Proteopedia

2cw6

Crystal Structure of Human HMG-CoA Lyase: Insights into Catalysis and the Molecular Basis for Hydroxymethylglutaric AciduriaCrystal Structure of Human HMG-CoA Lyase: Insights into Catalysis and the Molecular Basis for Hydroxymethylglutaric Aciduria

Structural highlights

2cw6 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.1Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Function

HMGCL_HUMAN Key enzyme in ketogenesis (ketone body formation). Terminal step in leucine catabolism.[11] [12] [13]

Evolutionary Conservation

 

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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

2cw6, resolution 2.10Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=2cw6&oldid=4088513"