Abstract
Cytochrome P450 1A2 (CYP1A2) is one of the main hepatic CYPs involved in metabolism of carcinogens and clinically used drugs. Nonsynonymous single nucleotide polymorphisms (nsSNPs) of this enzyme could affect cancer susceptibility and drug efficiency. Hence, identification of human CYP1A2 pathogenic nsSNPs could be of great importance in personalized medicine and pharmacogenetics. Here, 176 nsSNPs of human CYP1A2 were evaluated using a variety of computational tools, of which 18 nsSNPs were found to be associated with pathogenicity. Further analysis suggested possible association of 9 nsSNPs (G73R, G73W, R108Q, R108W, E168K, E346K, R431W, F432S and R456H) with the risk of hepatocellular carcinoma. Molecular dynamics simulations revealed higher overall flexibility, decreased intramolecular hydrogen bonds and lower content of regular secondary structures for both cancer driver variants G73W and F432S when compared to the wild-type structure. In case of F432S, loss of the conserved hydrogen bond between Arg137 and heme propionate oxygen may affect heme stability and the observed significant rise in fluctuation of the CD loop could modify CYP1A2 interactions with its redox partners. Together, these findings propose CYP1A2 as a possible candidate for hepatocellular carcinoma and provide structural insights into how cancer driver nsSNPs could affect protein structure, heme stability and interaction network.
Highlights
The genome of two individuals, except for identical twins, shares 99.9% identity and only differs by 0.1%
Since Cytochrome P450 1A2 (CYP1A2) is one of the main hepatic cytochrome P450 (CYP) involved in the bioactivation of carcinogens and metabolism of clinically used drugs, single nucleotide polymorphisms (SNPs) of this enzyme could affect cancer susceptibility or drug efficiency
The Nonsynonymous single nucleotide polymorphisms (nsSNPs) which met at least one of the following criteria in the validation method were entered to the evaluation: (1) sequenced in 1000Genome project (1000G), (2) validated by multiple independent submissions to the refSNP cluster, (3) validated by frequency or genotype data, (4) genotyped by HapMap project, (5) validated by submitter confirmation, and (6) observed in at least two chromosome apiece
Summary
The genome of two individuals, except for identical twins, shares 99.9% identity and only differs by 0.1%. Single nucleotide polymorphisms in the enzymes of this superfamily play an important role in differences between individuals in response to drugs and other xenobiotics as well as the susceptibility to develop various diseases[10]. Among 18 cytochrome P450 families encoded by the human genome, members of CYP1 family are important due to their major contribution to the metabolism of carcinogenic compounds such as polycyclic aromatic hydrocarbons (PAHs)[11,12,13]. This family of CYPs has three members CYP1A1, CYP1A2 and CYP1B1 grouped into A and B subfamilies[11,13]
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