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Title: Molecular Basis for the Inhibition of Human NMPRTase, a Novel Target for Anticancer Agents

Abstract

Nicotinamide phosphoribosyltransferase (NMPRTase) has a crucial role in the salvage pathway of NAD{sup +} biosynthesis, and a potent inhibitor of NMPRTase, FK866, can reduce cellular NAD+ levels and induce apoptosis in tumors. We have determined the crystal structures at up to 2.1-Angstroms resolution of human and murine NMPRTase, alone and in complex with the reaction product nicotinamide mononucleotide or the inhibitor FK866. The structures suggest that Asp219 is a determinant of substrate specificity of NMPRTase, which is confirmed by our mutagenesis studies. FK866 is bound in a tunnel at the interface of the NMPRTase dimer, and mutations in this binding site can abolish the inhibition by FK866. Contrary to current knowledge, the structures show that FK866 should compete directly with the nicotinamide substrate. Our structural and biochemical studies provide a starting point for the development of new anticancer agents.

Authors:
; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
914019
Report Number(s):
BNL-78587-2007-JA
TRN: US0801478
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nat. Struct. Mol. Biol.; Journal Volume: 13; Journal Issue: 7
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; 43 PARTICLE ACCELERATORS; APOPTOSIS; BIOSYNTHESIS; CRYSTAL STRUCTURE; MUTAGENESIS; MUTATIONS; NEOPLASMS; NICOTINAMIDE; RESOLUTION; SPECIFICITY; SUBSTRATES; TARGETS; DIMERS; NSLS; national synchrotron light source

Citation Formats

Khan,J., Tao, X., and Tong, L.. Molecular Basis for the Inhibition of Human NMPRTase, a Novel Target for Anticancer Agents. United States: N. p., 2006. Web. doi:10.1038/nsmb1105.
Khan,J., Tao, X., & Tong, L.. Molecular Basis for the Inhibition of Human NMPRTase, a Novel Target for Anticancer Agents. United States. doi:10.1038/nsmb1105.
Khan,J., Tao, X., and Tong, L.. Sun . "Molecular Basis for the Inhibition of Human NMPRTase, a Novel Target for Anticancer Agents". United States. doi:10.1038/nsmb1105.
@article{osti_914019,
title = {Molecular Basis for the Inhibition of Human NMPRTase, a Novel Target for Anticancer Agents},
author = {Khan,J. and Tao, X. and Tong, L.},
abstractNote = {Nicotinamide phosphoribosyltransferase (NMPRTase) has a crucial role in the salvage pathway of NAD{sup +} biosynthesis, and a potent inhibitor of NMPRTase, FK866, can reduce cellular NAD+ levels and induce apoptosis in tumors. We have determined the crystal structures at up to 2.1-Angstroms resolution of human and murine NMPRTase, alone and in complex with the reaction product nicotinamide mononucleotide or the inhibitor FK866. The structures suggest that Asp219 is a determinant of substrate specificity of NMPRTase, which is confirmed by our mutagenesis studies. FK866 is bound in a tunnel at the interface of the NMPRTase dimer, and mutations in this binding site can abolish the inhibition by FK866. Contrary to current knowledge, the structures show that FK866 should compete directly with the nicotinamide substrate. Our structural and biochemical studies provide a starting point for the development of new anticancer agents.},
doi = {10.1038/nsmb1105},
journal = {Nat. Struct. Mol. Biol.},
number = 7,
volume = 13,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 2006},
month = {Sun Jan 01 00:00:00 EST 2006}
}