P35914 (HMGCL_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Hydroxymethylglutaryl-CoA lyase, mitochondrial
Short name=HL
Short name=HMG-CoA lyase
EC=4.1.3.4

Alternative name(s):
3-hydroxy-3-methylglutarate-CoA lyase

Gene names

Name:

HMGCL

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	325 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	Involved in the catabolism of branched amino acids such as leucine Probable.
Catalytic activity	(S)-3-hydroxy-3-methylglutaryl-CoA = acetyl-CoA + acetoacetate.
Cofactor	Divalent metal cations. Ref.4
Enzyme regulation	Stimulated by reducing agents (e.g. DTT). Ref.4
Pathway	Metabolic intermediate metabolism; (S)-3-hydroxy-3-methylglutaryl-CoA degradation; acetoacetate from (S)-3-hydroxy-3-methylglutaryl-CoA: step 1/1.
Subunit structure	Homodimer. Ref.8
Subcellular location	Mitochondrion matrix.
Tissue specificity	Fibroblasts, liver and lymphoblasts.
Involvement in disease	Defects in HMGCL are the cause of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) [MIM:246450]; also known as hydroxymethylglutaricaciduria or HL deficiency. An 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. Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18
Sequence similarities	Belongs to the HMG-CoA lyase family.
Biophysicochemical properties	Kinetic parameters: KM=200 µM for magnesium ion Ref.4 Ref.5 KM=48 µM for HMG-CoA Vmax=191 µmol/min/mg enzyme

Ontologies

Keywords
Cellular component	Mitochondrion
Disease	Disease mutation
Domain	Transit peptide
Ligand	Metal-binding
Molecular function	Lyase
PTM	Acetylation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	acetoacetic acid biosynthetic process Traceable author statement. Source: Reactome ketone body biosynthetic process Traceable author statement. Source: Reactome
Cellular component	mitochondrial matrix Traceable author statement. Source: Reactome
Molecular function	hydroxymethylglutaryl-CoA lyase activity Traceable author statement. Source: Reactome metal ion binding Inferred from direct assay Ref.8. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 27

27

Mitochondrion By similarity

Chain

28 – 325

298

Hydroxymethylglutaryl-CoA lyase, mitochondrial

PRO_0000013478

Sites

Active site

266

1

By similarity

Metal binding

42

1

Divalent metal cation

Metal binding

233

1

Divalent metal cation

Metal binding

235

1

Divalent metal cation

Metal binding

275

1

Divalent metal cation

Binding site

41

1

Substrate

Amino acid modifications

Modified residue

48

1

N6-acetyllysine Ref.6

Natural variations

Natural variant

37

1

E → K in HMGCLD; activity lower than 5% respect to the wild-type. Ref.18

VAR_058440

Natural variant

41

1

R → Q in HMGCLD; loss of activity and of proton exchange. Ref.10 Ref.14

VAR_003744

Natural variant

42

1

D → E in HMGCLD; reduced activity. Ref.10

VAR_003745

Natural variant

42

1

D → G in HMGCLD; loss of activity. Ref.10 Ref.18

VAR_003746

Natural variant

42

1

D → H in HMGCLD; loss of activity. Ref.10

VAR_003747

Natural variant

48

1

K → N in HMGCLD. Ref.16

VAR_058441

Natural variant

70

1

V → L in HMGCLD.

VAR_003748

Natural variant

75

1

S → R in HMGCLD. Ref.13

VAR_058442

Natural variant

142

1

S → F in HMGCLD; activity lower than 5% respect to the wild-type. Ref.18

VAR_058443

Natural variant

165

1

R → Q in HMGCLD. Ref.17

VAR_065453

Natural variant

174

1

C → Y in HMGCLD; activity lower than 5% respect to the wild-type. Ref.18

VAR_058444

Natural variant

192

1

F → S in HMGCLD; activity lower than 5% respect to the wild-type. Ref.18

VAR_058445

Natural variant

200

1

I → F in HMGCLD; activity lower than 5% respect to the wild-type. Ref.18

VAR_058446

Natural variant

201

1

S → Y in HMGCLD. Ref.13

VAR_058447

Natural variant

203

1

G → E in HMGCLD; complete loss of activity. Ref.15

VAR_058448

Natural variant

204

1

D → N in HMGCLD. Ref.13

VAR_058449

Natural variant

233

1

H → R in HMGCLD; loss of activity. Ref.9 Ref.11 Ref.18

VAR_003749

Natural variant

263

1

L → P in HMGCLD. Ref.11

VAR_058450

Natural variant

279

1

E → K in HMGCLD. Ref.12
Corresponds to variant rs28934894 [ dbSNP | Ensembl ].

