Palmitoyl-functionalized

Because of some aggregation (H aggregation) of the azobenzene chromophores, the collapse pressure increased with higher azobenzene/palmitoyl ratios. However, only the palmitoyl functionalized dendrimer exhibited a change in surface area upon irradiation with 365-nm light. The lack of photoinduced surface area changes... 

Figure 11.44 (Left) Structures of photoresponsive poly (propylene imine) dendrimers. (Right) The isomerization behavior of palmitoyl-functionalized amphiphilic dendrimers at the water surface.

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. 

Uchegbu and coworkers have studied the complexation and delivery of DNA using a unique poly(amino acid)-based polymer vesicle. A polymer of either poly (L-lysine) or poly(L-omithine) was functionalized with methoxy-poly(ethylene glycol) (mPEG) and hydrophobic palmitic acid chains to synthesize an amphiphilic triblock of either mPEG-6-poly(L-lysine)-6-palmitoyl or mPEG-Z>-poly(L-omithine)-6-palmitoyl. Vesicles formed from these polymers were complexed with DNA and showed improved transfection in vitro over poly(amino acid) complexed with DNA or DNA alone [82]. 

Post-translational modification of proteins plays a critical role in cellular function. For, example protein phosphorylation events control the majority of the signal transduction pathways in eukaryotic cells. Therefore, an important goal of proteomics is the identification of post-translational modifications. Proteins can undergo a wide range of post-translational modifications such as phosphorylation, glycosylation, sulphonation, palmitoylation and ADP-ribosylation. These modifications can play an essential role in the function of the protein and mass spectrometry has been used to characterize such modifications. 

In the x-ray structure of rhodopsin, an amphipathic helix runs parallel to the membrane from the intracellular end of TM-VII beneath the seven-helical bundle to the other side of TM-I and TM-II. At this point, one or more Cys residues are often found and are known to be subject to a dynamic posttranslational modification with palmitic acid residues. Like the phosphorylation event, the palmitoylation process appears to be dynamically regulated by receptor occupancy and is also involved in the desensitization phenomenon. The two posttranslational modifications can influence each other. For example, the conformational constraint induced by palmitoylation may alter the accessibility of certain phosphorylation sites. Like the phosphorylation process, the functional consequences of palmitoylation also appear to vary from receptor to receptor. 

Weener et al. prepared photo-responsive monolayers from azobenzene modified polypropylene imine) dendrimers which also hold promise in the area of optical data storage [74], A fifth generation polypropylene imine) dendrimer was functionalized with equal amounts of palmitoyl and azobenzene containing alkyl chains, resulting in the formation of an amphiphilic copolymer with a random shell structure (Figure 16.5). 

The distinguishing structural and functional protein for caveolae is caveolin. Caveolin proteins display properties that are likely involved in the distinguishing morphology of caveolae. Caveolins have a high affinity for both cholesterol and sphingolipids coupled with 3 carboxy-terminal palmitoylated cysteine residues. Three isoforms of caveolin exist and show distinct tissue distribution. Likely because it was discovered first and is perhaps most abundant, caveolin-1 has garnered the lion s share of research attention. 

Acylation is used by the cell for diverse purposes, the most common being membrane association. The membrane affinity of soluble proteins is increased via acylation, which affects the localization and function of proteins. This is found for singly and dually lipidated proteins. The localization of doubly lipidated proteins is determined by dynamic palmitoylation and depalmitoylation. Palmitoylation is therefore a tool for regulating protein trafficking in the cell. The most prominent examples are the small Ras GTPases. 

The second family of secreted proteins that is covalently lipidated is the family of Wnt proteins. They are also involved in numerous processes like proliferation of stem cells, specification of the neural crest, and the expanding of specific cell types. The correct regulation of this pathway is important for animal development. Willert and coworkers were the first to isolate an active Wnt molecule. Mass spectroscopy studies carried out with the isolated protein revealed that cysteine 93 is palmitoylated. Mutating this amino acid to alanine led to almost complete loss of the signaling activity. Later in 2006, a second lipidation was found on a serine in Wnt3a. " In this case, the hydroxyl side chain is acylated with palmitoleic acid. This unsaturated fatty acid seems to be crucial for the progression of the protein through the secretory pathway. The attachment of two different lipid chains may therefore serve different functions. ... 

Scheme 15 Synthesis of the doubly palmitoylated heptapeptide corresponding to the C-terminus of hemagglutinin A bearing an N-terminal NBD function using Boc, Aloe, and the allyl ester as protecting groups.

Scheme 25 Assembly and cleavage of a NBD-functionalized, palmitoylated, and farnesylated peptide on the hydrazine linker.

As discussed for N-myristoylation and S-prenylation, even S-acylation of proteins with a fatty acid which in the vast majority of cases is the C16 0 palmitic acid, plays a fundamental role in the cellular signal-transduction process (Table l). 2-5 14 While N-myristoylation and S-prenylation are permanent protein modifications due to the amide- and sulfide-type linkage, the thioester bond between palmitic acid and the peptide chain is rather labile and palmi-toylation is referred to as a dynamic modification. 64 This reversibility plays a crucial role in the modulation of protein functions since the presence or absence of a palmitoyl chain can determine the membrane localization of the protein and can also be used to regulate the interactions of these proteins with other proteins. Furthermore, a unique consensus sequence for protein palmitoylation has not been found, in contrast to the strict consensus sequences required for N-myristoylation and S-prenylation. Palmitoylation can occur at N- or C-terminal parts of the polypeptide chain depending on the protein family and often coexists with other types of lipidation (see Section 6.4.1.4). Given the diversity of protein sequences... 

To prevent the S—>N acyl shift, S-palmitoylation with palmitoyl chloride is performed in anhydrous solvents on N -aminoacylated cysteines, e.g. dipeptide building blocks, whereby the residual functionalities of the peptide have to be protected taking into account the base-lability of the thioester bond. 

FIGURE 21-31 Biosynthesis of sphingolipids. Condensation of palmitoyl-CoA and serine followed by reduction with NADPH yields sphinganine, which is then acylated to N-acylsphinganine (a ceramide). In animals, a double bond (shaded pink) is created by a mixed-function oxidase, before the final addition of a head group phosphatidylcholine, to form sphingomyelin glucose, to form a cerebroside. 

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