279(Val→Phe) Polymorphism of lipoprotein-associated phospholipase A(2) resulted in changes of folding kinetics and recognition to substrate.

Abstract

INTRODUCTION:

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.

RESULT:

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.

CONCLUSION:

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: Ainun Nizar Masbuchin, Mohammad Saifur Rohman, Jayarani Fatimah Putri, Miryanti Cahyaningtyas, Widodo
• Journal: Computational biology and chemistry (Comput Biol Chem) Vol. 59 Pt A Pg. 199-207 (Dec 2015) ISSN: 1476-928X [Electronic] England
• PMID: 26595893 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Phenylalanine
• 1-Alkyl-2-acetylglycerophosphocholine Esterase
• PLA2G7 protein, human
• Valine

Topics

• 1-Alkyl-2-acetylglycerophosphocholine Esterase (chemistry, genetics, metabolism)
• Acute Disease
• Case-Control Studies
• Computational Biology
• Coronary Artery Disease (diagnosis, genetics, metabolism)
• Genotype
• Humans
• Kinetics
• Male
• Middle Aged
• Molecular Dynamics Simulation
• Phenylalanine (genetics)
• Polymorphism, Genetic (genetics)
• Protein Folding
• Software
• Substrate Specificity
• Valine (genetics)