title: 279(Val→Phe) Polymorphism of lipoprotein-associated phospholipase A(2) resulted in changes of folding kinetics and recognition to substrate.
abstract: BACKGROUND
  PLA2G7 encodes Lp-PLA2 having role in the formation of atherosclerotic plaques by catalyzing its substrate, phosphatydilcholine (PC), to be pro-inflammatory substances. The increased risk for coronary artery disease (CAD) in Asian population has been related with this enzyme. 279(Val→Phe) variant was reported to have a protective role against CAD due to, in part, secretion defect or loss of enzymatic function. Therefore, We study folding kinetics and enzyme-substrate interaction in 279(Val→Phe) by using clinical and computational biology approach.
  
  
  METHODS
  Polymorphisms were detected by genotyping among 103 acute myocardial infarction patients and 37 controls. Folding Lp-PLA2 was simulated using GROMACS software by assessing helicity, hydrogen bond formation and stability. The interactions of Lp-PLA2 and its substrate were simulated using Pyrx software followed by molecular dynamics simulation using YASARA software.
  
  
  RESULTS
  Polymorphism of 279(Val→Phe) was represented by the change of nucleotide from G to T of 994th PLA2G7 gene. The folding simulation suggested a decreased percentage of α-helix, hydrogen bond formation, hydrogen bond stability and hydrophobicity in 279(Val→Phe). The PC did not interact with active site of 279(Val→Phe) as paradoxically observed in 279 valine. 279(Val→Phe) polymorphism is likely to cause unstable binding to the substrate and decrease the enzymatic activity as observed in molecular dynamics simulations. The results of our computational biology study supported a protected effect of 279(Val→Phe) Polymorphism showed by the odd ratio for MI of 0.22 (CI 95% 0.035-1.37) in this study.
  
  
  CONCLUSIONS
  279(Val→Phe) Polymorphism of Lp-PLA2 may lead to decrease the enzymatic activity via changes of folding kinetics and recognition to its substrate.
authors.affiliation: Department of Biomedical Science, Faculty of Medicine, Brawijaya University, Malang, Indonesia. Electronic address: nizar.fkub08@gmail.com.
authors.forename: Ainun Nizar
authors.initials: AN
authors.lastname: Masbuchin
authors.affiliation: Department of Cardiology and Vascular Medicine, Faculty of Medicine, Brawijaya University, Malang, Indonesia.
authors.forename: Mohammad Saifur
authors.initials: MS
authors.lastname: Rohman
authors.affiliation: Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, Malang, Indonesia.
authors.forename: Jayarani Fatimah
authors.initials: JF
authors.lastname: Putri
authors.affiliation: Department of Cardiology and Vascular Medicine, Faculty of Medicine, Brawijaya University, Malang, Indonesia.
authors.forename: Miryanti
authors.initials: M
authors.lastname: Cahyaningtyas
authors.affiliation: Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, Malang, Indonesia.
authors.lastname: Widodo
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000208:Acute Disease; D016022:Case-Control Studies; D019295:Computational Biology; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D056004:Molecular Dynamics Simulation; D010649:Phenylalanine / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D017510:Protein Folding; D012984:Software; D013379:Substrate Specificity; D014633:Valine / Q000235:genetics*
chemical_list: D010649:Phenylalanine; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526684:PLA2G7 protein, human; D014633:Valine
keywords: Enzymatic activity; Folding kinetic; Lp-PLA(2); Polymorphism