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Protein

Hydroxymethylglutaryl-CoA lyase, mitochondrial

Gene

HMGCL

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

Functioni

Key enzyme in ketogenesis (ketone body formation). Terminal step in leucine catabolism. Ketone bodies (beta-hydroxybutyrate, acetoacetate and acetone) are essential as an alternative source of energy to glucose, as lipid precursors and as regulators of metabolism.3 Publications

Catalytic activityi

(S)-3-hydroxy-3-methylglutaryl-CoA = acetyl-CoA + acetoacetate.PROSITE-ProRule annotation2 Publications

Cofactori

a divalent metal cation1 Publication

Activity regulationi

Stimulated by reducing agents such as dithiothreitol (DTT).1 Publication

Kineticsi

  1. KM=200 µM for magnesium ion2 Publications
  2. KM=48 µM for HMG-CoA2 Publications
  1. Vmax=191 µmol/min/mg enzyme2 Publications

Pathwayi: (S)-3-hydroxy-3-methylglutaryl-CoA degradation

This protein is involved in step 1 of the subpathway that synthesizes acetoacetate from (S)-3-hydroxy-3-methylglutaryl-CoA.
Proteins known to be involved in this subpathway in this organism are:
  1. 3-hydroxymethyl-3-methylglutaryl-CoA lyase, cytoplasmic (HMGCLL1), Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL)
This subpathway is part of the pathway (S)-3-hydroxy-3-methylglutaryl-CoA degradation, which is itself part of Metabolic intermediate metabolism.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes acetoacetate from (S)-3-hydroxy-3-methylglutaryl-CoA, the pathway (S)-3-hydroxy-3-methylglutaryl-CoA degradation and in Metabolic intermediate metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei41Substrate1
Metal bindingi42Divalent metal cation1
Metal bindingi233Divalent metal cation1
Metal bindingi235Divalent metal cation1
Active sitei266PROSITE-ProRule annotation1
Metal bindingi275Divalent metal cation1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionLyase
LigandMetal-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS04116-MONOMER
BRENDAi4.1.3.4 2681
ReactomeiR-HSA-77111 Synthesis of Ketone Bodies
R-HSA-9033241 Peroxisomal protein import
SABIO-RKiP35914
UniPathwayi
UPA00896;UER00863

Chemistry databases

SwissLipidsiSLP:000001292 [P35914-1]

Names & Taxonomyi

Protein namesi
Recommended name:
Hydroxymethylglutaryl-CoA lyase, mitochondrial (EC:4.1.3.4)
Short name:
HL
Short name:
HMG-CoA lyase
Alternative name(s):
3-hydroxy-3-methylglutarate-CoA lyase
Gene namesi
Name:HMGCL
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000117305.14
HGNCiHGNC:5005 HMGCL
MIMi613898 gene
neXtProtiNX_P35914

