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J. Biol. Chem., Vol. 266, Issue 14, 8835-8855, 05, 1991
NS Kishore, TB Lu, LJ Knoll, A Katoh, DA Rudnick, PP Mehta, B Devadas, M Huhn, JL Atwood and SP Adams
We have explored the acyl-CoA substrate specificity of Saccharomyces
cerevisiae myristoyl-CoA:protein N-myristoyltransferase (NMT) by
synthesizing 81 fatty acid analogs and surveying their activity in a
coupled in vitro assay containing Pseudomonas acyl-CoA synthetase and
Escherichia coli-derived yeast NMT. Single oxygen or sulfur substitution
for C-3 through C-13 is well tolerated by both enzymes. Detailed kinetic
analyses suggest that the acyl-CoA and peptide-binding sites of NMT are
relatively insensitive to placement of single group 6B heteroatoms. By
contrast, di-oxygen-substituted analogs were very poor substrates,
producing dramatic reductions in the affinity of NMTs peptide-binding site
for a synthetic octapeptide substrate derived from the NH2-terminal
sequence of a known N-myristoylprotein, the gag poly- protein precursor of
human immunodeficiency virus 1 (HIV-1). This observation provides an
example of binding site cooperativity in NMT. Replacement of one oxygen
with sulfur at either the 6, 9, or 12 position of dioxatetradecanoic acids
results in a general increase in peptide catalytic efficiency (Vmax/Km). An
analysis of five fatty acids from octanoic to dodecanoic having terminal
phenyl groups indicated that the best substrate was 10-phenyldecanoic acid
even though Corey- Pauling-Koltun molecular models indicate that it has a
length equivalent to that of tridecanoic acid. Six analogs having an
equivalent length of 13 carbon atoms were subsequently prepared in which
the phenyl group was systematically moved one methylene group closer to
carboxyl. Movement of the phenyl just one carbon closer to carboxyl
(producing 9-(p-methylphenyl) nonanoic acid) decreases peptide catalytic
efficiency (Vmax/Km) severalfold compared to 10- phenyldecanoic acid.
10-(4-Tolyl)decanoic acid has the same relative positions of phenyl and
carboxyl as 10-phenyldecanoic acid even though a methyl group is present on
the phenyl ring. It produces peptide Km and Vmax values that are the same
as 10-phenyldecanoic acid. Substitution of either oxygen or sulfur for a
methylene group fails to override the effects noted when the phenyl group
position is altered in the C-14 equivalent fatty acid series. Several fatty
acids of differing chain lengths with cyclohexyl-, 2-furyl, and 2-thienyl
groups at their omega termnius had activity profiles that paralleled those
of the comparable phenyl-substituted compounds. Myristic acid analogs with
triple bonds (beginning at positions 2 through 13), cis-double bonds
(positions 3 through 13) and trans-double bond isomers (E5, E6, and E7)
were also tested.(ABSTRACT TRUNCATED AT 400 WORDS)
The substrate specificity of Saccharomyces cerevisiae myristoyl- CoA:protein N-myristoyltransferase. Analysis of myristic acid analogs containing oxygen, sulfur, double bonds, triple bonds, and/or an aromatic residue
Monsanto Company, St. Louis, Missouri 63198.
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