P54868 (HMCS2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

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) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › 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.8
Involvement in disease	HMG-CoA synthase deficiency (HMGCS deficiency) [MIM:605911]: 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. Note: The disease is caused by mutations affecting the gene represented in this entry.
Sequence similarities	Belongs to the HMG-CoA synthase family.

Ontologies

Keywords
Biological process	Cholesterol biosynthesis Cholesterol metabolism Lipid biosynthesis Lipid metabolism Steroid biosynthesis Steroid metabolism Sterol biosynthesis Sterol metabolism
Cellular component	Mitochondrion
Coding sequence diversity	Alternative splicing
Disease	Disease mutation
Domain	Transit peptide
Molecular function	Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cellular lipid metabolic process Traceable author statement. Source: Reactome cholesterol biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW isoprenoid biosynthetic process Inferred from electronic annotation. Source: InterPro ketone body biosynthetic process Traceable author statement. Source: Reactome
Cellular_component	mitochondrial inner membrane Inferred from electronic annotation. Source: Compara mitochondrial matrix Traceable author statement. Source: Reactome
Molecular_function	hydroxymethylglutaryl-CoA synthase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P54868-1)

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: P54868-2)

The sequence of this isoform differs from the canonical sequence as follows:
     187-228: Missing.

Note: No experimental confirmation available.

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

310

1

N6-succinyllysine By similarity

Modified residue

433

1

Phosphoserine By similarity

Modified residue

437

1

N6-acetyllysine By similarity

Natural variations

Alternative sequence

187 – 228

42

Missing in isoform 2.

VSP_042892

Natural variant

54

1

V → M in HMGCS deficiency. Ref.11
Corresponds to variant rs28937320 [ dbSNP | Ensembl ].

VAR_032757

Natural variant

167

1

Y → C in HMGCS deficiency. Ref.11

VAR_032758

Natural variant

174

1

F → L in HMGCS deficiency; reduced peptide level; no enzymatic activity. Ref.10

VAR_032711

Natural variant

212

1

G → R in HMGCS deficiency. Ref.9

VAR_032759

Natural variant

500

1

R → H in HMGCS deficiency. Ref.9

VAR_032760

Secondary structure

1

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508

Helix Strand Turn

Details...

Beta strand

55 – 62

8

Beta strand

65 – 69

5

Helix

70 – 76

7

Helix

83 – 88

6

Beta strand

92 – 94

3

Helix

102 – 117

16

Helix

121 – 123

3

Beta strand

124 – 130

7

Beta strand

137 – 139

3

Helix

141 – 145

5

Helix

146 – 148

3

Helix

150 – 152

3

Beta strand

161 – 164

4

Helix

165 – 167

3

Helix

168 – 180

13

Beta strand

189 – 198

10

Helix

206 – 208

3

Beta strand

210 – 221

12

Beta strand

223 – 226

4

Beta strand

232 – 235

4

Beta strand

240 – 242

3

Helix

255 – 283

29

Helix

292 – 294

3

Beta strand

296 – 300

5

Helix

305 – 322

18

Helix

325 – 331

7

Helix

333 – 338

6

Helix

343 – 347

5

Helix

350 – 367

18

Helix

369 – 372

4

Helix

373 – 378

6

Helix

382 – 384

3

Helix

385 – 396

12

Helix

399 – 402

4

Beta strand

406 – 413

8

Turn

414 – 416

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)
	Isoform 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
	Isoform 2 [UniParc]. Checksum: 9D3C527559B74618	FASTA	466	52,482
	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 ESSSWDGLRG THMENVYDFY KPNLASEYPI VDGKLSIQCY LRALDRCYTS YRKKIQNQWK 250 260 270 280 290 300 QAGSDRPFTL DDLQYMIFHT PFCKMVQKSL ARLMFNDFLS ASSDTQTSLY KGLEAFGGLK 310 320 330 340 350 360 LEDTYTNKDL DKALLKASQD MFDKKTKASL YLSTHNGNMY TSSLYGCLAS LLSHHSAQEL 370 380 390 400 410 420 AGSRIGAFSY GSGLAASFFS FRVSQDAAPG SPLDKLVSST SDLPKRLASR KCVSPEEFTE 430 440 450 460 IMNQREQFYH KVNFSPPGDT NSLFPGTWYL ERVDEQHRRK YARRPV

