3-Hydroxymethyl-3-Methylglutaryl Coenzyme A Lyase (HMGCL)

HL; Hydroxymethylglutaricaciduria; Hydroxymethylglutaryl-CoA lyase, mitochondrial

SPN	T099
HGNC	5005
MGI	96158
PubMed	15308132
RGD	620554
UniProt	P35914

3-Hydroxy-3-methylglutaryl coenzyme A lyase is a homodimeric mitochondrial matrix enzyme that catalyzes the cleavage of HMG-CoA to acetoacetic acid and acetyl-CoA, the last step of both ketogenesis and leucine catabolism. A shortage of glucose-sparing ketone bodies normally produced during fasting was thought to be responsible for the hypoglycemia which characterizes this metabolic defect. The absence of ketonuria in this disorder is a direct consequence of the metabolic lesion. HMG-CoA lyase is involved in ketogenesis, and the patient with the deficiency is compromised in the ability to generate ketone bodies. Both parents had reduced levels of HMG-CoA lyase in leukocytes. Clinically, deficiency of the enzyme results in metabolic acidosis and hypoglycemia.

Reference

"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."
J. Biol. Chem. 268:4376-4381(1993) [PubMed] [Europe PMC] [Abstract]

"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]

"The DNA sequence and biological annotation of human chromosome 1."
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]

"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]

"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."
Genomics 33:99-104(1996) [PubMed] [Europe PMC] [Abstract]

"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. 39:4777-4785(2012) [PubMed] [Europe PMC] [Abstract]

"3-Hydroxy-3-methylglutaryl-CoA lyase is present in mouse and human liver peroxisomes."
J. Biol. Chem. 269:31929-31932(1994) [PubMed] [Europe PMC] [Abstract]

"Ketogenic flux from lipids and leucine, assessment in 3-hydroxy-3-methylglutaryl CoA lyase deficiency."
Biochem. Soc. Trans. 23:489S-489S(1995) [PubMed] [Europe PMC] [Abstract]

"Investigation of the oligomeric status of the peroxisomal isoform of human 3-hydroxy-3-methylglutaryl-CoA lyase."
Arch. Biochem. Biophys. 408:286-294(2002) [PubMed] [Europe PMC] [Abstract]

"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. 278:37092-37098(2003) [PubMed] [Europe PMC] [Abstract]

"Evaluation of 3-hydroxy-3-methylglutaryl-coenzyme A lyase arginine-41 as a catalytic residue: use of acetyldithio-coenzyme A to monitor product enolization."
Biochemistry 43:5287-5295(2004) [PubMed] [Europe PMC] [Abstract]

"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]

"Initial characterization of the human central proteome."
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]

"Identification and characterization of an extramitochondrial human 3-Hydroxy-3-methylglutaryl-CoA lyase."
J. Biol. Chem. 287:33227-33236(2012) [PubMed] [Europe PMC] [Abstract]

"Characterization of a novel HMG-CoA Lyase enzyme with a dual location in endoplasmic reticulum and cytosol."
J. Lipid Res. 53:2046-2056(2012) [PubMed] [Europe PMC] [Abstract]

"An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome."
J. Proteomics 96:253-262(2014) [PubMed] [Europe PMC] [Abstract]

"Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria."
J. Biol. Chem. 281:7526-7532(2006) [PubMed] [Europe PMC] [Abstract]

"Modeling of a mutation responsible for human 3-hydroxy-3-methylglutaryl-CoA lyase deficiency implicates histidine-233 as an active site residue."
J. Biol. Chem. 271:24604-24609(1996) [PubMed] [Europe PMC] [Abstract]

"HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q."
Am. J. Hum. Genet. 62:295-300(1998) [PubMed] [Europe PMC] [Abstract]

"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."
Arch. Biochem. Biophys. 358:197-203(1998) [PubMed] [Europe PMC] [Abstract]

"Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency."
Hum. Genet. 107:320-326(2000) [PubMed] [Europe PMC] [Abstract]

"Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase."
J. Biol. Chem. 278:29016-29023(2003) [PubMed] [Europe PMC] [Abstract]

"Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population."
BMC Med. Genet. 7:86-86(2006) [PubMed] [Europe PMC] [Abstract]

"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."
J. Inherit. Metab. Dis. 29:64-70(2006) [PubMed] [Europe PMC] [Abstract]

"C-terminal end and aminoacid Lys48 in HMG-CoA lyase are involved in substrate binding and enzyme activity."
Mol. Genet. Metab. 91:120-127(2007) [PubMed] [Europe PMC] [Abstract]

"Molecular analysis of Taiwanese patients with 3-hydroxy-3-methylglutaryl CoA lyase deficiency."
Clin. Chim. Acta 401:33-36(2009) [PubMed] [Europe PMC] [Abstract]

"Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria."
Hum. Mutat. 30:E520-E529(2009) [PubMed] [Europe PMC] [Abstract]