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J. Biol. Chem., Vol. 269, Issue 49, 30888-30892, Dec, 1994
SM Peseckis and MD Resh
N-Myristyl transferase (Nmt) catalyzes attachment of myristate onto the N
terminus of suitable proteins. In order to identify amino acids important
for catalytic functions, human Nmt and mutants representing all six
conserved cysteine and histidine residues (Cys-169, Cys-214, His-131,
His-171, His-218, and His-293) were expressed in Escherichia coli and
analyzed for their ability to bind and transfer myristic acid. N-Terminal
histidine-tagged fusion proteins displayed varying abilities to form an
association with radiolabeled myristic acid indicative of an acyl-enzyme
intermediate. When co-expressed with an acceptor substrate protein,
pp60v-src, the mutants showed differential incorporation of radiolabeled
myristic acid into v-Src protein. In vitro experiments monitoring transfer
of myristyl CoA to a peptide homologous to the N terminus of pp60 v-src
gave results similar to those obtained in vivo. Our studies showed that
mutation at Cys-169, His-171, and especially His-293 interfered with
formation of an acyl-enzyme intermediate, while human Nmts containing
mutations at Cys-169, His-218, or His-293 showed greatly attenuated
abilities to form acylated product. We propose a model for the Nmt reaction
mechanism in which Cys-169 serves as the fatty acid attachment site for a
covalent myristyl enzyme intermediate, while His-171 acts as a general
acid/base and His-293 as a specific acid/base during acyl-enzyme
intermediate formation. His-218 could then act as an acid or base needed to
catalyze transfer of the acyl group from the acyl-enzyme intermediate to a
polypeptide substrate. This working model will be useful for the design of
regulators of Nmt function.
Fatty acyl transfer by human N-myristyl transferase is dependent upon conserved cysteine and histidine residues
Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
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