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Title: Structural Basis of Substrate-Binding Specificity of Human Arylamine N-acetyltransferases

Abstract

The human arylamine N-acetyltransferases NAT1 and NAT2 play an important role in the biotransformation of a plethora of aromatic amine and hydrazine drugs. They are also able to participate in the bioactivation of several known carcinogens. Each of these enzymes is genetically variable in human populations, and polymorphisms in NAT genes have been associated with various cancers. Here we have solved the high resolution crystal structures of human NAT1 and NAT2, including NAT1 in complex with the irreversible inhibitor 2-bromoacetanilide, a NAT1 active site mutant, and NAT2 in complex with CoA, and have refined them to 1.7-, 1.8-, and 1.9- Angstroms resolution, respectively. The crystal structures reveal novel structural features unique to human NATs and provide insights into the structural basis of the substrate specificity and genetic polymorphism of these enzymes.

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959567
Report Number(s):
BNL-82553-2009-JA
Journal ID: ISSN 0021-9258; JBCHA3; TRN: US201016%%711
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Biological Chemistry; Journal Volume: 282; Journal Issue: 41
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; AMINES; AROMATICS; CARCINOGENS; CRYSTAL STRUCTURE; ENZYMES; GENES; GENETICS; HUMAN POPULATIONS; HYDRAZINE; RESOLUTION; SPECIFICITY; SUBSTRATES; national synchrotron light source

Citation Formats

Wu,H., Dombrovsky, L., Tempel, W., Martin, F., Loppnau, P., Goodfellow, G., Grant, D., and Plotnikov, A. Structural Basis of Substrate-Binding Specificity of Human Arylamine N-acetyltransferases. United States: N. p., 2007. Web. doi:10.1074/jbc.M704138200.
Wu,H., Dombrovsky, L., Tempel, W., Martin, F., Loppnau, P., Goodfellow, G., Grant, D., & Plotnikov, A. Structural Basis of Substrate-Binding Specificity of Human Arylamine N-acetyltransferases. United States. doi:10.1074/jbc.M704138200.
Wu,H., Dombrovsky, L., Tempel, W., Martin, F., Loppnau, P., Goodfellow, G., Grant, D., and Plotnikov, A. Mon . "Structural Basis of Substrate-Binding Specificity of Human Arylamine N-acetyltransferases". United States. doi:10.1074/jbc.M704138200.
@article{osti_959567,
title = {Structural Basis of Substrate-Binding Specificity of Human Arylamine N-acetyltransferases},
author = {Wu,H. and Dombrovsky, L. and Tempel, W. and Martin, F. and Loppnau, P. and Goodfellow, G. and Grant, D. and Plotnikov, A.},
abstractNote = {The human arylamine N-acetyltransferases NAT1 and NAT2 play an important role in the biotransformation of a plethora of aromatic amine and hydrazine drugs. They are also able to participate in the bioactivation of several known carcinogens. Each of these enzymes is genetically variable in human populations, and polymorphisms in NAT genes have been associated with various cancers. Here we have solved the high resolution crystal structures of human NAT1 and NAT2, including NAT1 in complex with the irreversible inhibitor 2-bromoacetanilide, a NAT1 active site mutant, and NAT2 in complex with CoA, and have refined them to 1.7-, 1.8-, and 1.9- Angstroms resolution, respectively. The crystal structures reveal novel structural features unique to human NATs and provide insights into the structural basis of the substrate specificity and genetic polymorphism of these enzymes.},
doi = {10.1074/jbc.M704138200},
journal = {Journal of Biological Chemistry},
number = 41,
volume = 282,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}