VAR_014202

Experimental info

Mutagenesis

37

1

E → D: Normal activity. Ref.4

Mutagenesis

41

1

R → M: Reduced activity, and loss of proton exchange. Ref.5

Mutagenesis

42

1

D → A or N: Loss of activity, and reduced proton exchange rate. Ref.4 Ref.5

Mutagenesis

72

1

E → A: Loss of activity, and reduced affinity for metal cofactor and substrate. Ref.4

Mutagenesis

204

1

D → A: Reduced activity, and reduced affinity for metal cofactor and substrate. Ref.4

Mutagenesis

233

1

H → A: Loss of activity, and reduced proton exchange rate. Ref.4 Ref.5

Mutagenesis

266

1

C → A: Loss of activity.

Mutagenesis

279

1

E → A: Reduced thermal stability, but normal activity. Ref.4

Mutagenesis

280

1

D → A: Normal activity. Ref.4

Sequence conflict

243

1

A → T in AAA92733. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

325

Helix Strand Turn

Details...

Beta strand

34 – 37

4

Turn

39 – 41

3

Helix

42 – 45

4

Helix

53 – 65

13

Beta strand

69 – 71

3

Turn

79 – 81

3

Helix

83 – 85

3

Helix

88 – 94

7

Helix

110 – 118

9

Beta strand

122 – 130

9

Helix

132 – 139

8

Helix

143 – 159

17

Beta strand

163 – 169

7

Turn

170 – 172

3

Turn

175 – 177

3

Helix

182 – 194

13

Beta strand

198 – 204

7

Helix

211 – 224

14

Helix

227 – 229

3

Beta strand

230 – 235

6

Helix

241 – 250

10

Beta strand

255 – 259

5

Helix

278 – 288

11

Helix

296 – 309

14

Helix

317 – 322

6

Sequences

	Sequence		Length	Mass (Da)
	P35914 [UniParc]. Last modified October 25, 2002. Version 2. Checksum: B82B2488A10D6980	FASTA	325	34,360
	10 20 30 40 50 60 MAAMRKALPR RLVGLASLRA VSTSSMGTLP KRVKIVEVGP RDGLQNEKNI VSTPVKIKLI 70 80 90 100 110 120 DMLSEAGLSV IETTSFVSPK WVPQMGDHTE VLKGIQKFPG INYPVLTPNL KGFEAAVAAG 130 140 150 160 170 180 AKEVVIFGAA SELFTKKNIN CSIEESFQRF DAILKAAQSA NISVRGYVSC ALGCPYEGKI 190 200 210 220 230 240 SPAKVAEVTK KFYSMGCYEI SLGDTIGVGT PGIMKDMLSA VMQEVPLAAL AVHCHDTYGQ 250 260 270 280 290 300 ALANTLMALQ MGVSVVDSSV AGLGGCPYAQ GASGNLATED LVYMLEGLGI HTGVNLQKLL 310 320 EAGNFICQAL NRKTSSKVAQ ATCKL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"3-hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency." Mitchell G.A., Robert M.-F., Hruz P.W., Wang S., Fontaine G., Behnke C.E., Mende-Mueller L.M., Schappert K., Lee C., Gibson K.M., Miziorko H.M. J. Biol. Chem. 268:4376-4381(1993) [PubMed: 8440722] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[2]	"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.
[3]	"3-hydroxy-3-methylglutaryl CoA lyase (HL): mouse and human HL gene (HMGCL) cloning and detection of large gene deletions in two unrelated HL-deficient patients." Wang S.P., Robert M.-F., Gibson K.M., Wanders R.J.A., Mitchell G.A. Genomics 33:99-104(1996) [PubMed: 8617516] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 21-325.
[4]	"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: 12874287] [Abstract] Cited for: MUTAGENESIS OF GLU-37; ASP-42; GLU-72; ASP-204; HIS-233; GLU-279 AND ASP-280, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION.
[5]	"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: 15122894] [Abstract] Cited for: MUTAGENESIS OF ARG-41; ASP-42 AND HIS-233, BIOPHYSICOCHEMICAL PROPERTIES.
[6]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-48, MASS SPECTROMETRY.
[7]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[8]	"Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria." Fu Z., Runquist J.A., Forouhar F., Hussain M., Hunt J.F., Miziorko H.M., Kim J.J. J. Biol. Chem. 281:7526-7532(2006) [PubMed: 16330550] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 28-325 IN COMPLEX WITH MAGNESIUM AND SUBSTRATE ANALOG, HOMODIMERIZATION.
