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Protein

Hydroxymethylglutaryl-CoA synthase, mitochondrial

Gene

HMGCS2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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

Catalytic activityi

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

Pathwayi: (R)-mevalonate biosynthesis

This protein is involved in step 2 of the subpathway that synthesizes (R)-mevalonate from acetyl-CoA.
Proteins known to be involved in the 3 steps of the subpathway in this organism are:
  1. no protein annotated in this organism
  2. 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMGCS1), 3-hydroxy-3-methylglutaryl coenzyme A synthase, Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1), Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2), 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl coenzyme A synthase
  3. 3-hydroxy-3-methylglutaryl coenzyme A reductase, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), 3-hydroxy-3-methylglutaryl coenzyme A reductase
This subpathway is part of the pathway (R)-mevalonate biosynthesis, which is itself part of Metabolic intermediate biosynthesis.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes (R)-mevalonate from acetyl-CoA, the pathway (R)-mevalonate biosynthesis and in Metabolic intermediate biosynthesis.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei80Substrate1
Active sitei132Proton donor/acceptor1 Publication1
Active sitei166Acyl-thioester intermediatePROSITE-ProRule annotation1 Publication1
Binding sitei204Substrate1
Binding sitei258Substrate1
Active sitei301Proton donor/acceptor1 Publication1
Binding sitei380Substrate1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionTransferase
Biological processCholesterol biosynthesis, Cholesterol metabolism, Lipid biosynthesis, Lipid metabolism, Steroid biosynthesis, Steroid metabolism, Sterol biosynthesis, Sterol metabolism

Enzyme and pathway databases

BioCyciMetaCyc:HS05836-MONOMER
BRENDAi2.3.3.10 2681
ReactomeiR-HSA-1989781 PPARA activates gene expression
R-HSA-77111 Synthesis of Ketone Bodies
UniPathwayiUPA00058; UER00102

Chemistry databases

SwissLipidsiSLP:000001249 [P54868-1]

Names & Taxonomyi

Protein namesi
Recommended name:
Hydroxymethylglutaryl-CoA synthase, mitochondrial (EC:2.3.3.10)
Short name:
HMG-CoA synthase
Alternative name(s):
3-hydroxy-3-methylglutaryl coenzyme A synthase
Gene namesi
Name:HMGCS2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000134240.11
HGNCiHGNC:5008 HMGCS2
MIMi600234 gene
neXtProtiNX_P54868

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Mitochondrion

Pathology & Biotechi

Involvement in diseasei

3-hydroxy-3-methylglutaryl-CoA synthase-2 deficiency (HMGCS2D)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA metabolic disorder characterized by severe hypoketotic hypoglycemia, encephalopathy, and hepatomegaly.
See also OMIM:605911
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03275754V → M in HMGCS2D. 1 PublicationCorresponds to variant dbSNP:rs28937320EnsemblClinVar.1
Natural variantiVAR_032758167Y → C in HMGCS2D. 1 PublicationCorresponds to variant dbSNP:rs137852640EnsemblClinVar.1
Natural variantiVAR_032711174F → L in HMGCS2D; reduced peptide level; no enzymatic activity. 1 PublicationCorresponds to variant dbSNP:rs137852636EnsemblClinVar.1
Natural variantiVAR_032759212G → R in HMGCS2D. 1 PublicationCorresponds to variant dbSNP:rs137852638EnsemblClinVar.1
Natural variantiVAR_032760500R → H in HMGCS2D. 1 PublicationCorresponds to variant dbSNP:rs137852639Ensembl.1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi3158
MalaCardsiHMGCS2
MIMi605911 phenotype
OpenTargetsiENSG00000134240
Orphaneti35701 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
PharmGKBiPA29338

Polymorphism and mutation databases

BioMutaiHMGCS2
DMDMi1708234

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 37MitochondrionCuratedAdd BLAST37
ChainiPRO_000001348338 – 508Hydroxymethylglutaryl-CoA synthase, mitochondrialAdd BLAST471

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei52N6-succinyllysineBy similarity1
Modified residuei83N6-acetyllysine; alternateBy similarity1
Modified residuei83N6-succinyllysine; alternateBy similarity1
Modified residuei221N6-succinyllysineBy similarity1
Modified residuei243N6-acetyllysineBy similarity1
Modified residuei256N6-acetyllysine; alternateBy similarity1
Modified residuei256N6-succinyllysine; alternateBy similarity1
Modified residuei306N6-acetyllysineBy similarity1
Modified residuei310N6-acetyllysine; alternateBy similarity1
Modified residuei310N6-succinyllysine; alternateBy similarity1
Modified residuei333N6-succinyllysineBy similarity1
Modified residuei342N6-acetyllysine; alternateBy similarity1
Modified residuei342N6-succinyllysine; alternateBy similarity1
Modified residuei350N6-acetyllysine; alternateBy similarity1
Modified residuei350N6-succinyllysine; alternateBy similarity1
Modified residuei354N6-acetyllysine; alternateBy similarity1
Modified residuei354N6-succinyllysine; alternateBy similarity1
Modified residuei358N6-acetyllysine; alternateBy similarity1
Modified residuei358N6-succinyllysine; alternateBy similarity1
Modified residuei433PhosphoserineCombined sources1
Modified residuei437N6-acetyllysineBy similarity1
Modified residuei440PhosphoserineCombined sources1
Modified residuei447N6-acetyllysine; alternateBy similarity1
Modified residuei447N6-succinyllysine; alternateBy similarity1
Modified residuei456PhosphoserineBy similarity1
Modified residuei473N6-acetyllysine; alternateBy similarity1
Modified residuei473N6-succinyllysine; alternateBy similarity1
Modified residuei477PhosphoserineBy similarity1

