Protein Modifications | Protein N-Myristoylation

Protein N-myristoylation refers to the covalent attachment of myristic acid, a 14-carbon saturated fatty acid (C14:0), to the N-terminal glycine of proteins. Linkage occurs via an amide bond and takes place as proteins are being synthesized. N-myristoylproteins have varied intracellular destinations and are involved in myriad cellular functions ranging from signal transduction to protein and vesicular trafficking. N-myristoylproteins are encountered in members of all kingdoms of the eukaryotic domain (Protist, Fungi, Plant, and Animal), but are not produced by members of Bacteria or Archaea. MyristoylCoA: protein N-myristoyltransferase (Nmt), E.C. 2.3.1.97, a member of the GCN5 acetyltransferase (GNAT) superfamily, is responsible for catalyzing the transfer of myristate from myristoylCoA to proteins. While the acylCoA substrate specificity of Nmt has been highly conserved during evolution, its peptide substrate specificities have diverged among eukaryotes. Protein N-myristoylation has relevance to a number of diseases. Genetic and pharmacologic studies have shown that Nmt activity is essential for the survival of a number of fungi that cause systemic infections in immunocompromised humans. These organisms include Candida albicans and Cryptococcus neoformans . Protein N-myristoylation is also critical to the life cycle of viruses, such as human immunodeficiency virus-1. Nmt levels are elevated in human gastrointestinal tract malignancies. Other pathogens, including Plasmodium falciparum , the parasite that causes malaria, have Nmts. Therefore, understanding the contributions of myristate to protein function, elucidating the structural basis for the divergent protein substrate specificities of orthologous Nmts, characterizing the myristoyl transfer reaction, and identifying biologically active, species-selective Nmt inhibitors may provide new therapeutic strategies and agents.