[9]	"Modeling of a mutation responsible for human 3-hydroxy-3-methylglutaryl-CoA lyase deficiency implicates histidine-233 as an active site residue." Roberts J., Mitchell G.A., Miziorko H.M. J. Biol. Chem. 271:24604-24609(1996) [PubMed: 8798725] [Abstract] Cited for: VARIANT HMGCLD ARG-233.
[10]	"HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q." Mitchell G.A., Ozand P.T., Robert M.-F., Ashmarina L., Roberts J., Gibson K.M., Wanders R.J., Wang S., Chevalier I., Ploechl E., Miziorko H. Am. J. Hum. Genet. 62:295-300(1998) [PubMed: 9463337] [Abstract] Cited for: VARIANTS HMGCLD GLN-41; GLU-42; GLY-42 AND HIS-42.
[11]	"Two missense point mutations in different alleles in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene produce 3-hydroxy-3-methylglutaric aciduria in a French patient." Zapater N., Pie J., Lloberas J., Rolland M.O., Leroux B., Vidailhet M., Divry P., Hegardt F.G., Casals N. Arch. Biochem. Biophys. 358:197-203(1998) [PubMed: 9784232] [Abstract] Cited for: VARIANTS HMGCLD ARG-233 AND PRO-263.
[12]	"Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency." Muroi J., Yorifuji T., Uematsu A., Shigematsu Y., Onigata K., Maruyama H., Nobutoki T., Kitamura A., Nakahata T. Hum. Genet. 107:320-326(2000) [PubMed: 11129331] [Abstract] Cited for: VARIANT HMGCLD LYS-279.
[13]	"Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase." Casals N., Gomez-Puertas P., Pie J., Mir C., Roca R., Puisac B., Aledo R., Clotet J., Menao S., Serra D., Asins G., Till J., Elias-Jones A.C., Cresto J.C., Chamoles N.A., Abdenur J.E., Mayatepek E., Besley G., Valencia A., Hegardt F.G. J. Biol. Chem. 278:29016-29023(2003) [PubMed: 12746442] [Abstract] Cited for: VARIANTS HMGCLD ARG-75; TYR-201 AND ASN-204.
[14]	"Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population." Al-Sayed M., Imtiaz F., Alsmadi O.A., Rashed M.S., Meyer B.F. BMC Med. Genet. 7:86-86(2006) [PubMed: 17173698] [Abstract] Cited for: VARIANT HMGCLD GLN-41.
[15]	"A single-residue mutation, G203E, causes 3-hydroxy-3-methylglutaric aciduria by occluding the substrate channel in the 3D structural model of HMG-CoA lyase." Mir C., Lopez-Vinas E., Aledo R., Puisac B., Rizzo C., Dionisi-Vici C., Deodato F., Pie J., Gomez-Puertas P., Hegardt F.G., Casals N. J. Inherit. Metab. Dis. 29:64-70(2006) [PubMed: 16601870] [Abstract] Cited for: VARIANT HMGCLD GLU-203, CHARACTERIZATION OF VARIANT HMGCLD GLU-203.
[16]	"C-terminal end and aminoacid Lys48 in HMG-CoA lyase are involved in substrate binding and enzyme activity." Carrasco P., Menao S., Lopez-Vinas E., Santpere G., Clotet J., Sierra A.Y., Gratacos E., Puisac B., Gomez-Puertas P., Hegardt F.G., Pie J., Casals N. Mol. Genet. Metab. 91:120-127(2007) [PubMed: 17459752] [Abstract] Cited for: VARIANT HMGCLD ASN-48.
[17]	"Molecular analysis of Taiwanese patients with 3-hydroxy-3-methylglutaryl CoA lyase deficiency." Lin W.D., Wang C.H., Lai C.C., Tsai Y., Wu J.Y., Chen C.P., Tsai F.J. Clin. Chim. Acta 401:33-36(2009) [PubMed: 19036343] [Abstract] Cited for: VARIANT HMGCLD GLN-165.
[18]	"Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria." Menao S., Lopez-Vinas E., Mir C., Puisac B., Gratacos E., Arnedo M., Carrasco P., Moreno S., Ramos M., Gil M.C., Pie A., Ribes A., Perez-Cerda C., Ugarte M., Clayton P.T., Korman S.H., Serra D., Asins G. , Ramos F.J., Gomez-Puertas P., Hegardt F.G., Casals N., Pie J. Hum. Mutat. 30:E520-E529(2009) [PubMed: 19177531] [Abstract] Cited for: VARIANTS HMGCLD LYS-37; GLY-42; PHE-142; TYR-174; SER-192; PHE-200 AND ARG-233, CHARACTERIZATION OF VARIANTS HMGCLD LYS-37; PHE-142; TYR-174; SER-192 AND PHE-200.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L07033 mRNA. Translation: AAA92733.1.
BC010570 mRNA. Translation: AAH10570.1.
U49719 , U49712, U49713, U49714, U49715, U49716, U49717, U49718 Genomic DNA. Translation: AAB19099.1.

