Reviewed, UniProtKB/Swiss-Prot P54868 (HMCS2_HUMAN)

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

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.

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.

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.8 Inferred from Experiment. Source: Reactome
Molecular function	hydroxymethylglutaryl-CoA synthase activity Ref.8 Inferred from Experiment. Source: Reactome
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 37

37

Mitochondrion Probable

Chain

38 – 508

471

Hydroxymethylglutaryl-CoA synthase, mitochondrial

PRO_0000013483

Sites

Active site

166

1

Potential

Amino acid modifications

Modified residue

83

1

N6-acetyllysine By similarity

Modified residue

433

1

Phosphoserine By similarity

Modified residue

437

1

N6-acetyllysine By similarity

Natural variations

Natural variant

54

1

V → M in HMG-CoA synthase deficiency. dbSNP rs28937320. Ref.10

VAR_032757

Natural variant

167

1

Y → C in HMG-CoA synthase deficiency. Ref.10

VAR_032758

Natural variant

174

1

F → L in HMG-CoA synthase deficiency; reduced peptide level; no enzymatic activity. Ref.9

VAR_032711

Natural variant

212

1

G → R in HMG-CoA synthase deficiency. Ref.8

VAR_032759

Natural variant

500

1

R → H in HMG-CoA synthase deficiency. Ref.8

VAR_032760

Secondary structure

1

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508

Helix Strand Turn

Details...

Beta strand

58 – 61

4

Beta strand

65 – 69

5

Helix

70 – 76

7

Helix

102 – 117

16

Helix

121 – 123

3

Beta strand

127 – 129

3

Beta strand

137 – 139

3

Helix

141 – 145

5

Helix

146 – 148

3

Turn

149 – 151

3

Beta strand

161 – 164

4

Helix

171 – 180

10

Beta strand

190 – 194

5

Beta strand

214 – 218

5

Beta strand

223 – 226

4

Beta strand

240 – 242

3

Helix

257 – 283

27

Helix

292 – 294

3

Helix

305 – 322

18

Helix

325 – 331

7

Helix

343 – 346

4

Helix

350 – 367

18

Helix

369 – 372

4

Helix

373 – 377

5

Helix

382 – 384

3

Helix

390 – 396

7

Helix

399 – 402

4

Beta strand

409 – 411

3

Beta strand

417 – 425

9

Helix

434 – 440

7

Turn

441 – 444

4

Helix

445 – 450

6

Beta strand

452 – 455

4

Helix

457 – 470

14

Helix

482 – 484

3

Beta strand

490 – 495

6

Beta strand

501 – 505

5

Sequences

	Sequence		Length	Mass (Da)
	P54868-1 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: BD362D631F7C3C80	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

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 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. , 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. , 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 , 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.

IPI

IPI00008934.

PIR

S71623.

RefSeq

NP_001159579.1.
NP_005509.1.

UniGene

Hs.59889
Hs.603127

3D structure databases

PDBe
RCSB PDB
PDBj

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

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.

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

eggNOG

prNOG16021.

HOGENOM

HBG578402.

HOVERGEN

P54868.

InParanoid

P54868.

OMA

GKYSTEQ.

OrthoDB

EOG9S4S1K.

PhylomeDB

P54868.

Enzyme and pathway databases

BioCyc

MetaCyc:ENSG00000134240-MONOMER.

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.
IPR016039. Thiolase-like.
[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...

Entry information

Entry name

HMCS2_HUMAN

Accession

Primary (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 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.