HMGCL

Functionⁱ

Mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis. 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

(3S)-hydroxy-3-methylglutaryl-CoA
Search proteins in UniProtKB for this molecule.
Search chemical reactions in Rhea for this molecule.
See the description of this molecule in ChEBI.
=
acetoacetate
Search proteins in UniProtKB for this molecule.
Search chemical reactions in Rhea for this molecule.
See the description of this molecule in ChEBI.
+
acetyl-CoA
Search proteins in UniProtKB for this molecule.
Search chemical reactions in Rhea for this molecule.
See the description of this molecule in ChEBI.
2 Publications
Manual assertion based on experiment inⁱ
- Ref.17
  "Identification and characterization of an extramitochondrial human 3-Hydroxy-3-methylglutaryl-CoA lyase."
  Montgomery C., Pei Z., Watkins P.A., Miziorko H.M.
  J. Biol. Chem. 287:33227-33236(2012) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF CYS-323.
- Ref.18
  "Characterization of a novel HMG-CoA Lyase enzyme with a dual location in endoplasmic reticulum and cytosol."
  Arnedo M., Menao S., Puisac B., Teresa-Rodrigo M.E., Gil-Rodriguez M.C., Lopez-Vinas E., Gomez-Puertas P., Casals N., Casale C.H., Hegardt F.G., Pie J.
  J. Lipid Res. 53:2046-2056(2012) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, CATALYTIC ACTIVITY.
EC:
4.1.3.4
- Search proteins in UniProtKB for this EC number.
- See the description of this EC number in ENZYME.
- Search reactions for this EC number in Rhea.
2 Publications
Manual assertion based on experiment inⁱ
- Ref.17
  "Identification and characterization of an extramitochondrial human 3-Hydroxy-3-methylglutaryl-CoA lyase."
  Montgomery C., Pei Z., Watkins P.A., Miziorko H.M.
  J. Biol. Chem. 287:33227-33236(2012) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF CYS-323.
- Ref.18
  "Characterization of a novel HMG-CoA Lyase enzyme with a dual location in endoplasmic reticulum and cytosol."
  Arnedo M., Menao S., Puisac B., Teresa-Rodrigo M.E., Gil-Rodriguez M.C., Lopez-Vinas E., Gomez-Puertas P., Casals N., Casale C.H., Hegardt F.G., Pie J.
  J. Lipid Res. 53:2046-2056(2012) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, CATALYTIC ACTIVITY.
Source:
Rhea
Search for this reaction in UniProtKB.
See the description of this reaction in Rhea.
. Show »« Hide
(3S)-hydroxy-3-methylglutaryl-CoA
zoom
=
acetoacetate
zoom
+
acetyl-CoA
zoom

Cofactorⁱ

a divalent metal cation1 Publication

Activity regulationⁱ

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

Kineticsⁱ

V_max=
191 µmol/min/mg enzyme
2 Publications
Manual assertion based on experiment inⁱ
Ref.13
"Investigation of conserved acidic residues in 3-hydroxy-3-methylglutaryl-CoA lyase: implications for human disease and for functional roles in a family of related proteins."
Tuinstra R.L., Miziorko H.M.
J. Biol. Chem. 278:37092-37098(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF GLU-37; ASP-42; GLU-72; ASP-204; HIS-233; GLU-279 AND ASP-280, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION.
Ref.14
"Evaluation of 3-hydroxy-3-methylglutaryl-coenzyme A lyase arginine-41 as a catalytic residue: use of acetyldithio-coenzyme A to monitor product enolization."
Tuinstra R.L., Wang C.-Z., Mitchell G.A., Miziorko H.M.
Biochemistry 43:5287-5295(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF ARG-41; ASP-42 AND HIS-233, BIOPHYSICOCHEMICAL PROPERTIES.

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. 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 key	Position(s)	DescriptionActions	Length
Binding siteⁱ	41	Substrate	1
Metal bindingⁱ	42	Divalent metal cation	1
Metal bindingⁱ	233	Divalent metal cation	1
Metal bindingⁱ	235	Divalent metal cation	1
Active siteⁱ	266	PROSITE-ProRule annotation	1
Metal bindingⁱ	275	Divalent metal cation	1

GO - Molecular functionⁱ

Complete GO annotation on QuickGO ...