Post-translational modificationi

Succinylated. Desuccinylated by SIRT5. Succinylation, at least at Lys-83 and Lys-310, inhibits the enzymatic activity.By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiP54868
PaxDbiP54868
PeptideAtlasiP54868
PRIDEiP54868
ProteomicsDBi56743
56744 [P54868-2]

2D gel databases

REPRODUCTION-2DPAGEiIPI00008934

PTM databases

iPTMnetiP54868
PhosphoSitePlusiP54868
SwissPalmiP54868

Expressioni

Tissue specificityi

Expression in liver is 200-fold higher than in any other tissue. Low expression in colon, kidney, testis, and pancreas. Very low expression in heart and skeletal muscle. Not detected in brain. The relative expression of isoform 3 (at mRNA level) is highest in heart (70%) and skeletal muscle (60%).3 Publications

Gene expression databases

BgeeiENSG00000134240
CleanExiHS_HMGCS2
ExpressionAtlasiP54868 baseline and differential
GenevisibleiP54868 HS

Organism-specific databases

HPAiCAB032906
HPA027423
HPA027442

Interactioni

Subunit structurei

Homodimer.1 Publication

Protein-protein interaction databases

BioGridi109401, 6 interactors
IntActiP54868, 1 interactor
MINTiP54868
STRINGi9606.ENSP00000358414

Structurei

Secondary structure

1508
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi55 – 62Combined sources8
Beta strandi65 – 69Combined sources5
Helixi70 – 76Combined sources7
Helixi83 – 88Combined sources6
Beta strandi92 – 94Combined sources3
Helixi102 – 117Combined sources16
Helixi121 – 123Combined sources3
Beta strandi124 – 130Combined sources7
Beta strandi137 – 139Combined sources3
Helixi141 – 145Combined sources5
Helixi146 – 148Combined sources3
Helixi150 – 152Combined sources3
Beta strandi161 – 164Combined sources4
Helixi165 – 167Combined sources3
Helixi168 – 180Combined sources13
Beta strandi189 – 198Combined sources10
Helixi206 – 208Combined sources3
Beta strandi210 – 221Combined sources12
Beta strandi223 – 226Combined sources4
Beta strandi232 – 235Combined sources4
Beta strandi240 – 242Combined sources3
Helixi255 – 283Combined sources29
Helixi292 – 294Combined sources3
Beta strandi296 – 300Combined sources5
Helixi305 – 322Combined sources18
Helixi325 – 331Combined sources7
Helixi333 – 338Combined sources6
Helixi343 – 347Combined sources5
Helixi350 – 367Combined sources18
Helixi369 – 372Combined sources4
Helixi373 – 378Combined sources6
Helixi382 – 384Combined sources3
Helixi385 – 396Combined sources12
Helixi399 – 402Combined sources4
Beta strandi406 – 413Combined sources8
Turni414 – 416Combined sources3
Beta strandi417 – 425Combined sources9
Helixi434 – 440Combined sources7
Turni441 – 444Combined sources4
Helixi445 – 450Combined sources6
Beta strandi452 – 455Combined sources4
Helixi457 – 470Combined sources14
Helixi482 – 484Combined sources3
Beta strandi490 – 495Combined sources6
Beta strandi501 – 505Combined sources5

3D structure databases

ProteinModelPortaliP54868
SMRiP54868
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP54868

Family & Domainsi

Sequence similaritiesi

Belongs to the HMG-CoA synthase family.Curated

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG1393 Eukaryota
COG3425 LUCA
GeneTreeiENSGT00390000006096
HOGENOMiHOG000012351
HOVERGENiHBG051912
InParanoidiP54868
KOiK01641
OMAiARLMFND
OrthoDBiEOG091G0791
PhylomeDBiP54868
TreeFamiTF105361

Family and domain databases

Gene3Di3.40.47.10, 1 hit
InterProiView protein in InterPro
IPR000590 HMG_CoA_synt_AS
IPR013746 HMG_CoA_synt_C_dom
IPR013528 HMG_CoA_synth_N
IPR010122 HMG_CoA_synthase_euk
IPR016039 Thiolase-like
PfamiView protein in Pfam
PF08540 HMG_CoA_synt_C, 1 hit
PF01154 HMG_CoA_synt_N, 1 hit
SUPFAMiSSF53901 SSF53901, 3 hits
TIGRFAMsiTIGR01833 HMG-CoA-S_euk, 1 hit
PROSITEiView protein in PROSITE
PS01226 HMG_COA_SYNTHASE, 1 hit

