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Gene Review

HMGCL  -  3-hydroxymethyl-3-methylglutaryl-CoA lyase

Homo sapiens

Synonyms: 3-hydroxy-3-methylglutarate-CoA lyase, HL, HMG-CoA lyase, Hydroxymethylglutaryl-CoA lyase, mitochondrial
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Disease relevance of HMGCL

  • Deficiency of mitochondrial 3-hydroxy-3-methylglutaryl CoA lyase (HL, EC4.1.3.4.) is an autosomal recessive genetic disorder characterized by acute episodes of vomiting, hypotonia, and lethargy in the neonatal period or in infancy [1].
  • Autosomal-recessive HL deficiency in humans results in episodes of hypoketotic hypoglycemia and coma [2].
  • Although native HL from Streptococcus agalactiae is composed of four domains, it finally stabilizes after autocatalytic conversion as a 92-kDa enzyme composed of the N-terminal spacer, middle alpha-, and C-terminal domains [3].
  • Expression studies in Escherichia coli show that S75R and S201Y substitutions completely abolished the HMG-CoA lyase activity, whereas D204N reduced catalytic efficiency to 6.6% of the wild type [4].
  • Therefore, a genetic deficiency of HMGCoA lyase activity can cause a clinical syndrome similar to that of Reye syndrome when the patient is stressed by an acute viral infection [5].

Psychiatry related information on HMGCL


High impact information on HMGCL

  • HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q [7].
  • In purified mutant recombinant HL, all four missense mutations in codons 41 and 42 cause a marked decrease in HL activity [7].
  • Thus, no evidence was obtained for biochemical or genetic heterogeneity in fibroblasts of these seven patients with a deficiency of HMG-CoA lyase that would account for their different clinical presentations [8].
  • Unfused cells from patients with isovaleric acidemia or a deficiency of 3-methylcrotonyl-CoA carboxylase also had incorporations of less than 5% of normal, and when fused with cells of patients with a deficiency of HMG-CoA lyase, gave positive complementation with an incorporation of 30% of normal [8].
  • We report the experimental determination of a crystal structure at 2.1 A resolution of the recombinant human mitochondrial HMG-CoA lyase containing a bound activator cation and the dicarboxylic acid 3-hydroxyglutarate [9].

Biological context of HMGCL

  • The severe genetic lesion identified in the patient, which is in contrast with the mild clinical phenotype, stresses the importance of early diagnosis and therapy in HMGCL deficiency [10].
  • Assignment of arginine-41 as an active site residue is also supported by a homology model for HMG-CoA lyase based on the structure of 4-hydroxy-2-ketovalerate aldolase [11].
  • These aberrant spliced mRNAs are predicted to encode two abnormal HMG-CoA lyase proteins: the first results in a protein with an internal deletion of 42 amino acids, whose enzyme activity is largely abolished, as the catalytic site was completely removed; the second contains 17 missense amino acids that precede a stop codon [12].
  • We also isolated two human HL genomic clones that include HL exons 2 to 9 within 18 kb [2].
  • We identified multiple transcription start sites in the mouse HL gene, 35 to 9 bases upstream of the translation start codon [2].

Anatomical context of HMGCL

  • The human HL locus (HMGCL) was mapped to distal Chr 1p by analysis of a human-hamster hybrid cell panel and by in situ hybridization [13].
  • A defect of HMGCL activity was suspected and then confirmed on cultured skin fibroblasts [10].
  • A distinct species of enzymatically active HL exists in peroxisomes and may play a role in HMG-CoA metabolism in that organelle [14].
  • We investigated the subcellular distribution of HMG-CoA lyase (HL), which is found principally in mitochondria but in which we observed the potential peroxisomal targeting motif cysteine-lysine/arginine-leucine at the carboxyl terminus [14].
  • Heterozygosity was proven by intermediate HMG-CoA lyase activities determined in cultured fibroblasts and in lymphocytes in the parents and the paternal grandmother [15].