GO - Biological processⁱ

Complete GO annotation on QuickGO ...

Keywordsⁱ

Molecular function	Lyase
Biological process	Lipid metabolism
Ligand	Metal-binding

Enzyme and pathway databases

BRENDAⁱ	4.1.3.4, 2681
PathwayCommonsⁱ	P35914
Reactomeⁱ	R-HSA-77111, Synthesis of Ketone Bodies R-HSA-9033241, Peroxisomal protein import
SABIO-RKⁱ	P35914
SignaLinkⁱ	P35914
UniPathwayⁱ	UPA00896;UER00863

Chemistry databases

SwissLipidsⁱ	SLP:000001292 [P35914-1]

SwissLipidsⁱ

SLP:000001292 [P35914-1]

Names & Taxonomyⁱ

Protein namesⁱ	Recommended name: Hydroxymethylglutaryl-CoA lyase, mitochondrial (EC:4.1.3.42 Publications) Short name: HL Short name: HMG-CoA lyase Alternative name(s): 3-hydroxy-3-methylglutarate-CoA lyase
Gene namesⁱ	Name:HMGCL
Organismⁱ	Homo sapiens (Human)
Taxonomic identifierⁱ	9606 [NCBI]
Taxonomic lineageⁱ	cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo
Proteomesⁱ	UP000005640 Componentⁱ: Chromosome 1

Organism-specific databases

Human Gene Nomenclature Database More...HGNCⁱ	HGNC:5005, HMGCL
MIMⁱ	613898, gene
neXtProtⁱ	NX_P35914
VEuPathDBⁱ	HostDB:ENSG00000117305

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 variants 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.

Related information in OMIM

Feature key	Position(s)	DescriptionActions	Length
Natural variantⁱVAR_058440	37	E → K in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication	1
Natural variantⁱVAR_003744	41	R → Q in HMGCLD; loss of activity and of proton exchange. 2 PublicationsCorresponds to variant dbSNP:rs121964997EnsemblClinVar.	1
Natural variantⁱVAR_003745	42	D → E in HMGCLD; reduced activity. 1 Publication	1
Natural variantⁱVAR_003746	42	D → G in HMGCLD; loss of activity. 2 PublicationsCorresponds to variant dbSNP:rs1467902610Ensembl.	1
Natural variantⁱVAR_003747	42	D → H in HMGCLD; loss of activity. 1 Publication	1
Natural variantⁱVAR_058441	48	K → N in HMGCLD; abolishes almost all enzymatic activity. 1 Publication	1
Natural variantⁱVAR_003748	70	V → L in HMGCLD. Corresponds to variant dbSNP:rs121964996EnsemblClinVar.	1
Natural variantⁱVAR_058442	75	S → R in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs1357942068Ensembl.	1
Natural variantⁱVAR_058443	142	S → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication	1
Natural variantⁱVAR_065453	165	R → Q in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs199587895EnsemblClinVar.	1
Natural variantⁱVAR_058444	174	C → Y in HMGCLD; activity lower than 5% respect to the wild-type. 1 PublicationCorresponds to variant dbSNP:rs765475941Ensembl.	1
Natural variantⁱVAR_058445	192	F → S in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication	1
Natural variantⁱVAR_058446	200	I → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication	1
Natural variantⁱVAR_058447	201	S → Y in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs760106433EnsemblClinVar.	1
Natural variantⁱVAR_058448	203	G → E in HMGCLD; complete loss of activity. 1 PublicationCorresponds to variant dbSNP:rs1553131940EnsemblClinVar.	1
Natural variantⁱVAR_058449	204	D → N in HMGCLD. 1 Publication	1
Natural variantⁱVAR_003749	233	H → R in HMGCLD; loss of activity. 3 PublicationsCorresponds to variant dbSNP:rs727503963EnsemblClinVar.	1
Natural variantⁱVAR_058450	263	L → P in HMGCLD. 1 Publication	1
Natural variantⁱVAR_014202	279	E → K in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs121964998EnsemblClinVar.	1