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, Peroxisome

Pathology & Biotechi

Involvement in diseasei

3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD)10 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal recessive disease affecting ketogenesis and L-leucine catabolism. The disease usually appears in the first year of life after a fasting period and its clinical acute symptoms include vomiting, seizures, metabolic acidosis, hypoketotic hypoglycemia and lethargy. These symptoms sometimes progress to coma, with fatal outcome in some cases.
See also OMIM:246450
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_05844037E → K in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication1
Natural variantiVAR_00374441R → Q in HMGCLD; loss of activity and of proton exchange. 2 PublicationsCorresponds to variant dbSNP:rs121964997EnsemblClinVar.1
Natural variantiVAR_00374542D → E in HMGCLD; reduced activity. 1 Publication1
Natural variantiVAR_00374642D → G in HMGCLD; loss of activity. 2 Publications1
Natural variantiVAR_00374742D → H in HMGCLD; loss of activity. 1 Publication1
Natural variantiVAR_05844148K → N in HMGCLD; abolishes almost all enzymatic activity. 1 Publication1
Natural variantiVAR_00374870V → L in HMGCLD. Corresponds to variant dbSNP:rs121964996EnsemblClinVar.1
Natural variantiVAR_05844275S → R in HMGCLD. 1 Publication1
Natural variantiVAR_058443142S → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication1
Natural variantiVAR_065453165R → Q in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs199587895EnsemblClinVar.1
Natural variantiVAR_058444174C → Y in HMGCLD; activity lower than 5% respect to the wild-type. 1 PublicationCorresponds to variant dbSNP:rs765475941Ensembl.1
Natural variantiVAR_058445192F → S in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication1
Natural variantiVAR_058446200I → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication1
Natural variantiVAR_058447201S → Y in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs760106433EnsemblClinVar.1
Natural variantiVAR_058448203G → E in HMGCLD; complete loss of activity. 1 Publication1
Natural variantiVAR_058449204D → N in HMGCLD. 1 Publication1
Natural variantiVAR_003749233H → R in HMGCLD; loss of activity. 3 PublicationsCorresponds to variant dbSNP:rs727503963EnsemblClinVar.1
Natural variantiVAR_058450263L → P in HMGCLD. 1 Publication1
Natural variantiVAR_014202279E → K in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs121964998EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi37E → D: Normal activity. 1 Publication1
Mutagenesisi41R → M: Reduced activity, and loss of proton exchange. 1 Publication1
Mutagenesisi42D → A or N: Loss of activity, and reduced proton exchange rate. 2 Publications1
Mutagenesisi72E → A: Loss of activity, and reduced affinity for metal cofactor and substrate. 1 Publication1
Mutagenesisi204D → A: Reduced activity, and reduced affinity for metal cofactor and substrate. 1 Publication1
Mutagenesisi233H → A: Loss of activity, and reduced proton exchange rate. 2 Publications1
Mutagenesisi266C → A: Loss of activity. 1
Mutagenesisi279E → A: Reduced thermal stability, but normal activity. 1 Publication1
Mutagenesisi280D → A: Normal activity. 1 Publication1
Mutagenesisi323C → S: Abolishes interchain homodimerization. Exhibits no DTT stimulated activity. 2 Publications1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi3155
MalaCardsiHMGCL
MIMi246450 phenotype
OpenTargetsiENSG00000117305
Orphaneti20 3-hydroxy-3-methylglutaric aciduria
PharmGKBiPA29336

Chemistry databases

DrugBankiDB04594 3-hydroxyglutaric acid

Polymorphism and mutation databases

BioMutaiHMGCL
DMDMi24418852

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 27MitochondrionAdd BLAST27
ChainiPRO_000001347828 – 325Hydroxymethylglutaryl-CoA lyase, mitochondrialAdd BLAST298

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei48N6-acetyllysine; alternateCombined sources1
Modified residuei48N6-succinyllysine; alternateBy similarity1
Modified residuei111N6-acetyllysineBy similarity1
Modified residuei137N6-acetyllysine; alternateBy similarity1
Modified residuei137N6-succinyllysine; alternateBy similarity1
Modified residuei179N6-acetyllysine; alternateBy similarity1
Modified residuei179N6-succinyllysine; alternateBy similarity1
Disulfide bondi323Interchain1 Publication
Modified residuei324N6-acetyllysineBy similarity1

Keywords - PTMi

Acetylation, Disulfide bond

Proteomic databases

EPDiP35914
PaxDbiP35914
PeptideAtlasiP35914
PRIDEiP35914
ProteomicsDBi55164
55165 [P35914-2]

PTM databases

iPTMnetiP35914
PhosphoSitePlusiP35914

Expressioni

Tissue specificityi

Highest expression in liver. Expressed in pancreas, kidney, intestine, testis, fibroblasts and lymphoblasts. Very low expression in brain and skeletal muscle. The relative expression of isoform 2 (at mRNA level) is highest in heart (30%), skeletal muscle (22%), and brain (14%).1 Publication

