The Arylamine N-Acetyltransferases as Therapeutic Targets in Metabolic Diseases Associated with Mitochondrial Dysfunction

Abstract

In humans, there are two arylamine N-acetyltransferase genes that encode functional enzymes (NAT1 and NAT2) as well as one pseudogene, all of which are located together on chromosome 8. While they were first identified by their role in the acetylation of drugs and other xenobiotics, recent studies have shown strong associations for both enzymes in a variety of diseases including cancer, cardiovascular disease, and diabetes. There is growing evidence that this association may be causal. Consistently, NAT1 and NAT2 are shown to be required for healthy mitochondria. This review discusses the current literature on the role of both NAT1 and NAT2 in mitochondrial bioenergetics. It will attempt to relate our understanding of the evolution of the two genes with biological function and then present evidence that several major metabolic diseases are influenced by NAT1 and NAT2. Finally, it will discuss current and future approaches to inhibit or enhance NAT1 and NAT2 activity/expression using small molecule drugs. Significance statementThe arylamine N-acetyltransferases, NAT1 and NAT2, share common features in their associations with mitochondrial bioenergetics. Together, they are potential drug targets for diseases where mitochondrial dysfunction is a hallmark of onset and progression.

Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration

“…For example, high NAT1 expression in patients with amyotrophic lateral sclerosis correlates with a hypermetabolic state, which predicts poorer outcomes . Patients with high NAT1 show a significantly shorter survival, suggesting that inhibition of NAT1 may have therapeutic potential. We postulate that Cmp350 may also be useful in diseases where fatty acid oxidation is prevalent since it can switch cell metabolism to a more glucose-dependent phenotype.…”