Mutagenesis

Feature key	Position(s)	DescriptionActions	Length
Mutagenesisⁱ	37	E → D: Normal activity. 1 Publication	1
Mutagenesisⁱ	41	R → M: Reduced activity, and loss of proton exchange. 1 Publication	1
Mutagenesisⁱ	42	D → A or N: Loss of activity, and reduced proton exchange rate. 2 Publications	1
Mutagenesisⁱ	72	E → A: Loss of activity, and reduced affinity for metal cofactor and substrate. 1 Publication	1
Mutagenesisⁱ	204	D → A: Reduced activity, and reduced affinity for metal cofactor and substrate. 1 Publication	1
Mutagenesisⁱ	233	H → A: Loss of activity, and reduced proton exchange rate. 2 Publications	1
Mutagenesisⁱ	266	C → A: Loss of activity.	1
Mutagenesisⁱ	279	E → A: Reduced thermal stability, but normal activity. 1 Publication	1
Mutagenesisⁱ	280	D → A: Normal activity. 1 Publication	1
Mutagenesisⁱ	323	C → S: Abolishes interchain homodimerization. Exhibits no DTT stimulated activity. 2 Publications	1

Keywords - Diseaseⁱ

Disease variant

Organism-specific databases

DisGeNET More...DisGeNETⁱ	3155
MalaCards human disease database More...MalaCardsⁱ	HMGCL
MIMⁱ	246450, phenotype
Open Targets More...OpenTargetsⁱ	ENSG00000117305
Orphanetⁱ	20, 3-hydroxy-3-methylglutaric aciduria
PharmGKBⁱ	PA29336

Miscellaneous databases

Pharosⁱ	P35914, Tbio

Pharosⁱ

P35914, Tbio

Chemistry databases

Drug and drug target database More...DrugBankⁱ	DB04594, 3-hydroxyglutaric acid

DrugBankⁱ

DB04594, 3-hydroxyglutaric acid

Genetic variation databases

BioMutaⁱ	HMGCL
DMDMⁱ	24418852

PTM / Processingⁱ

Molecule processing

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Transit peptideⁱ	1 – 27	MitochondrionAdd BLAST		27
ChainⁱPRO_0000013478	28 – 325	Hydroxymethylglutaryl-CoA lyase, mitochondrialAdd BLAST		298

Amino acid modifications

Feature key	Position(s)	DescriptionActions	Length
Modified residueⁱ	48	N6-acetyllysine; alternateCombined sources	1
Modified residueⁱ	48	N6-succinyllysine; alternateBy similarity	1
Modified residueⁱ	111	N6-acetyllysineBy similarity	1
Modified residueⁱ	137	N6-acetyllysine; alternateBy similarity	1
Modified residueⁱ	137	N6-succinyllysine; alternateBy similarity	1
Modified residueⁱ	179	N6-acetyllysine; alternateBy similarity	1
Modified residueⁱ	179	N6-succinyllysine; alternateBy similarity	1
Disulfide bondⁱ	323	Interchain1 Publication
Modified residueⁱ	324	N6-acetyllysineBy similarity	1

Keywords - PTMⁱ

Acetylation, Disulfide bond

Proteomic databases

EPDⁱ	P35914
jPOSTⁱ	P35914
MassIVEⁱ	P35914
MaxQB - The MaxQuant DataBase More...MaxQBⁱ	P35914
PaxDbⁱ	P35914
PeptideAtlas More...PeptideAtlasⁱ	P35914
PRIDEⁱ	P35914
ProteomicsDBⁱ	55164 [P35914-1] 55165 [P35914-2]

PTM databases

GlyGenⁱ	P35914, 1 site, 1 O-linked glycan (1 site)
iPTMnetⁱ	P35914
PhosphoSitePlusⁱ	P35914

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

Bgeeⁱ	ENSG00000117305, Expressed in right lobe of liver and 242 other tissues
ExpressionAtlasⁱ	P35914, baseline and differential
Genevisibleⁱ	P35914, HS

Organism-specific databases

Human Protein Atlas More...HPAⁱ	ENSG00000117305, Tissue enhanced (liver)

HPAⁱ

ENSG00000117305, Tissue enhanced (liver)

Interactionⁱ

Subunit structureⁱ

Homodimer; disulfide-linked. Can also form homotetramers.

