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The structure of myristoyl-CoA : protein N-myristoyltransferase

Bhatnagar, RS; Futterer, K; Waksman, G; Gordon, JI; (1999) The structure of myristoyl-CoA : protein N-myristoyltransferase. BBA-MOL CELL BIOL L , 1441 (2-3) 162 - 172.

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Abstract

Protein N-myristoylation is a covalent modification that occurs co-translationally in eukaryotes. Myristate, a rare 14 carbon saturated fatty acid (C14:0), is attached, via an amide linkage, to the N-terminal glycine of a subset of eukaryotic and viral proteins by myristoyl-CoA:protein N-myristoyltransferase (Nmt). Genetic and biochemical studies have established that Nmt is a target for development of a new class of fungicidal drugs. The enzyme is also a potential target for development of antiviral and antineoplastic agents. The structure of Saccharomyces cerevisiae Nmt1p has been determined recently with bound substrate analogs. The Nmt fold resembles the fold of members of the GCN5-related N-acetyltransferase superfamily. The structure reveals how Nmt's myristoyl-CoA and peptide substrates are recognized and bound, and what elements control the enzyme's ordered kinetic mechanism. Acyl transfer occurs through the nucleophilic addition-elimination reaction: an oxyanion hole formed by main chain atoms polarizes the thioester carbonyl and stabilizes the transition state while deprotonation of the ammonium of the Gly acceptor appears to be mediated by Nmt's C-terminal carboxylate. The use of main chain carboxylate atoms as general base catalyst is a novel feature. (C) 1999 Elsevier Science B.V. All rights reserved.

Type: Article
Title: The structure of myristoyl-CoA : protein N-myristoyltransferase
Keywords: protein N-myristoylation, acyltransferase, GCN5, acyl CoA recognition, enzyme mechanism, oxyanion hole, CRYSTAL-STRUCTURE, INHIBITORS, ACETYLTRANSFERASE, POTENT, SWITCH
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/97121
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