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Myristoylated Peptides.

Myristoylated Peptides
 
N-myristoylation is a post translational modification that attaches a 14-carbon fatty acid to the N-terminal glycine residue of target proteins and peptides. However, its role in targeting proteins to specific subcellular compartments has not been clearly defined. The modification reaction is catalyzed by the enzyme N-myristoyl-transferase which is a ubiquitous and essential enzyme present in eukaryotes.

The modification of a protein N-Terminus with a myristoyl group [a (cis,cis-delta 5, delta 8)-tetradecadienoyl group =  myristoylation with 2 double bonds] adds an average mass of 206 dalton, and the myristoleylation (= myristoyl with one double bond) adds a mass of 208 daltons to the target protein.

Many target proteins of N-myristoyl-transferase are crucial components of cell signaling pathways and studies on a variety of N-myristoylated proteins suggest that myristic acid may have different roles when attached to different acceptor proteins. Myristoylation typically promotes membrane binding that is essential for proper protein localization or biological function during cell signaling. Since N-myristoyl-transferase adds the myristoyl group as a post translational modification to targeted proteins or peptides it is a validated therapeutic target in opportunistic infections of humans caused by fungi or parasitic protozoa.

N-myristoyl-transferase has also been implicated in carcinogenesis, particularly in colon cancer. Apparently the enzyme is involved in cell signaling and there is evidence for its upregulation in the early stages of tumor formation. Furthermore, an N-myristoylated 5-mer peptide derived from the simian immunodeficiency virus Nef protein specifically recognizes T cells that were isolated from a rhesus macaque cytotoxic T cell line.

Figure 1: Structural models of HIV-1 Nef anchor domain.

On a brighter side, myristoylated peptides are used in cosmetic creams to tread wrinkles and to increase the length of eyelashes. The myristoyl pentapeptide-17 is a keratin stimulating peptide that has been shown to visibly increase eyelash length by 25 percent when used together with the myristoyl hexapeptide-16. Myristoylation has been studied as a means to transport peptides into living cells. For this purpose synthetic myristoylated peptides can be labeled with fluorophores during solid phase peptide synthesis. The uptake of these fluorescently tagged peptides by the investigated cells can be monitored using confocal or fluorescence microscopy based image analysis. Recently, the combination of live cell imaging analyses with proteomics and biochemical approaches allowed the identification of substrates of N-myristoyl-transferase 1 that control secretion and integrity of the endoplasmic reticulum and the Golgi.

Reference

Geyer M, Munte CE, Schorr J, Kellner R, Kalbitzer HR.; Structure of the anchor-domain of myristoylated and non-myristoylated HIV-1 Nef protein. J Mol Biol. 1999 May 28;289(1):123-38.


N-Myristoylation
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