2 Publications

Protein-protein interaction databases

BioGRIDⁱ	109398, 50 interactors
IntActⁱ	P35914, 11 interactors
Molecular INTeraction database More...MINTⁱ	P35914
STRINGⁱ	9606.ENSP00000363614

Miscellaneous databases

RNActⁱ	P35914, protein

RNActⁱ

P35914, protein

Structureⁱ

Secondary structure

Legend: HelixTurnBeta strandPDB Structure known for this area

Feature key	Position(s)	DescriptionActions	Length
Beta strandⁱ	34 – 37	Combined sources	4
Turnⁱ	39 – 41	Combined sources	3
Helixⁱ	42 – 45	Combined sources	4
Helixⁱ	53 – 65	Combined sources	13
Beta strandⁱ	69 – 71	Combined sources	3
Turnⁱ	79 – 81	Combined sources	3
Helixⁱ	83 – 85	Combined sources	3
Helixⁱ	88 – 94	Combined sources	7
Helixⁱ	110 – 118	Combined sources	9
Beta strandⁱ	122 – 130	Combined sources	9
Helixⁱ	132 – 139	Combined sources	8
Helixⁱ	143 – 159	Combined sources	17
Beta strandⁱ	163 – 169	Combined sources	7
Turnⁱ	170 – 172	Combined sources	3
Turnⁱ	175 – 177	Combined sources	3
Helixⁱ	182 – 194	Combined sources	13
Beta strandⁱ	198 – 204	Combined sources	7
Helixⁱ	211 – 224	Combined sources	14
Helixⁱ	227 – 229	Combined sources	3
Beta strandⁱ	230 – 235	Combined sources	6
Helixⁱ	241 – 250	Combined sources	10
Beta strandⁱ	255 – 259	Combined sources	5
Helixⁱ	278 – 288	Combined sources	11
Helixⁱ	296 – 309	Combined sources	14
Helixⁱ	317 – 322	Combined sources	6

Show more details

3D structure databases

AlphaFoldDBⁱ	P35914
SMRⁱ	P35914
ModBaseⁱ	Search...
PDBe-KBⁱ	Search...

Miscellaneous databases

EvolutionaryTraceⁱ	P35914

EvolutionaryTraceⁱ

P35914

Family & Domainsⁱ

Domains and Repeats

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Domainⁱ	33 – 300	Pyruvate carboxyltransferasePROSITE-ProRule annotationAdd BLAST		268

Motif

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Motifⁱ	323 – 325	Microbody targeting signalSequence analysis		3

Sequence similaritiesⁱ

Belongs to the HMG-CoA lyase family.Curated

Keywords - Domainⁱ

Transit peptide

Phylogenomic databases

eggNOGⁱ	KOG2368, Eukaryota
Ensembl GeneTree More...GeneTreeⁱ	ENSGT00940000158484
HOGENOMⁱ	CLU_022138_3_1_1
InParanoidⁱ	P35914
OMAⁱ	FGGCPMA
Database of Orthologous Groups More...OrthoDBⁱ	1029775at2759
PhylomeDBⁱ	P35914
TreeFamⁱ	TF105363

Family and domain databases

Gene3Dⁱ	3.20.20.70, 1 hit
InterProⁱ	View protein in InterPro IPR013785, Aldolase_TIM IPR000138, HMG_CoA_lyase_AS IPR043594, HMGL IPR000891, PYR_CT
PANTHERⁱ	PTHR42738, PTHR42738, 1 hit
Pfam protein domain database More...Pfamⁱ	View protein in Pfam PF00682, HMGL-like, 1 hit
PROSITEⁱ	View 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. Align Add to basket

This entry has 3 described isoforms and 1 potential isoform that is computationally mapped.Show all Align All

Isoform 1 (identifier: P35914-1) [UniParc]FASTA Add to basket

This isoform has been chosen as the canonicalⁱ 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]FASTA Add to basket

