3-Hydroxy-3-methylglutaryl-CoA lyase

3-hydroxy-3-methylglutaryl-CoA lyase
Identifiers
Aliases	HMG-CoA_lyasehydroxymethylglutaryl-CoA lyaseHMG-CoA lyase3-hydroxy-3-methylglutaryl coenzyme A lyase(S)-3-hydroxy-3-methylglutaryl-CoA acetoacetate-lyase (acetyl-CoA-forming)(S)-3-hydroxy-3-methylglutaryl-CoA acetoacetate-lyase3-hydroxy-3-methylglutarate-CoA lyasehydroxymethylglutaryl coenzyme A lyase
External IDs	GeneCards: ; OMA:- orthologs
Orthologs Species Human Mouse Entrez n/a n/a Ensembl n/a n/a UniProt n a n/a RefSeq (mRNA) n/a n/a RefSeq (protein) n/a n/a Location (UCSC) n/a n/a PubMed search n/a n/a
Wikidata
View/Edit Human

Hydroxymethylglutaryl-CoA lyase
HMG-CoA lyase dimer, Human
Identifiers
EC no.	4.1.3.4
CAS no.	9030-83-5
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase (hydroxymethylglutaricaciduria)
Identifiers
Symbol	HMGCL
NCBI gene	3155
HGNC	5005
OMIM	246450
RefSeq	NM_000191
UniProt	P35914
Other data
EC number	4.1.3.4
Locus	Chr. 1 p36.1-p35
Search for Structures Swiss-model Domains InterPro

Substrate binding site makes a salt bridge between the 3HG (3-Hydroxy-3-methylglutaryl-CoA lyase) substrate and active Arg 41 with bond distance of 3.3Å. Also displays the bond between Arg 41 and Glu72 holding the structure in place. PDB code: 2cw6

Metal-Ligand binding site displays octahedral bonding coordination utilizing 4 amino acids and 2 water molecules all with distances within 2.2Å . PDB code: 2cw6

3-Hydroxy-3-methylglutaryl-CoA lyase (or HMG-CoA lyase ) is an enzyme (EC 4.1.3.4 that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis (ketone body formation). It is a ketogenic enzyme in the liver that catalyzes the formation of acetoacetate from HMG-CoA within the mitochondria. It also plays a prominent role in the catabolism of the amino acid leucine.

Structure

The HMGCL gene encodes a 34.5-kDa protein that is localized to the mitochondrion and peroxisome. ^[1] Multible isoforms of the proteins are known due to alternative splicing. The major isoform (isoform 1) is most highly expressed in the liver ^[1] whereas isoform 2 is found in energy-demanding tissues including the brain, heart, and skeletal muscle. ^[2]

Structure of the HMGCL protein has been resolved by X-ray crystallography at 2.1-Å resolution, and reveals that the protein may function as a dimer. Substrate access to the active site of the HMGCL enzyme involves substrate binding across a cavity located at the C-terminal end of a beta barrel structure. ^[3] In addition, the lysine 48 residue which is mutated in patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency is also found to be necessary for substrate binding. ^[4]

Electron density was observed indicating a bound metal ion, presumably Mg²⁺ due to its inclusion in the crystallization medium. The enzyme activity is dependent on the presence of the metal this was determined by mutating His233 to Ala233 and Asp42 to Asn42 and experiencing catalytic deficiency of 6.4E⁻³ k_cat/k_M and 1.3E⁻⁵ k_cat/k_M respectively. The substrate binding site includes arginine 41 making a salt bridge to the carboxylate of the hydroxyglutaric acid closest to metal ion. A mutation in Arg 41 results in a drastic decrease of catalytic activity. The extreme decrease in efficiency suggests the direct involvement in the chemistry of the catalytic reaction. This Arg41 also salt bridges to Glu72 to fold into the correct position and charge balance Arg41 to bind to the substrate.

Function

The HMGCL protein plays an essential role in breaking down dietary proteins and fats for energy. It catalyzes the reaction:

(S)-3-hydroxy-3-methylglutaryl-CoA = acetyl-CoA + acetoacetate

and requires a divalent metal ion as co-factor. ^[5]

The enzyme is required for ketogenesis in the liver, and is also responsible for processing the amino acid leucine inside the mitochondrion

Deficiency HMG-CoA lyase deficiency causes hypoketotic hypoglycemia similar to that is caused by HMGCS2 mutations but also leads to organic acid accumulation and metabolic acidosis due to altered leucine metabolism. This disorder can be mistaken for Reye syndrome because of the symptoms of vomiting, lethargy, and convulsions.

