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Comput Biol Chem. 2015 Dec;59 Pt A:199-207. doi: 10.1016/j.compbiolchem.2015.10.001. Epub 2015 Oct 19.

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

Author information

1
Department of Biomedical Science, Faculty of Medicine, Brawijaya University, Malang, Indonesia. Electronic address: nizar.fkub08@gmail.com.
2
Department of Cardiology and Vascular Medicine, Faculty of Medicine, Brawijaya University, Malang, Indonesia.
3
Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, Malang, Indonesia.

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.

KEYWORDS:

Enzymatic activity; Folding kinetic; Lp-PLA(2); Polymorphism

[Indexed for MEDLINE]

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