Also known as: HMGCS2delta5,6

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

« 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 KGFEAAVTKK FYSMGCYEIS LGDTIGVGTP GIMKDMLSAV 
       160        170        180        190        200
MQEVPLAALA VHCHDTYGQA LANTLMALQM GVSVVDSSVA GLGGCPYAQG 
       210        220        230        240        250
ASGNLATEDL VYMLEGLGIH TGVNLQKLLE AGNFICQALN RKTSSKVAQA 

TCKL

Note: The transcript is not translated, but would result in a catalytically impaired product if it was.Curated

Show »

Length:254

Mass (Da):26,910

Checksum:ⁱFAD9D90A1A62F3AD

GO

Isoform 3 (identifier: P35914-3) [UniParc]FASTA Add 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.

« 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 KGFEAAMGVS VVDSSVAGLG GCPYAQGASG NLATEDLVYM 
       160        170        180        190 
LEGLGIHTGV NLQKLLEAGN FICQALNRKT SSKVAQATCK L

Note: Very low expression. The transcript is not translated, but would result in a catalytically inactive product if it was.Curated

Show »

Length:191

Mass (Da):20,222

Checksum:ⁱD5540BECDB75D854

GO

Computationally mapped potential isoform sequencesⁱ

There is 1 potential isoform mapped to this entry.BLAST Align Show all Add to basket

	Entry	Entry name		Protein names	Gene names	Length	Annotation

	H0Y2L7	H0Y2L7_HUMAN		Hydroxymethylglutaryl-CoA lyase, mi... Hydroxymethylglutaryl-CoA lyase, mitochondrial, EC 4.1.3.4 (3-hydroxy-3-methylglutarate-CoA lyase)	HMGCL	182	Annotation score:

Experimental Info

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Sequence conflictⁱ	243	A → T in AAA92733 (PubMed:8440722).Curated		1

Natural variant

Feature key	Position(s)	DescriptionActions	Length
Natural variantⁱVAR_058440	37	E → K in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication	1
Natural variantⁱVAR_003744	41	R → Q in HMGCLD; loss of activity and of proton exchange. 2 PublicationsCorresponds to variant dbSNP:rs121964997EnsemblClinVar.	1
Natural variantⁱVAR_003745	42	D → E in HMGCLD; reduced activity. 1 Publication	1
Natural variantⁱVAR_003746	42	D → G in HMGCLD; loss of activity. 2 PublicationsCorresponds to variant dbSNP:rs1467902610Ensembl.	1
Natural variantⁱVAR_003747	42	D → H in HMGCLD; loss of activity. 1 Publication	1
Natural variantⁱVAR_058441	48	K → N in HMGCLD; abolishes almost all enzymatic activity. 1 Publication	1
Natural variantⁱVAR_003748	70	V → L in HMGCLD. Corresponds to variant dbSNP:rs121964996EnsemblClinVar.	1
Natural variantⁱVAR_058442	75	S → R in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs1357942068Ensembl.	1
Natural variantⁱVAR_058443	142	S → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication	1
Natural variantⁱVAR_065453	165	R → Q in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs199587895EnsemblClinVar.	1
Natural variantⁱVAR_058444	174	C → Y in HMGCLD; activity lower than 5% respect to the wild-type. 1 PublicationCorresponds to variant dbSNP:rs765475941Ensembl.	1
Natural variantⁱVAR_058445	192	F → S in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication	1
Natural variantⁱVAR_058446	200	I → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication	1
Natural variantⁱVAR_058447	201	S → Y in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs760106433EnsemblClinVar.	1
Natural variantⁱVAR_058448	203	G → E in HMGCLD; complete loss of activity. 1 PublicationCorresponds to variant dbSNP:rs1553131940EnsemblClinVar.	1
Natural variantⁱVAR_058449	204	D → N in HMGCLD. 1 Publication	1
Natural variantⁱVAR_003749	233	H → R in HMGCLD; loss of activity. 3 PublicationsCorresponds to variant dbSNP:rs727503963EnsemblClinVar.	1
Natural variantⁱVAR_058450	263	L → P in HMGCLD. 1 Publication	1
Natural variantⁱVAR_014202	279	E → K in HMGCLD. 1 PublicationCorresponds to variant dbSNP:rs121964998EnsemblClinVar.	1