Gene expression databases

BgeeiENSG00000117305 Expressed in 228 organ(s), highest expression level in right lobe of liver
CleanExiHS_HMGCL
ExpressionAtlasiP35914 baseline and differential
GenevisibleiP35914 HS

Organism-specific databases

HPAiHPA004727

Interactioni

Subunit structurei

Homodimer; disulfide-linked. Can also form homotetramers.2 Publications

GO - Molecular functioni

Protein-protein interaction databases

BioGridi109398, 24 interactors
IntActiP35914, 11 interactors
MINTiP35914
STRINGi9606.ENSP00000363614

Structurei

Secondary structure

1325
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP35914
SMRiP35914
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP35914

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini33 – 300Pyruvate carboxyltransferasePROSITE-ProRule annotationAdd BLAST268

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi323 – 325Microbody targeting signalSequence analysis3

Sequence similaritiesi

Belongs to the HMG-CoA lyase family.Curated

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG2368 Eukaryota
COG0119 LUCA
GeneTreeiENSGT00390000017690
HOGENOMiHOG000219757
HOVERGENiHBG064656
InParanoidiP35914
KOiK01640
OMAiFGGCPMA
OrthoDBiEOG091G0DA9
PhylomeDBiP35914
TreeFamiTF105363

Family and domain databases

Gene3Di3.20.20.70, 1 hit
InterProiView protein in InterPro
IPR013785 Aldolase_TIM
IPR000138 HMG_CoA_lyase_AS
IPR000891 PYR_CT
PfamiView protein in Pfam
PF00682 HMGL-like, 1 hit
PROSITEiView protein in PROSITE
PS01062 HMG_COA_LYASE, 1 hit
PS50991 PYR_CT, 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

This entry has 3 described isoforms and 2 potential isoforms that are computationally mapped.iShow all

Isoform 1 (identifier: P35914-1) [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
MAAMRKALPR RLVGLASLRA VSTSSMGTLP KRVKIVEVGP RDGLQNEKNI
60 70 80 90 100
VSTPVKIKLI DMLSEAGLSV IETTSFVSPK WVPQMGDHTE VLKGIQKFPG
110 120 130 140 150
INYPVLTPNL KGFEAAVAAG AKEVVIFGAA SELFTKKNIN CSIEESFQRF
160 170 180 190 200
DAILKAAQSA NISVRGYVSC ALGCPYEGKI SPAKVAEVTK KFYSMGCYEI
210 220 230 240 250
SLGDTIGVGT PGIMKDMLSA VMQEVPLAAL AVHCHDTYGQ ALANTLMALQ
260 270 280 290 300
MGVSVVDSSV AGLGGCPYAQ GASGNLATED LVYMLEGLGI HTGVNLQKLL
310 320
EAGNFICQAL NRKTSSKVAQ ATCKL
Length:325
Mass (Da):34,360
Last modified:October 25, 2002 - v2
Checksum:iB82B2488A10D6980
GO
Isoform 2 (identifier: P35914-2) [UniParc]FASTAAdd to basket
Also known as: HMGCS2delta5,6

The sequence of this isoform differs from the canonical sequence as follows:
     117-187: Missing.

Note: The transcript is not translated, but would result in a catalytically impaired product if it was.
Show »
Length:254
Mass (Da):26,910
Checksum:iFAD9D90A1A62F3AD
GO
Isoform 3 (identifier: P35914-3) [UniParc]FASTAAdd to basket
Also known as: HMGCS2delta5,6,7

The sequence of this isoform differs from the canonical sequence as follows:
     117-187: Missing.
     188-250: Missing.

