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Abstract
Myristoyl-CoA:protein N-myristoyltransferase (NMT) catalyzes the covalent attachment of myristic acid to the NH2-terminal Gly residues of a number of viral and cellular proteins. The remarkable specificity of this enzyme for myristoyl CoA observed in vivo appears to arise in large part from a cooperativity between NMT's acylCoA and peptide binding sites: the length of the acylCoA bound to NMT influences the interactions of peptide substrates with NMT. We have previously synthesized analogs of myristic acid with single oxygen or sulfur for methylene substitutions. These heteroatom substitutions produce significant reductions in acyl chain hydrophobicity without accompanying alterations in chain length or stereochemical restrictions. In vitro studies have shown that the CoA thioesters of these analogs are substrates for S. cerevisiae NMT and that the efficiency of their transfer to octapeptide substrates is peptide sequence-dependent. In vivo studies with cultured mammalian cells have confirmed that these fatty acid analogs are selectively incorporated into a subset of cellular N-myristoylproteins, that only a subset of analog-substituted proteins undergo redistribution from membrane to cytosolic fractions, and that these analogs can inhibit the replication of human immunodeficiency virus I and Moloney murine leukemia viruses--two retroviruses that depend upon N-myristoylation of their gag polyprotein precursors for assembly. We have now extended our analysis of NMT-acylCoA interactions by synthesizing additional analogs of myristic acid and testing them in a coupled in vitro assay system. Myristic acid analogs with two oxygen or two sulfur substitutions have hydrophobicities comparable to that of hexanoic acid and decanoic acid, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Highlights
Myristoyl-CoA:pmtein N-myristoyltransferase (NMT) catalyzes the covalent attachment of myristic acid to the NH2terminal Gly residues of a number of viral and cellular proteins
We have recently demonstrated that replication of human immunodeficiency virus-I (HIV-I) and the Moloney murine leukemia virus (MoMLV) can be inhibited by heteroatom-containing analogs of myristic acid without accompanying cellular toxicity [28]
The first had to do with the hydrophobic/hydrophilic requirements of NMT’s acyl CoA binding site
Summary
Pseudomonas CoA ligase (acyl coenzyme A synthetase, E.C. 6.2.1.3)was purchased from Sigma (St. Louis, MO). N M T was partially purified ( - 150-fold)from S. cerevisiue strain BJ405 [33] by ammonium sulfate precipitation, and DEAE Sepharose CLGB and agarose GOAchromatography [16]. Isomyristic acid and anteisopentadecanoic acid were kindly supplied by David Silbert (Washington University)
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