IPI

IPI00293564.

PIR

A45470.

RefSeq

NP_000182.2. NM_000191.2.
NP_001159531.1. NM_001166059.1.

UniGene

Hs.533444.
Hs.603409.

3D structure databases

PDBe
RCSB PDB
PDBj

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	[»]

ProteinModelPortal

P35914.

SMR

P35914. Positions 28-323.

ModBase

Search...

Protein-protein interaction databases

IntAct

P35914. 3 interactions.

STRING

P35914.

PTM databases

PhosphoSite

P35914.

Polymorphism databases

DMDM

24418852.

Proteomic databases

PRIDE

P35914.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000374490; ENSP00000363614; ENSG00000117305.

GeneID

3155.

KEGG

hsa:3155.

UCSC

uc001bib.1. human.

Organism-specific databases

CTD

3155.

GeneCards

GC01M024128.

H-InvDB

HIX0000257.

HGNC

HGNC:5005. HMGCL.

HPA

HPA004727.

MIM

246450. phenotype.
613898. gene.

neXtProt

NX_P35914.

Orphanet

20. 3-hydroxy-3-methylglutaric aciduria.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG19774.

HOGENOM

HBG454130.

HOVERGEN

HBG064656.

InParanoid

P35914.

OMA

ILYKMGC.

OrthoDB

EOG4H9XKS.

PhylomeDB

P35914.

Enzyme and pathway databases

BioCyc

MetaCyc:HS04116-MONOMER.

BRENDA

4.1.3.4. 2681.

Reactome

REACT_22258. Metabolism of lipids and lipoproteins.

Gene expression databases

ArrayExpress

P35914.

Bgee

P35914.

CleanEx

HS_HMGCL.

Genevestigator

P35914.

GermOnline

ENSG00000117305. Homo sapiens.

Family and domain databases

InterPro

IPR013785. Aldolase_TIM.
IPR000138. HMG_CoA_lyase_AS.
IPR000891. PYR_CT.
[Graphical view]

Gene3D

G3DSA:3.20.20.70. Aldolase_TIM. 1 hit.

KO

K01640.

Pfam

PF00682. HMGL-like. 1 hit.
[Graphical view]

PROSITE

PS01062. HMG_COA_LYASE. 1 hit.
PS50991. PYR_CT. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

12496.

SOURCE

Search...

Entry information

Entry name

HMGCL_HUMAN

Accession

Primary (citable) accession number: P35914
Secondary accession number(s): Q96FP8

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	October 25, 2002
Last modified:	January 25, 2012
This is version 121 of the entry and version 2 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.