Ketogenesis

Clinical significance

Mutations in the HMGCL gene cause 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD), a rare autosomal recessive inborn error of metabolism characterized by disruption of ketogenesis and L-leucine catabolism. To-date more than 30 different mutations including missense mutations of different residues have been associated with patients with HMGCLD in diverse families and ethnicities. ^[6] HMGCLD typically presents in the first year of the patient's life after a fasting period. Clinical acute symptoms include vomiting, seizures, metabolic acidosis, hypoketotic hypoglycemia, and lethargy. ^[7]

Interactions

HMGCL interacts with itself to form homodimers and homotetramers. It is also shown in yeast two-hybrid experiments to interact with DNAJA1.

References

1. Ashmarina LI, Robert MF, Elsliger MA, Mitchell GA (1996). "Characterization of the hydroxymethylglutaryl-CoA lyase precursor, a protein targeted to peroxisomes and mitochondria". Biochem. J. 315 (Pt 1): 71–5. doi:10.1042/bj3150071. PMC   1217198 . PMID   8670134.
2. Puisac B, Ramos M, Arnedo M, Menao S, Gil-Rodríguez MC, Teresa-Rodrigo ME, Pié A, de Karam JC, Wesselink JJ, Giménez I, Ramos FJ, Casals N, Gómez-Puertas P, Hegardt FG, Pié J (2012). "Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway". Mol. Biol. Rep. 39 (4): 4777–85. doi:10.1007/s11033-011-1270-8. PMID   21952825. S2CID   16280588.
3. Fu Z, Runquist JA, Montgomery C, Miziorko HM, Kim JJ (2010). "Functional insights into human HMG-CoA lyase from structures of Acyl-CoA-containing ternary complexes". J. Biol. Chem. 285 (34): 26341–9. doi: 10.1074/jbc.M110.139931 . PMC   2924059 . PMID   20558737.
4. Carrasco P, Menao S, López-Viñas E, Santpere G, Clotet J, Sierra AY, Gratacós E, Puisac B, Gómez-Puertas P, Hegardt FG, Pie J, Casals N (2007). "C-terminal end and aminoacid Lys48 in HMG-CoA lyase are involved in substrate binding and enzyme activity". Mol. Genet. Metab. 91 (2): 120–7. doi:10.1016/j.ymgme.2007.03.007. PMID   17459752.
5. Tuinstra RL, Miziorko HM (2003). "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". J. Biol. Chem. 278 (39): 37092–8. doi: 10.1074/jbc.M304472200 . PMID   12874287.
6. Menao S, López-Viñas E, Mir C, Puisac B, Gratacós E, Arnedo M, Carrasco P, Moreno S, Ramos M, Gil MC, Pié A, Ribes A, Pérez-Cerda C, Ugarte M, Clayton PT, Korman SH, Serra D, Asins G, Ramos FJ, Gómez-Puertas P, Hegardt FG, Casals N, Pié J (2009). "Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria". Human Mutation. 30 (3): E520–9. doi: 10.1002/humu.20966 . PMID   19177531. S2CID   2826349.
7. Online Mendelian Inheritance in Man (OMIM): 3-hydroxy-3-methylglutaryl-coa lyase deficiency; HMGCLD - 246450

Further reading

• Zhuji Fu, Jennifer A. Runquist, Farhad Forouhar, Munif Hussain, John F. Hunt, Henry M. Miziorko, Jung-Ja P. Kim, Crystal Structure of Human 3-Hydroxy-3-methylglutaryl-CoA Lyase: INSIGHTS INTO CATALYSIS AND THE MOLECULAR BASIS FOR HYDROXYMETHYLGLUTARIC ACIDURIA*, Journal of Biological Chemistry, Volume 281, Issue 11, 2006, Pages 7526–7532, ISSN 0021-9258, doi:10.1074/jbc.M506880200.

External links

• 3-hydroxy-3-methylglutaryl-coenzyme+A+lyase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)