Regulatory Role of Free Fatty Acids (FFAs)—Palmitoylation and Myristoylation

Abstract

Multicellular organisms use chemical messengers to\rtransmit signals among organelles and to other cells. Relatively small hydrophobic molecules such as lipids\rare excellent candidates for this signaling purpose. In most proteins, palmitic\racid and other saturated and some unsaturated fatty acids are esterified to the\rfree thiol of cysteines and to the N-amide terminal. This palmitoylation\rprocess enhances the surface hydrophobicity and membrane affinity of protein\rsubstrates and plays important roles in modulating proteins’ trafficking, stability, and sorting\retc. Protein palmitoylation has been involved in numerous cellular processes,\rincluding signaling, apoptosis, and neuronal transmission. The palmitoylation\rprocess is involved in multiple diseases such as Huntington’s disease, various\rcardiovascular and T-cell mediated immune disorders, as well as cancer. Protein\rpalmitoylation through the thioester (S-acylation) is unique in that it is the only\rreversible lipid modification. Our study on lipopolysaccharide (LPS) and\rdeoxynivalenol (DON) treatment to rats provides some insights to the complex role of protein palmitoylation in\rchemical and microbial toxicity. In contrast, myrisoylated proteins\rcontain the 14-carbon fatty acid myristate attached via amide linkage to the\rN-terminal glycine residue of protein, and occur cotranslationally. The\rbacterial outer membrane enzyme lipid A palmitoyltransferase (PagP) confers\rresistance to host immune defenses by transferring a palmitate chain from a\rphospholipid to the lipid A component of LPS. PagP is sensitive to cationic\rantimicrobial peptides (CAMP) which are included among the products of the\rToll-like receptor 4 (TLR4) signal transduction pathway. This modification of\rlipid A with a palmitate appears to both and protects the pathogenic bacteria\rfrom host immune defenses and attenuates the activation of those same defenses\rthrough the TLR4 signal transduction pathway.