Effects of Single Nucleotide Polymorphisms on Human N-Acetyltransferase 2 Structure and Dynamics by Molecular Dynamics Simulation
Resource
PLOS ONE, 6(9), e25801
Journal
PLoS ONE
Pages
e25801
Date Issued
2011
Date
2011
Author(s)
Rajasekaran, M.
Abirami, Santhanam
Chen, Chinpan
Zheng, Jie
Abstract
Background: Arylamine N-acetyltransferase 2 (NAT2) is an important catalytic enzyme that metabolizes the carcinogenic arylamines, hydrazine drugs and chemicals. This enzyme is highly polymorphic in different human populations. Several polymorphisms of NAT2, including the single amino acid substitutions R64Q, I114T, D122N, L137F, Q145P, R197Q, and G286E, are classified as slow acetylators, whereas the wild-type NAT2 is classified as a fast acetylator. The slow acetylators are often associated with drug toxicity and efficacy as well as cancer susceptibility. The biological functions of these 7 mutations have previously been characterized, but the structural basis behind the reduced catalytic activity and reduced protein level is not clear. Methodology/Principal Findings: We performed multiple molecular dynamics simulations of these mutants as well as NAT2 to investigate the structural and dynamical effects throughout the protein structure, specifically the catalytic triad, cofactor binding site, and the substrate binding pocket. None of these mutations induced unfolding; instead, their effects were confined to the inter-domain, domain 3 and 17-residue insert region, where the flexibility was significantly reduced relative to the wild-type. Structural effects of these mutations propagate through space and cause a change in catalytic triad conformation, cofactor binding site, substrate binding pocket size/shape and electrostatic potential. Conclusions/Significance: Our results showed that the dynamical properties of all the mutant structures, especially in inter-domain, domain 3 and 17-residue insert region were affected in the same manner. Similarly, the electrostatic potential of all the mutants were altered and also the functionally important regions such as catalytic triad, cofactor binding site, and substrate binding pocket adopted different orientation and/or conformation relative to the wild-type that may affect the functions of the mutants. Overall, our study may provide the structural basis for reduced catalytic activity and protein level, as was experimentally observed for these polymorphisms. ? 2011 Rajasekaran et al.
SDGs
Other Subjects
arylamine acetyltransferase; NAT2 protein, human; ubiquitin; amino acid sequence; article; binding site; catalysis; conformational transition; electric potential; enzyme activity; enzyme structure; enzyme substrate; gene insertion; gene mutation; molecular dynamics; molecular model; mutant; protein domain; protein unfolding; single nucleotide polymorphism; wild type; chemistry; coenzyme; enzyme active site; genetics; human; hydrogen bond; metabolism; molecular genetics; mutation; static electricity; X ray crystallography; Amino Acid Sequence; Arylamine N-Acetyltransferase; Catalytic Domain; Coenzymes; Crystallography, X-Ray; Humans; Hydrogen Bonding; Molecular Dynamics Simulation; Molecular Sequence Data; Mutation; Polymorphism, Single Nucleotide; Static Electricity; Ubiquitin
Type
journal article
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