Alternative sequence

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Alternative sequenceⁱVSP_047444	117 – 187	Missing in isoform 2 and isoform 3. 2 PublicationsAdd BLAST		71
Alternative sequenceⁱVSP_043788	188 – 250	Missing in isoform 3. 1 PublicationAdd BLAST		63

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
The Consensus CDS (CCDS) project More...CCDSⁱ	CCDS243.1 [P35914-1] CCDS53279.1 [P35914-2]
PIRⁱ	A45470
NCBI Reference Sequences More...RefSeqⁱ	NP_000182.2, NM_000191.2 [P35914-1] NP_001159531.1, NM_001166059.1 [P35914-2]

Genome annotation databases

Ensemblⁱ	ENST00000374490.8; ENSP00000363614.3; ENSG00000117305.15 ENST00000436439.6; ENSP00000389281.2; ENSG00000117305.15 [P35914-2]
GeneIDⁱ	3155
KEGGⁱ	hsa:3155
MANE-Selectⁱ	ENST00000374490.8; ENSP00000363614.3; NM_000191.3; NP_000182.2
UCSC genome browser More...UCSCⁱ	uc001bib.4, human [P35914-1]

Keywords - Coding sequence diversityⁱ

Alternative splicing

Similar proteinsⁱ

100% Identity
90% Identity
50% Identity

Protein	Similar proteins		Species	Score	Length	Source
P35914	Hydroxymethylglutaryl-CoA lyase, mitochondrial		PANPA		325	UniRef100_P35914
Hydroxymethylglutaryl-CoA lyase, mitochondrial		HUMAN		300
+2
P35914-2	Hydroxymethylglutaryl-CoA lyase, mitochondrial		PANPA		254	UniRef100_A0A2R9BA57
+1

Protein	Similar proteins		Species	Score	Length	Source
P35914	Hydroxymethylglutaryl-CoA lyase, mitochondrial		PONAB		325	UniRef90_P35914
Hydroxymethylglutaryl-CoA lyase, mitochondrial		MACFA		325
Hydroxymethylglutaryl-CoA lyase, mitochondrial		PANPA		325
Hydroxymethylglutaryl-CoA lyase, mitochondrial		HUMAN		300
Hydroxymethylglutaryl-CoA lyase, mitochondrial (Fragment)		MACMU		218
+54

Protein	Similar proteins		Species	Score	Length	Source
P35914	Hydroxymethylglutaryl-CoA lyase, mitochondrial		PONAB		325	UniRef50_P35914
Hydroxymethylglutaryl-CoA lyase, mitochondrial		MACFA		325
Hydroxymethylglutaryl-CoA lyase, mitochondrial		RAT		325
Hydroxymethylglutaryl-CoA lyase, mitochondrial		MOUSE		325
Hydroxymethylglutaryl-CoA lyase, mitochondrial		CHICK		298
+1112
P35914-3	Hydroxymethylglutaryl-CoA lyase		PERMB		177	UniRef50_P35914-3
Hydroxymethylglutaryl-CoA lyase		CRIGR		177
3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic		RAT		177
Hydroxymethylglutaryl-CoA lyase		CEBIM		174
Hydroxymethylglutaryl-CoA lyase		PROSS		174
+55

Cross-referencesⁱ

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
CCDSⁱ	CCDS243.1 [P35914-1] CCDS53279.1 [P35914-2]
PIRⁱ	A45470
RefSeqⁱ	NP_000182.2, NM_000191.2 [P35914-1] NP_001159531.1, NM_001166059.1 [P35914-2]

3D structure databases

Select the link destinations: Protein Data Bank Europe More...PDBeⁱ Protein Data Bank RCSB More...RCSB PDBⁱ Protein Data Bank Japan More...PDBjⁱ Links Updated	PDB entry	Method	Resolution (Å)	Chain	Positions	PDBsum
	2CW6	X-ray	2.10	A/B/C/D/E/F	28-325	[»]
	3MP3	X-ray	2.40	A/B/C/D/E/F	28-325	[»]
	3MP4	X-ray	2.20	A/B/C/D/E/F	28-325	[»]
	3MP5	X-ray	2.25	A/B/C/D/E/F	28-325	[»]
AlphaFoldDBⁱ	P35914
SMRⁱ	P35914
ModBaseⁱ	Search...
PDBe-KBⁱ	Search...

