid modifications

Modified residue

N6-acetyllysine By similarity

Modified residue

433

Phosphoserine By similarity

Modified residue

437

N6-acetyllysine By similarity

Natural variations

Natural variant

V → M in HMG-CoA synthase deficiency. Ref.8

VAR_032757

Natural variant

167

Y → C in HMG-CoA synthase deficiency. Ref.8

VAR_032758

Natural variant

174

F → L in HMG-CoA synthase deficiency; reduced peptide level; no enzymatic activity. Ref.7

VAR_032711

Natural variant

212

G → R in HMG-CoA synthase deficiency. Ref.6

VAR_032759

Natural variant

500

R → H in HMG-CoA synthase deficiency. Ref.6

VAR_032760

Secondary structure

508

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P54868-1 [UniParc].

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

508

56,635

        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

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References

	« Hide 'large scale' referencesShow '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 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.
[4]	"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.
[5]	"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.
[6]	"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.
[7]	"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.
[8]	"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.

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Cross-references

Sequence databases

X83618 mRNA. Translation: CAA58593.1.
U81859

U81858 Genomic DNA. Translation: AAB72036.1.
BC044217 mRNA. Translation: AAH44217.1.
U12788 mRNA. Translation: AAA92673.1.
U12789 mRNA. Translation: AAA92674.1.

IPI

IPI00008934.

PIR

S71623.

RefSeq

NP_005509.1.

UniGene

Hs.59889

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2V4W	X-ray	1.70	A/B/C/D	51-508	[»]

SMR

P54868. Positions 53-507.

ModBase

Search...

Protein-protein interaction databases

STRING

P54868.

PTM databases

PhosphoSite

P54868.

2-D gel databases

REPRODUCTION-2DPAGE

IPI00008934.

Proteomic databases

PeptideAtlas

P54868.

PRIDE

P54868.

Genome annotation databases

Ensembl

ENST00000369406; ENSP00000358414; ENSG00000134240; Homo sapiens. [Genome view]

GeneID

3158.

KEGG

hsa:3158.

UCSC

uc001eid.1. human.

Organism-specific databases

CTD

3158.

GeneCards

GC01M120003.

H-InvDB

HIX0023645.

HGNC

HGNC:5008. HMGCS2.

MIM

600234. gene.
605911. phenotype.

Orphanet

35701. 3-hydroxy 3-methylglutaryl-CoA (HMG) synthase deficiency.

PharmGKB

PA29338.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P54868.

HOVERGEN

P54868.

OMA

GKYSTEQ.

Enzyme and pathway databases

BRENDA

2.3.3.10. 247.

Reactome

REACT_602. Metabolism of lipids and lipoproteins.

Gene expression databases

ArrayExpress

P54868.

Bgee

P54868.

CleanEx

HS_HMGCS2.

Genevestigator

P54868.

GermOnline

ENSG00000134240. Homo sapiens.

Family and domain databases

InterPro

IPR000590. HMG_CoA_synt_AS.
IPR013746. HMG_CoA_synt_C.
IPR013528. HMG_CoA_synth_N.
IPR010122. HMG_CoA_synthase_euk.
[Graphical view]

Pfam

PF08540. HMG_CoA_synt_C. 1 hit.
PF01154. HMG_CoA_synt_N. 1 hit.
[Graphical view]

TIGRFAMs

TIGR01833. HMG-CoA-S_euk. 1 hit.

PROSITE

PS01226. HMG_COA_SYNTHASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

12510.

SOURCE

Search...

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Entry information

Entry name

HMCS2_HUMAN

Accession

Primary (citable) accession number: P54868

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	November 3, 2009
This is version 95 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.

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