3D model of human arylamine N-acetyltransferase 2: structural basis of the slow acetylator phenotype of the R64Q variant and analysis of the active-site loop.

Abstract:

:The human arylamine N-acetyltransferase NAT2 is responsible for the biotransformation of numerous arylamine drugs and carcinogens. A common polymorphism of the NAT2 gene has been associated with susceptibility to drug toxicity and various malignancies. In this study, we used the crystal structure of the Salmonella typhimurium NAT (StNAT) to construct a high-quality model of a catalytic N-terminal region of NAT2 (residues 34-131). We show that this region has a similar structure in StNAT and the human isoforms NAT1 and NAT2. Comparison of the structures of these three molecules suggests that NATs have an active-site loop with a conserved structure, which is involved in substrate recognition. Our model is consistent with previous experimental data and provides the first plausible structural basis of the effects of a common genetic polymorphism (Arg(64)-->Gln) on NAT2 activity.

authors

Rodrigues-Lima F,Dupret JM

doi

10.1006/bbrc.2002.6414

subject

Has Abstract

pub_date

2002-02-15 00:00:00

pages

116-23

issue

1

eissn

0006-291X

issn

1090-2104

pii

S0006291X02964144

journal_volume

291

pub_type

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