Paper Info
Title
Structural basis for the mutation-induced dysfunction of human CYP2J2: a computational study.
Abstract
Arachidonic acid is an essential fatty acid in cells, acting as a key inflammatory intermediate in inflammatory reactions. In cardiac tissues, CYP2J2 can adopt arachidonic acid as a major substrate to produce epoxyeicosatrienoic acids (EETs), which can protect endothelial cells from ischemic or hypoxic injuries and have been implicated in the pathogenesis,, of coronary artery disease and hypertension. However, some CYP2J2 polymorphisms, i.e., T143A and N404Y, significantly reduce the metabolism of arachidonic acid. Lacking experimental structural data for CYP2J2, the detailed mechanism for the mutation-induced dysfunction in, the metabolism arachidonic acid is still unknown. In the current study three-dimensional structural models of the wild-type CYP2J2 and two mutants (T143A and N404Y) were constructed by a coordinate reconstruction approach and ab initio modeling using CYP2R1 as a template. The structural analysis of the computational models showed that the wild-type CYP2J2 exhibited a typical CYP fold with 12 alpha-helices and three beta-sheets on one side and with the heme group buried deeply inside the core. Due to the small and hydrophobic side-chain T143A mutation could destabilize the C helix, further placing the water access channel in a closed state to prevent the escape of the produced water molecules during the catalytic processes. N404Y mutation could reposition the side-chain of Leu(378), making it no longer form a hydrogen bond with the carboxyl group of arachidonic acid. However, this hydrogen bond was essential for substrate recognition and positioning in a correct orientation.
Year
DOI
Venue
2013
10.1021/ci400003p
JOURNAL OF CHEMICAL INFORMATION AND MODELING
DocType
Volume
Issue
Journal
53
6
ISSN
Citations 
PageRank 
1549-9596
0
0.34
References 
Authors
0
4
Name
Order
Citations
PageRank
Shan Cong100.34
Xiaotu Ma2644.96
Yixue Li378960.24
Jing-Fang Wang421.75