Abstract
BackgroundThe arylamine N-acetyltransferases (NATs) are a unique family of enzymes widely distributed in nature that play a crucial role in the detoxification of aromatic amine xenobiotics. Considering the temporal changes in the levels and toxicity of environmentally available chemicals, the metabolic function of NATs is likely to be under adaptive evolution to broaden or change substrate specificity over time, making NATs a promising subject for evolutionary analyses. In this study, we trace the molecular evolutionary history of the NAT gene family during the last ~450 million years of vertebrate evolution and define the likely role of gene duplication, gene conversion and positive selection in the evolutionary dynamics of this family.ResultsA phylogenetic analysis of 77 NAT sequences from 38 vertebrate species retrieved from public genomic databases shows that NATs are phylogenetically unstable genes, characterized by frequent gene duplications and losses even among closely related species, and that concerted evolution only played a minor role in the patterns of sequence divergence. Local signals of positive selection are detected in several lineages, probably reflecting response to changes in xenobiotic exposure. We then put a special emphasis on the study of the last ~85 million years of primate NAT evolution by determining the NAT homologous sequences in 13 additional primate species. Our phylogenetic analysis supports the view that the three human NAT genes emerged from a first duplication event in the common ancestor of Simiiformes, yielding NAT1 and an ancestral NAT gene which in turn, duplicated in the common ancestor of Catarrhini, giving rise to NAT2 and the NATP pseudogene. Our analysis suggests a main role of purifying selection in NAT1 protein evolution, whereas NAT2 was predicted to mostly evolve under positive selection to change its amino acid sequence over time. These findings are consistent with a differential role of the two human isoenzymes and support the involvement of NAT1 in endogenous metabolic pathways.ConclusionsThis study provides unequivocal evidence that the NAT gene family has evolved under a dynamic process of birth-and-death evolution in vertebrates, consistent with previous observations made in fungi.
Highlights
The arylamine N-acetyltransferases (NATs) are a unique family of enzymes widely distributed in nature that play a crucial role in the detoxification of aromatic amine xenobiotics
The importance of NAT1 and NAT2 in the metabolism of drugs and in the activation of common environmental carcinogens has led to a plethora of molecular epidemiological studies that have shown associations of Arylamine N-acetyltransferase (NAT) gene polymorphisms with individual drug response and susceptibility to cancers linked to arylamine exposure [14,15,16]
Phylogenetic analysis of vertebrate NAT sequences To study the molecular evolution of the NAT gene family in vertebrates, we retrieved all available NAT-homologous sequences from public genomic databases and compiled a dataset of 77 NAT coding sequences from 38 species representing all major vertebrate taxa (‘vertebrate dataset’)
Summary
The arylamine N-acetyltransferases (NATs) are a unique family of enzymes widely distributed in nature that play a crucial role in the detoxification of aromatic amine xenobiotics. Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes found in a wide range of species across all major clades of life (bacteria, archaea, eukaryotes), except plants [1,2,3]. This unique family of enzymes catalyses the transfer of an acetyl group from acetyl-coenzyme A (acetyl-CoA) to the terminal nitrogen of arylamine, hydrazine and heterocyclic amine compounds. The pseudogene NATP displays high sequence identity to NAT1 and NAT2 (79%) but contains multiple frameshift and premature stop codon mutations leading to loss of function [9] Despite their high degree of sequence identity, NAT1 and NAT2 encode isoenzymes with distinct substrate specificities, tissue distribution and expression levels during development. The importance of NAT1 and NAT2 in the metabolism of drugs and in the activation of common environmental carcinogens has led to a plethora of molecular epidemiological studies that have shown associations of NAT gene polymorphisms with individual drug response and susceptibility to cancers linked to arylamine exposure [14,15,16]
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