Palmitoylation

Palmitoylation is, after myristoylation, the most common modification of the a-sub-rmit of the heterotrimeric G-proteins (see chapter 5). The a-subunit of G-proteins can be lipidated in a two-fold marmer, with a myristoic acid and a pahnitoic acid anchor at the N-terminus. It appears in this case that two lipid anchors are necessary to mediate a stable association of the protein with the membrane. The lipidation of cytoplasmic protein tyrosine kinase also includes both myristoylation and palmitoylation. H-Ras protein also requires, apart from C-terminal farnesylation (see below), a pahnitoyl modification in order to bind to the plasma membrane. In all mentioned examples the fatty acid anchors play an essential role in the signal transduction. 

Proteins with an isoprenoid modification possess either a C15-famesyl residue or a C20-geranyl-geranyl residue. Both residues are bound via a thioester linkage to a cysteine residue. As with myristoylation, these are constitutive, stable modification performed by farnesyl or geranyl transferases. 

The isoprenylation occurs at the Cys-residue of the consensus sequence Cys-A-A-X-COOH, whereby the nature of the C-terminal X-residue determines if farnesylation or geranylation occurs (fig. 3.13-1-14). After the isoprenoid residue is appended the three C-terminal residues are removed and the new COOH-group of the Cys-residue is methylated to increases the hydrophobicity of the C-terminus. A two-fold geranylation is found on two Cys residues of the Rab protein (see chapter 9). 

The isoprenoid modification can be found, among others, on the Ras protein and other members of the Ras superfamily (see chapter 9), as well as with the a-subunit of G-protein (see chapter 5). The Pycomplex of G-proteins is also associated with the membrane via geranylation. 

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Energetic cost of forming palmitoyl-CoA from palmitate and CoA -2 -61... 

Because this enzyme catalyzes the committed step in fatty acid biosynthesis, it is carefully regulated. Palmitoyl-CoA, the final product of fatty acid biosynthesis, shifts the equilibrium toward the inactive protomers, whereas citrate, an important allosteric activator of this enzyme, shifts the equilibrium toward the active polymeric form of the enzyme. Acetyl-CoA carboxylase shows the kinetic behavior of a Monod-Wyman-Changeux V-system allosteric enzyme (Chapter 15). 

Phosphorylation of ACC Modulates Activation by Citrate and Inhibition by Palmitoyl-CoA... 

The regulatory effects of citrate and palmitoyl-CoA are dependent on the phosphorylation state of acetyl-CoA carboxylase. The animal enzyme is phosphorylated at 8 to 10 sites on each enzyme subunit (Figure 25.4). Some of these sites are reg-... 

In the end, seven malonyl-CoA molecules and one acetyl-CoA yield a palmi-tate (shown here as palmitoyl-CoA) ... 

FIGURE 25.20 Triacylglycerols are formed primarily by the action of acyltransferases on mono- and diacylglycerol. Acyltransferase in E. coli is an integral membrane protein (83 kD) and can utilize either fatty acyl-CoAs or acylated acyl carrier proteins as substrates. It shows a particular preference for palmitoyl groups. Eukaryotic acyltransferases nse only fatty acyl-CoA molecnles as substrates. 

FIGURE 25.25 Biosynthesis of sphingolipids in animals begins with the 3-ketosphinga-nine synthase reaction, a PLP-dependent condensation of palmitoyl-CoA and serine. Subsequent rednction of the keto group, acylation, and desatnration (via rednction of an electron acceptor, X) form ceramide, the precnrsor of other sphingolipids. 

Carefully count and account for each of the atoms and charges in the equations for the synthesis of palmitoyl-CoA, the synthesis of malonyl-CoA, and the overall reaction for the synthesis of palmi-toyl-CoA from acetyl-CoA. 

The net effect of the eight steps in the fattv-acid biosynthesis pathway is to take two 2-carbon acetyl groups and combine them into a 4-carbon butyryl group. Further condensation of the butyryl group with another malonyl AGP yields a 6-carbon unit, and still further repetitions of the pathway add two more carbon atoms to the chain each time until the 16-carbon palmitoyl ACP is reached. 

Protein Trafficking and Quality Control Intracellular Transport Palmitoylation Endothelins... 

Glycosydphosphatidylinositolation The GlycoPho-sphatidyl Inositol moiety anchor of AChE consists exclusively of diacyl molecular species. Over 85% of the molecular species are composed of palmitoyl, stearoyl and oleoyl. The post-translational process of glypiation takes place in the endoplasmic reticulum, after completion of the polypeptide chain the newly synthesized protein interacts with a transamidase... 

Fyn is a nonreceptor tyrosine kinase related to Src that is frequently found in cell junctions. Die protein is N-myristoylated and palmitoylated and thereby becomes associated with caveolae-like membrane microdomains. Fyn can interact with a variety of other signaling molecules and control a diversity of biological processes such as T cell receptor signaling, regulation of brain function, and adhesion mediated signaling. 

Lipidation -acylation TV -myristoylation Myristoy-lation S-prenylation Prenylation Palmitoylation Isoprenylation GPI anchors Glypiation... 

S-acyl (S-palmitoyl) 0 ii /WV VWVN S-Cys Cysteine, no defined consensus... 

Linder ME, Deschenes RJ (2007) Palmitoylation policing protein stability and traffic. Nat Rev Mol Cell Biol 8 74—84... 

Palmitoylation is the post-translational lipid modification of cysteine-residues in a variety of proteins. 

Many GPCRs contain one or more conserved cysteine residues within their C-terminal tails, which are modified by covalent attachment of palmitoyl or isoprenyl residues. The palmitoyl moiety is anchored in the lipid bilayer forming a fourth intracellular loop. There is evidence that palmitoylation of a GPCR is a dynamic process and may affect receptor desensitization. 

Pain and Nociception Pain Medication Palmitoylation PAMPs... 

Long-chain fatty acids (e.g., palmitate Cig) diffuse through pores in the outer mitochondrial membrane, and then form long-chain acyl-CoA esters catalyzed reversibly by palmitoyl-CoA synthase (assumed to be on the inner face of the outer membrane). 

The steps in the subsequent utilization of muscle LCFAs may be summarized as follows. The free fatty acids, liberated from triglycerides by a neutral triglyceride lipase, are activated to form acyl CoAs by the mediation of LCFAcyl-CoA synthetase which is situated on the outer mitochondrial membrane. The next step involves carnitine palmitoyl transferase I (CPT I, see Figure 9) which is also located on the outer mitochondrial membrane and catalyzes the transfer of LCFAcyl residues from CoA to carnitine (y-trimethyl-amino-P-hydroxybutyrate). LCFAcyl... 

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