Note: Very low expression. The transcript is not translated, but would result in a catalytically inactive product if it was.
Show »
Length:191
Mass (Da):20,222
Checksum:iD5540BECDB75D854
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H0Y2L7H0Y2L7_HUMAN
Hydroxymethylglutaryl-CoA lyase, mi...
HMGCL
182Annotation score:
D6REN8D6REN8_HUMAN
Hydroxymethylglutaryl-CoA lyase, mi...
HMGCL
77Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti243A → T in AAA92733 (PubMed:8440722).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_05844037E → K in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication1
Natural variantiVAR_00374441R → Q in HMGCLD; loss of activity and of proton exchange. 2 PublicationsCorresponds to variant dbSNP:rs121964997EnsemblClinVar.1
Natural variantiVAR_00374542D → E in HMGCLD; reduced activity. 1 Publication1
Natural variantiVAR_00374642D → G in HMGCLD; loss of activity. 2 Publications1
Natural variantiVAR_00374742D → H in HMGCLD; loss of activity. 1 Publication1
Natural variantiVAR_05844148K → N in HMGCLD; abolishes almost all enzymatic activity. 1 Publication1
Natural variantiVAR_00374870V → L in HMGCLD. Corresponds to variant dbSNP:rs121964996EnsemblClinVar.1
Natural variantiVAR_05844275S → R in HMGCLD. 1 Publication1
Natural variantiVAR_058443142S → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication1
Natural variantiVAR_065453165R → Q in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs199587895EnsemblClinVar.1
Natural variantiVAR_058444174C → Y in HMGCLD; activity lower than 5% respect to the wild-type. 1 PublicationCorresponds to variant dbSNP:rs765475941Ensembl.1
Natural variantiVAR_058445192F → S in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication1
Natural variantiVAR_058446200I → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication1
Natural variantiVAR_058447201S → Y in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs760106433EnsemblClinVar.1
Natural variantiVAR_058448203G → E in HMGCLD; complete loss of activity. 1 Publication1
Natural variantiVAR_058449204D → N in HMGCLD. 1 Publication1
Natural variantiVAR_003749233H → R in HMGCLD; loss of activity. 3 PublicationsCorresponds to variant dbSNP:rs727503963EnsemblClinVar.1
Natural variantiVAR_058450263L → P in HMGCLD. 1 Publication1
Natural variantiVAR_014202279E → K in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs121964998EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_047444117 – 187Missing in isoform 2 and isoform 3. 2 PublicationsAdd BLAST71
Alternative sequenceiVSP_043788188 – 250Missing in isoform 3. 1 PublicationAdd BLAST63

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L07033 mRNA Translation: AAA92733.1
AK300733 mRNA Translation: BAG62406.1
AK313869 mRNA Translation: BAG36597.1
BT009792 mRNA Translation: AAP88794.1
CR456884 mRNA Translation: CAG33165.1
AL031295 Genomic DNA No translation available.
AL590728 Genomic DNA No translation available.
CH471134 Genomic DNA Translation: EAW95094.1
BC010570 mRNA Translation: AAH10570.1
AH003700 Genomic DNA Translation: AAB19099.1
FJ472654 mRNA Translation: ACK58684.1
GU433941 mRNA Translation: ADD21697.1
CCDSiCCDS243.1 [P35914-1]
CCDS53279.1 [P35914-2]
PIRiA45470
RefSeqiNP_000182.2, NM_000191.2 [P35914-1]
NP_001159531.1, NM_001166059.1 [P35914-2]
UniGeneiHs.533444

Genome annotation databases

EnsembliENST00000374490; ENSP00000363614; ENSG00000117305 [P35914-1]
ENST00000436439; ENSP00000389281; ENSG00000117305 [P35914-2]
GeneIDi3155
KEGGihsa:3155
UCSCiuc001bib.4 human [P35914-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiHMGCL_HUMAN
AccessioniPrimary (citable) accession number: P35914
Secondary accession number(s): B4DUP4
, B7UCC6, D3Y5K7, Q6IBC0, Q96FP8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: October 25, 2002
Last modified: September 12, 2018
This is version 179 of the entry and version 2 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
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Main funding by: National Institutes of Health

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