[HMGCL_HUMAN] 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.
3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase is a key enzyme in the ketogenic pathway that supplies metabolic fuel to extrahepatic tissues. Enzyme deficiency may be due to a variety of human mutations and can be fatal. Diminished activity has been explained based on analyses of recombinant human mutant proteins or, more recently, in the context of structural models for the enzyme. 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. The enzyme adopts a (betaalpha)(8) barrel fold, and the N-terminal barrel end is occluded. The structure of a physiologically relevant dimer suggests that substrate access to the active site involves binding across the cavity located at the C-terminal end of the barrel. An alternative hypothesis that involves substrate insertion through a pore proposed to extend through the barrel is not compatible with the observed structure. The activator cation ligands included Asn(275), Asp(42),His(233), and His(235); the latter three residues had been implicated previously as contributing to metal binding or enzyme activity. Arg(41), previously shown to have a major effect on catalytic efficiency, is also located at the active site. In the observed structure, this residue interacts with a carboxyl group of 3-hydroxyglutarate, the hydrolysis product of the competitive inhibitor 3-hydroxyglutaryl-CoA required for crystallization of human enzyme. The structure provides a rationale for the decrease in enzyme activity due to clinical mutations, including H233R, R41Q, D42H, and D204N, that compromise active site function or enzyme stability.
Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria.,Fu Z, Runquist JA, Forouhar F, Hussain M, Hunt JF, Miziorko HM, Kim JJ J Biol Chem. 2006 Mar 17;281(11):7526-32. Epub 2005 Dec 5. PMID:16330550
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↑ Roberts JR, Mitchell GA, Miziorko HM. 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. 1996 Oct 4;271(40):24604-9. PMID:8798725
↑ Mitchell GA, Ozand PT, Robert MF, Ashmarina L, Roberts J, Gibson KM, Wanders RJ, Wang S, Chevalier I, Plochl E, Miziorko H. 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. 1998 Feb;62(2):295-300. PMID:9463337 doi:10.1086/301730
↑ Zapater N, Pie J, Lloberas J, Rolland MO, Leroux B, Vidailhet M, Divry P, Hegardt FG, Casals N. 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. 1998 Oct 15;358(2):197-203. PMID:9784232 doi:S0003-9861(98)90788-3
↑ Muroi J, Yorifuji T, Uematsu A, Shigematsu Y, Onigata K, Maruyama H, Nobutoki T, Kitamura A, Nakahata T. Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency. Hum Genet. 2000 Oct;107(4):320-6. PMID:11129331
↑ 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 AC, Cresto JC, Chamoles NA, Abdenur JE, Mayatepek E, Besley G, Valencia A, Hegardt FG. Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase. J Biol Chem. 2003 Aug 1;278(31):29016-23. Epub 2003 May 13. PMID:12746442 doi:10.1074/jbc.M304276200
↑ Al-Sayed M, Imtiaz F, Alsmadi OA, Rashed MS, Meyer BF. Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population. BMC Med Genet. 2006 Dec 16;7:86. PMID:17173698 doi:10.1186/1471-2350-7-86
↑ Mir C, Lopez-Vinas E, Aledo R, Puisac B, Rizzo C, Dionisi-Vici C, Deodato F, Pie J, Gomez-Puertas P, Hegardt FG, Casals N. 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. 2006 Feb;29(1):64-70. PMID:16601870 doi:10.1007/s10545-006-0138-x
↑ Carrasco P, Menao S, Lopez-Vinas E, Santpere G, Clotet J, Sierra AY, Gratacos E, Puisac B, Gomez-Puertas P, Hegardt FG, Pie J, Casals N. C-terminal end and aminoacid Lys48 in HMG-CoA lyase are involved in substrate binding and enzyme activity. Mol Genet Metab. 2007 Jun;91(2):120-7. Epub 2007 Apr 24. PMID:17459752 doi:10.1016/j.ymgme.2007.03.007
↑ Lin WD, Wang CH, Lai CC, Tsai Y, Wu JY, Chen CP, Tsai FJ. Molecular analysis of Taiwanese patients with 3-hydroxy-3-methylglutaryl CoA lyase deficiency. Clin Chim Acta. 2009 Mar;401(1-2):33-6. doi: 10.1016/j.cca.2008.11.004. Epub 2008, Nov 12. PMID:19036343 doi:10.1016/j.cca.2008.11.004
↑ Menao S, Lopez-Vinas E, Mir C, Puisac B, Gratacos E, Arnedo M, Carrasco P, Moreno S, Ramos M, Gil MC, Pie A, Ribes A, Perez-Cerda C, Ugarte M, Clayton PT, Korman SH, Serra D, Asins G, Ramos FJ, Gomez-Puertas P, Hegardt FG, Casals N, Pie J. Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria. Hum Mutat. 2009 Mar;30(3):E520-9. doi: 10.1002/humu.20966. PMID:19177531 doi:10.1002/humu.20966
↑ Holmes HC, Burns SP, Chalmers RA, Bain MS, Iles RA. Ketogenic flux from lipids and leucine, assessment in 3-hydroxy-3-methylglutaryl CoA lyase deficiency. Biochem Soc Trans. 1995 Aug;23(3):489S. PMID:8566388
↑ Montgomery C, Pei Z, Watkins PA, Miziorko HM. Identification and characterization of an extramitochondrial human 3-hydroxy-3-methylglutaryl-CoA lyase. J Biol Chem. 2012 Sep 28;287(40):33227-36. Epub 2012 Aug 3. PMID:22865860 doi:10.1074/jbc.M112.393231
↑ Arnedo M, Menao S, Puisac B, Teresa-Rodrigo ME, Gil-Rodriguez MC, Lopez-Vinas E, Gomez-Puertas P, Casals N, Casale CH, Hegardt FG, Pie J. Characterization of a novel HMG-CoA lyase enzyme with a dual location in endoplasmic reticulum and cytosol. J Lipid Res. 2012 Oct;53(10):2046-56. doi: 10.1194/jlr.M025700. Epub 2012 Jul 30. PMID:22847177 doi:10.1194/jlr.M025700
↑ Fu Z, Runquist JA, Forouhar F, Hussain M, Hunt JF, Miziorko HM, Kim JJ. Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria. J Biol Chem. 2006 Mar 17;281(11):7526-32. Epub 2005 Dec 5. PMID:16330550 doi:10.1074/jbc.M506880200