Protein-protein interaction databases

BioGRIDⁱ	109398, 50 interactors
IntActⁱ	P35914, 11 interactors
MINTⁱ	P35914
STRINGⁱ	9606.ENSP00000363614

Chemistry databases

DrugBankⁱ	DB04594, 3-hydroxyglutaric acid
SwissLipidsⁱ	SLP:000001292 [P35914-1]

PTM databases

GlyGenⁱ	P35914, 1 site, 1 O-linked glycan (1 site)
iPTMnetⁱ	P35914
PhosphoSitePlusⁱ	P35914

Genetic variation databases

BioMutaⁱ	HMGCL
DMDMⁱ	24418852

Proteomic databases

EPDⁱ	P35914
jPOSTⁱ	P35914
MassIVEⁱ	P35914
MaxQBⁱ	P35914
PaxDbⁱ	P35914
PeptideAtlasⁱ	P35914
PRIDEⁱ	P35914
ProteomicsDBⁱ	55164 [P35914-1] 55165 [P35914-2]

Protocols and materials databases

Antibodypediaⁱ	1373, 336 antibodies from 29 providers
The DNASU plasmid repository More...DNASUⁱ	3155

Genome annotation databases

Ensemblⁱ	ENST00000374490.8; ENSP00000363614.3; ENSG00000117305.15 ENST00000436439.6; ENSP00000389281.2; ENSG00000117305.15 [P35914-2]
GeneIDⁱ	3155
KEGGⁱ	hsa:3155
MANE-Selectⁱ	ENST00000374490.8; ENSP00000363614.3; NM_000191.3; NP_000182.2
UCSCⁱ	uc001bib.4, human [P35914-1]

Organism-specific databases

CTDⁱ	3155
DisGeNETⁱ	3155
GeneCardsⁱ	HMGCL
HGNCⁱ	HGNC:5005, HMGCL
HPAⁱ	ENSG00000117305, Tissue enhanced (liver)
MalaCardsⁱ	HMGCL
MIMⁱ	246450, phenotype 613898, gene
neXtProtⁱ	NX_P35914
OpenTargetsⁱ	ENSG00000117305
Orphanetⁱ	20, 3-hydroxy-3-methylglutaric aciduria
PharmGKBⁱ	PA29336
VEuPathDBⁱ	HostDB:ENSG00000117305
GenAtlas: human gene database More...GenAtlasⁱ	Search...

Phylogenomic databases

eggNOGⁱ	KOG2368, Eukaryota
GeneTreeⁱ	ENSGT00940000158484
HOGENOMⁱ	CLU_022138_3_1_1
InParanoidⁱ	P35914
OMAⁱ	FGGCPMA
OrthoDBⁱ	1029775at2759
PhylomeDBⁱ	P35914
TreeFamⁱ	TF105363

Enzyme and pathway databases

UniPathwayⁱ	UPA00896;UER00863
BRENDAⁱ	4.1.3.4, 2681
PathwayCommonsⁱ	P35914
Reactomeⁱ	R-HSA-77111, Synthesis of Ketone Bodies R-HSA-9033241, Peroxisomal protein import
SABIO-RKⁱ	P35914
SignaLinkⁱ	P35914

Miscellaneous databases

BioGRID-ORCSⁱ	3155, 6 hits in 1082 CRISPR screens
ChiTaRSⁱ	HMGCL, human
EvolutionaryTraceⁱ	P35914
GenomeRNAiⁱ	3155
Pharosⁱ	P35914, Tbio
Protein Ontology More...PROⁱ	PR:P35914
RNActⁱ	P35914, protein
SOURCEⁱ	Search...

