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J. Biol. Chem., Vol. 277, Issue 14, 12175-12181, April 5, 2002
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From the Department of Pharmacology, University of Oxford,
Mansfield Road, Oxford OX1 3QT, United Kingdom
Arylamine N-acetyltransferases (NATs)
are a homologous family of enzymes, which acetylate arylamines,
arylhydroxylamines, and arylhydrazines by acetyl transfer from
acetyl-coenzyme A (Ac-CoA) and are found in many organisms. NAT was
first identified as the enzyme responsible for the inactivation of the
anti-tubercular drug isoniazid in humans. The three-dimensional
structure of NAT from Salmonella typhimurium has been
resolved and shown to have three distinct domains and an active site
catalytic triad composed of
"Cys69-His107-Asp122," which is
typical of hydrolytic enzymes such as the cysteine proteases. The
crystal unit cell consists of a dimer of tetramers, with the C terminus
of individual monomers juxtaposed. To investigate the function of the
first two domains of full-length NAT from S. typhimurium
and to investigate the role of the C terminus of NAT, truncation
mutants were made with either the C-terminal undecapeptide or the
entire third domain (85 amino acids) missing. Unlike the full-length
NAT protein (281 amino acids), the truncation mutants of NAT from
S. typhimurium are toxic when overexpressed intracellularly in Escherichia coli. Full-length NAT hydrolyses Ac-CoA but
only in the presence of an arylamine substrate. Both truncation
mutants, however, hydrolyze Ac-CoA even in the absence of arylamine
substrate, illustrating that the C-terminal undecapeptide controls
hydrolysis of Ac-CoA by NAT from S. typhimurium.
The COOH Terminus of Arylamine N-Acetyltransferase
from Salmonella typhimurium Controls Enzymic Activity*
,
*
This work was supported by the Wellcome Trust and a Medical
Research Council (United Kingdom) studentship (to A. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Pharmacology,
University of Oxford, Oxford, OX1 3QT, United Kingdom. Tel.:
44-1865-271595; Fax: 44-1865-271853; E-mail:
adeel.mushtaq@pharm.ox.ac.uk.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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