Associations of HMGCL with chemical compounds


Other interactions of HMGCL


Analytical, diagnostic and therapeutic context of HMGCL


  1. 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. (2000) [Pubmed]
  2. 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., Mitchell, G.A. Genomics (1996) [Pubmed]
  3. Insights into the Mechanism of Action of Hyaluronate Lyase: ROLE OF C-TERMINAL DOMAIN AND Ca2+ IN THE FUNCTIONAL REGULATION OF ENZYME. Akhtar, M.S., Krishnan, M.Y., Bhakuni, V. J. Biol. Chem. (2006) [Pubmed]
  4. Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase. Casals, N., Gómez-Puertas, P., Pié, 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. (2003) [Pubmed]
  5. Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome. Robinson, B.H., Oei, J., Sherwood, W.G., Slyper, A.H., Heininger, J., Mamer, O.A. Neurology (1980) [Pubmed]
  6. Molecular prenatal diagnosis of 3-hydroxy-3-methylglutaryl CoA lyase deficiency. Mitchell, G.A., Jakobs, C., Gibson, K.M., Robert, M.F., Burlina, A., Dionisi-Vici, C., Dallaire, L. Prenat. Diagn. (1995) [Pubmed]
  7. 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., Plöchl, E., Miziorko, H. Am. J. Hum. Genet. (1998) [Pubmed]
  8. Genetic complementation analysis of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency in cultured fibroblasts. Sovik, O., Sweetman, L., Gibson, K.M., Nyhan, W.L. Am. J. Hum. Genet. (1984) [Pubmed]
  9. 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. (2006) [Pubmed]
  10. 3-Hydroxy-3-methylglutaric aciduria in an Italian patient is caused by a new nonsense mutation in the HMGCL gene. Funghini, S., Pasquini, E., Cappellini, M., Donati, M.A., Morrone, A., Fonda, C., Zammarchi, E. Mol. Genet. Metab. (2001) [Pubmed]
  11. 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 (2004) [Pubmed]
  12. Aberrantly spliced mRNAs of the 3-hydroxy-3-methylglutaryl coenzyme A lyase (HL) gene with a donor splice-site point mutation produce hereditary HL deficiency. Buesa, C., Pié, J., Barceló, A., Casals, N., Mascaró, C., Casale, C.H., Haro, D., Duran, M., Smeitink, J.A., Hegardt, F.G. J. Lipid Res. (1996) [Pubmed]
  13. 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL): cloning and characterization of a mouse liver HL cDNA and subchromosomal mapping of the human and mouse HL genes. Wang, S., Nadeau, J.H., Duncan, A., Robert, M.F., Fontaine, G., Schappert, K., Johnson, K.R., Zietkiewicz, E., Hruz, P., Miziorko, H. Mamm. Genome (1993) [Pubmed]
  14. 3-Hydroxy-3-methylglutaryl-CoA lyase is present in mouse and human liver peroxisomes. Ashmarina, L.I., Rusnak, N., Miziorko, H.M., Mitchell, G.A. J. Biol. Chem. (1994) [Pubmed]
  15. Increased plasma amylase in the family of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Plöchl, E., Colombo, J.P., Wermuth, B., Gibson, K.M. Clin. Chem. (1992) [Pubmed]
  16. The E37X is a common HMGCL mutation in Portuguese patients with 3-hydroxy-3-methylglutaric CoA lyase deficiency. Cardoso, M.L., Rodrigues, M.R., Leão, E., Martins, E., Diogo, L., Rodrigues, E., Garcia, P., Rolland, M.O., Vilarinho, L. Mol. Genet. Metab. (2004) [Pubmed]
  17. Modeling of a mutation responsible for human 3-hydroxy-3-methylglutaryl-CoA lyase deficiency implicates histidine 233 as an active site residue. Roberts, J.R., Mitchell, G.A., Miziorko, H.M. J. Biol. Chem. (1996) [Pubmed]
  18. 3-Hydroxy-3-methylglutaryl-CoA lyase: expression and isolation of the recombinant human enzyme and investigation of a mechanism for regulation of enzyme activity. Roberts, J.R., Narasimhan, C., Hruz, P.W., Mitchell, G.A., Miziorko, H.M. J. Biol. Chem. (1994) [Pubmed]
  19. Chemical events in chloropropionyl coenzyme A inactivation of acyl coenzyme A utilizing enzymes. Miziorko, H.M., Behnke, C.E., Ahmad, F. Biochemistry (1989) [Pubmed]
  20. LCGreen I-based real-time PCR assays for detecting common ASL and HMGCL variants. Alsmadi, O., Alkayal, F., Al-Sayed, M., Rashed, M.S., Imtiaz, F., Meyer, B.F. Clin. Chem. (2006) [Pubmed]
  21. Investigation of the oligomeric status of the peroxisomal isoform of human 3-hydroxy-3-methylglutaryl-CoA lyase. Tuinstra, R.L., Burgner, J.W., Miziorko, H.M. Arch. Biochem. Biophys. (2002) [Pubmed]
  22. Evaluation of cysteine 266 of human 3-hydroxy-3-methylglutaryl-CoA lyase as a catalytic residue. Roberts, J.R., Narasimhan, C., Miziorko, H.M. J. Biol. Chem. (1995) [Pubmed]
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