Gene expression databases

Bgeeⁱ	ENSG00000117305, Expressed in right lobe of liver and 242 other tissues
ExpressionAtlasⁱ	P35914, baseline and differential
Genevisibleⁱ	P35914, HS

Family and domain databases

Gene3Dⁱ	3.20.20.70, 1 hit
InterProⁱ	View protein in InterPro IPR013785, Aldolase_TIM IPR000138, HMG_CoA_lyase_AS IPR043594, HMGL IPR000891, PYR_CT
PANTHERⁱ	PTHR42738, PTHR42738, 1 hit
Pfamⁱ	View protein in Pfam PF00682, HMGL-like, 1 hit
PROSITEⁱ	View protein in PROSITE PS01062, HMG_COA_LYASE, 1 hit PS50991, PYR_CT, 1 hit
MobiDBⁱ	Search...

Entry informationⁱ

Entry nameⁱ	HMGCL_HUMAN
Accessionⁱ	P35914Primary (citable) accession number: P35914 Secondary accession number(s): B4DUP4 , B7UCC6, D3Y5K7, Q6IBC0, Q96FP8
Entry historyⁱ	Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
	Last sequence update:	October 25, 2002
	Last modified:	May 25, 2022
	This is version 201 of the entry and version 2 of the sequence. See complete history.
Entry statusⁱ	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.

Miscellaneousⁱ

Keywords - Technical termⁱ

3D-structure, Reference proteome

Documents

Human chromosome 1
Human chromosome 1: entries, gene names and cross-references to MIM
Human entries with genetic variants
List of human entries with genetic variants
Human variants curated from literature reports
Index of human variants curated from literature reports
MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
PATHWAY comments
Index of metabolic and biosynthesis pathways
PDB cross-references
Index of Protein Data Bank (PDB) cross-references
SIMILARITY comments
Index of protein domains and families

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UniProtKB - P35914 (HMGCL_HUMAN)

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Hydroxymethylglutaryl-CoA lyase, mitochondrial

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<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

<p>This subsection of the <a href="http://www.uniprot.org/help/function%5Fsection">Function</a> section describes the catalytic activity of an enzyme, i.e. a chemical reaction that the enzyme catalyzes.<p><a href='/help/catalytic_activity' target='_top'>More...</a></p>Catalytic activityi

<p>This subsection of the 'Function' section describes biophysical and chemical properties, such as maximal absorption, kinetic parameters, pH dependence, redox potentials and temperature dependence.<p><a href='/help/biophysicochemical_properties' target='_top'>More...</a></p>Kineticsi

<p>This subsection of the <a href="http://www.uniprot.org/help/function%5Fsection">'Function'</a> section describes the metabolic pathway(s) associated with a protein.<p><a href='/help/pathway' target='_top'>More...</a></p>Pathwayi: (S)-3-hydroxy-3-methylglutaryl-CoA degradation

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<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

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<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

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Keywords - PTMi

Proteomic databases

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<p>This section provides information on the tertiary and secondary structure of a protein.<p><a href='/help/structure_section' target='_top'>More...</a></p>Structurei

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<p>This section provides information on sequence similarities with other proteins and the domain(s) present in a protein.<p><a href='/help/family_and_domains_section' target='_top'>More...</a></p>Family & Domainsi

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<p>This subsection of the 'Family and domains' section provides information about the sequence similarity with other proteins.<p><a href='/help/sequence_similarities' target='_top'>More...</a></p>Sequence similaritiesi

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Keywords - Coding sequence diversityi

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Functionⁱ

Catalytic activityⁱ

Kineticsⁱ

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

GO - Molecular functionⁱ

GO - Biological processⁱ

Names & Taxonomyⁱ

Subcellular locationⁱ

Keywords - Cellular componentⁱ

Pathology & Biotechⁱ

Keywords - Diseaseⁱ

PTM / Processingⁱ

Keywords - PTMⁱ

Expressionⁱ

Interactionⁱ

Structureⁱ

Family & Domainsⁱ

Sequence similaritiesⁱ

Keywords - Domainⁱ

Keywords - Coding sequence diversityⁱ

Cross-referencesⁱ

Entry informationⁱ

Miscellaneousⁱ

Keywords - Technical termⁱ