Covalent modification of proteins is a more recently discovered role of fatty acids. Fatty acylation of proteins frequently serves as a means of targeting or anchoring a protein to a membrane. Myristoyla-tion, the addition of 14:0 to a protein, occurs at N-terminal glycine residues after removal of the initiator methionine. This process is generally co-translational and irreversible. N-myristoyl proteins include many signal-transduction-associated proteins, e.g., src and ADP-ribosylation factors. The enzyme N-myristoyltransferase catalyzes the reaction and uses 14:0-CoA as substrate.
Palmitoylation, the addition of 16:0 to a protein, is also commonly observed. This modification to the sulfydryl side chain of cysteine residues occurs post-translationally and is reversible. Both membrane-associated proteins and integral membrane proteins can be palmitoylated; examples are ion channels, neurotransmitter receptors, and sonic hedgehog. Protein palmitoyl transferases also use the CoA derivative of the fatty acid as a substrate. Several proteins are modified with both an N-terminal 14:0 and an S-linked 16:0 elsewhere in the protein chain. a-subunits of heterotrimeric G-proteins and endothelial nitric oxide synthase are examples of dually acylated proteins.
There are instances of acylation by fatty acids with chain lengths other than 14 or 16 carbon atoms. One nutritionally important example is the recently identified orexigenic peptide ghrelin. The active form of this 28-amino-acid peptide hormone has the medium-chain fatty acid 8:0 covalently ester-ified to the hydroxyl group of serine-3. Octanoy-lated ghrelin is believed to act at the level of the hypothalamus to stimulate appetite, perhaps via neuropeptide Y.
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