Sequences (3)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P54868-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MQRLLTPVKR ILQLTRAVQE TSLTPARLLP VAHQRFSTAS AVPLAKTDTW
60 70 80 90 100
PKDVGILALE VYFPAQYVDQ TDLEKYNNVE AGKYTVGLGQ TRMGFCSVQE
110 120 130 140 150
DINSLCLTVV QRLMERIQLP WDSVGRLEVG TETIIDKSKA VKTVLMELFQ
160 170 180 190 200
DSGNTDIEGI DTTNACYGGT ASLFNAANWM ESSSWDGRYA MVVCGDIAVY
210 220 230 240 250
PSGNARPTGG AGAVAMLIGP KAPLALERGL RGTHMENVYD FYKPNLASEY
260 270 280 290 300
PIVDGKLSIQ CYLRALDRCY TSYRKKIQNQ WKQAGSDRPF TLDDLQYMIF
310 320 330 340 350
HTPFCKMVQK SLARLMFNDF LSASSDTQTS LYKGLEAFGG LKLEDTYTNK
360 370 380 390 400
DLDKALLKAS QDMFDKKTKA SLYLSTHNGN MYTSSLYGCL ASLLSHHSAQ
410 420 430 440 450
ELAGSRIGAF SYGSGLAASF FSFRVSQDAA PGSPLDKLVS STSDLPKRLA
460 470 480 490 500
SRKCVSPEEF TEIMNQREQF YHKVNFSPPG DTNSLFPGTW YLERVDEQHR

RKYARRPV
Length:508
Mass (Da):56,635
Last modified:October 1, 1996 - v1
Checksum:iBD362D631F7C3C80
GO
Isoform 2 (identifier: P54868-2) [UniParc]FASTAAdd to basket

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

Note: No experimental confirmation available.
Show »
Length:466
Mass (Da):52,482
Checksum:i9D3C527559B74618
GO
Isoform 3 (identifier: P54868-3) [UniParc]FASTAAdd to basket
Also known as: HMGCS2delta4

The sequence of this isoform differs from the canonical sequence as follows:
     229-283: Missing.

Show »
Length:453
Mass (Da):50,050
Checksum:i80C1D1EBB7403EC0
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti234H → Y in CAG33131 (Ref. 3) Curated1
Sequence conflicti385S → T in CAG33131 (Ref. 3) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03275754V → M in HMGCS2D. 1 PublicationCorresponds to variant dbSNP:rs28937320EnsemblClinVar.1
Natural variantiVAR_032758167Y → C in HMGCS2D. 1 PublicationCorresponds to variant dbSNP:rs137852640EnsemblClinVar.1
Natural variantiVAR_032711174F → L in HMGCS2D; reduced peptide level; no enzymatic activity. 1 PublicationCorresponds to variant dbSNP:rs137852636EnsemblClinVar.1
Natural variantiVAR_032759212G → R in HMGCS2D. 1 PublicationCorresponds to variant dbSNP:rs137852638EnsemblClinVar.1
Natural variantiVAR_032760500R → H in HMGCS2D. 1 PublicationCorresponds to variant dbSNP:rs137852639Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_042892187 – 228Missing in isoform 2. 1 PublicationAdd BLAST42
Alternative sequenceiVSP_047445229 – 283Missing in isoform 3. 1 PublicationAdd BLAST55

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X83618 mRNA Translation: CAA58593.1
U81859
, U81851, U81852, U81853, U81854, U81855, U81856, U81857, U81858 Genomic DNA Translation: AAB72036.1
CR456850 mRNA Translation: CAG33131.1
AK303777 mRNA Translation: BAH14049.1
AL589734 Genomic DNA No translation available.
CH471122 Genomic DNA Translation: EAW56709.1
BC044217 mRNA Translation: AAH44217.1
U12788 mRNA Translation: AAA92673.1
U12789 mRNA Translation: AAA92674.1
GU433940 mRNA Translation: ADD21696.1
CCDSiCCDS53353.1 [P54868-2]
CCDS905.1 [P54868-1]
PIRiS71623
RefSeqiNP_001159579.1, NM_001166107.1 [P54868-2]
NP_005509.1, NM_005518.3 [P54868-1]
XP_011539615.1, XM_011541313.1 [P54868-3]
UniGeneiHs.59889

Genome annotation databases

EnsembliENST00000369406; ENSP00000358414; ENSG00000134240 [P54868-1]
ENST00000544913; ENSP00000439495; ENSG00000134240 [P54868-2]
GeneIDi3158
KEGGihsa:3158
UCSCiuc001eid.4 human [P54868-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiHMCS2_HUMAN
AccessioniPrimary (citable) accession number: P54868
Secondary accession number(s): B7Z8R3
, D3Y5K6, Q5SZU2, Q6IBF4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: June 20, 2018
This is version 172 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

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