Identification of a novel allele at the human NAT1 acetyltransferase locus

Abstract

Humans possess two N-acetyltransferase isozymes (NAT1 and NAT2). We cloned and sequenced a novel NAT1 allele (Genbank HSU 80835) that contained nucleotide substitutions at -344 (C→T), -40 (A→T), 445 [G→A(Val→Ile)], 459 [G→A(silent)], 640 [T→G(Ser→Ala)], a 9 base pair deletion between nucleotides 1065 and 1090, and 1095 (C→A). The novel NAT1 allele which we have designated NAT1*17 is similar to NAT1*11 except for a G445A substitution (Val149→Ile) in the NAT1 coding region. The G445A (Val149→Ile) substitution yielded no significant changes in levels of immunoreactivity, as detected by Western blot, nor in intrinsic stability of the recombinant N-acetyltransferase protein. However, the G445A (Val149→Ile) substitution yielded expression of recombinant NAT1 protein that catalyzed the N-acetylation of aromatic amines and the O- and N,O-acetylation of their N-hydroxylated metabolites at rates up to 2-fold higher than wild-type recombinant human NAT1.