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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), 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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Liver.
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Liver.
[4]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	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].
[6]	"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). Tissue: Brain.
[7]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 36-508 (ISOFORM 1). Tissue: Liver.
[8]	"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] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY.
[9]	"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] [Europe PMC] [Abstract] Cited for: VARIANTS HMGCS DEFICIENCY ARG-212 AND HIS-500.
[10]	"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] [Europe PMC] [Abstract] Cited for: VARIANT HMGCS DEFICIENCY LEU-174, CHARACTERIZATION OF VARIANT HMGCS DEFICIENCY LEU-174.
[11]	"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] [Europe PMC] [Abstract] Cited for: VARIANTS HMGCS 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.
AK303777 mRNA. Translation: BAH14049.1.
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.
IPI00945760.

PIR

S71623.

RefSeq

NP_001159579.1. NM_001166107.1.
NP_005509.1. NM_005518.3.

UniGene

Hs.59889.

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	[»]

ProteinModelPortal

P54868.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000358414.

PTM databases

PhosphoSite

P54868.

Polymorphism databases

DMDM

1708234.

2D gel databases

REPRODUCTION-2DPAGE

IPI00008934.

Proteomic databases

PaxDb

P54868.

PeptideAtlas

P54868.

PRIDE

P54868.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000369406; ENSP00000358414; ENSG00000134240.
ENST00000544913; ENSP00000439495; ENSG00000134240.

GeneID

3158.

KEGG

hsa:3158.

UCSC

uc001eid.3. human.

Organism-specific databases

CTD

3158.

GeneCards

GC01M120290.

H-InvDB

HIX0160007.

HGNC

HGNC:5008. HMGCS2.

MIM

600234. gene.
605911. phenotype.

neXtProt

NX_P54868.

Orphanet

35701. 3-hydroxy 3-methylglutaryl-CoA synthase deficiency.

PharmGKB

PA29338.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG3425.

HOGENOM

HOG000012351.

HOVERGEN

HBG051912.

InParanoid

P54868.

KO

K01641.

OMA

DSVTMAS.

OrthoDB

EOG4H72B9.

PhylomeDB

P54868.

Enzyme and pathway databases

BioCyc

MetaCyc:HS05836-MONOMER.

BRENDA

2.3.3.10. 2681.

Reactome

REACT_111217. Metabolism.

UniPathway

UPA00058; UER00102.

Gene expression databases

Bgee

P54868.

CleanEx

HS_HMGCS2.

Genevestigator

P54868.

GermOnline

ENSG00000134240. Homo sapiens.

Family and domain databases

Gene3D

3.40.47.10. 1 hit.

InterPro

IPR000590. HMG_CoA_synt_AS.
IPR013746. HMG_CoA_synt_C.
IPR013528. HMG_CoA_synth_N.
IPR010122. HMG_CoA_synthase_euk.
IPR016039. Thiolase-like.
IPR016038. Thiolase-like_subgr.
[Graphical view]

Pfam

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

SUPFAM

SSF53901. Thiolase-like. 2 hits.

TIGRFAMs

TIGR01833. HMG-CoA-S_euk. 1 hit.

PROSITE

PS01226. HMG_COA_SYNTHASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P54868.

GenomeRNAi

3158.

NextBio

12510.

SOURCE

Search...

Entry information

Entry name

HMCS2_HUMAN

Accession

Primary (citable) accession number: P54868
Secondary accession number(s): B7Z8R3, Q5SZU2

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	May 1, 2013
This is version 128 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.