Mechanisms of protein and peptide

Proteins, peptides, and other polymeric macromolecules display varying degrees of chemical and physical stability. The degree of stability of these macromolecules influence the way they are manufactured, distributed, and administered. Chemical stability refers to how readily the molecule can undergo chemical reactions that modify specific amino-acid residues, the building blocks of the proteins and peptides. Chemical instability mechanisms of proteins and peptides include hydrolysis, deamidation, racemization, beta-elimination, disulfide exchange, and oxidation. Physical stability refers to how readily the molecule loses its tertiary and/or sec-... 

The cellular architecture associated with each non-invasive route of administration represents a formidable physical barrier to effective absorption into systemic circulation, and the large molecular weights and relatively hydrophilic nature of proteins and peptides does not favor effective permeation. The mechanism of protein and peptide absorption has been extensively studied however, exact details about the process remain poorly understood. A general but somewhat... 

Molecular mechanism of protein- and peptide-induced membrane fusion... 

The amide functionality plays an important role in the physical and chemical properties of proteins and peptides, especially in their ability to be involved in the photoinduced electron transfer process. Polyamides and proteins are known to take part in the biological electron transport mechanism for oxidation-reduction and photosynthesis processes. Therefore studies of the photochemistry of proteins or peptides are very important. Irradiation (at 254 nm) of the simplest dipeptide, glycylglycine, in aqueous solution affords carbon dioxide, ammonia and acetamide in relatively high yields and quantum yield (0.44)202 (equation 147). The reaction mechanism is thought to involve an electron transfer process. The isolation of intermediates such as IV-hydroxymethylacetamide and 7V-glycylglycyl-methyl acetamide confirmed the electron-transfer initiated free radical processes203 (equation 148). 

The third mechanism is peritubular extraction of peptides and proteins from postglomerular capillaries and intracellular metabolism. Experiments using iodi-nated growth hormone (125I-rGH) have demonstrated that, while reabsorption into endocytic vesicles at the proximal tubule is still the dominant route of disposition, a small percentage of the hormone may be extracted from the peritubular capillaries [79, 86]. Peritubular transport of proteins and peptides from the baso-lateral membrane has also been shown for insulin [87] and the mycotoxin ochra-toxin A [88]. 

In Nature, there are many examples of protein and peptide molecular self-assembly. Of the genetically engineered fibrous proteins, collagen, spider silks, and elastin have received attention due to their mechanical and biological properties which can be used for biomaterials and tissue engineering. 

More recently, MPO-mediated oxidation of tyrosine to dityrosine (o o -dityrosine, or 3,3 -diiyrosine) focused attention as a marker reaction of neutrophile-dependent oxidative damage of proteins and peptides (G11, H14, S3). The reaction occurs both with free tyrosine as well as with tyrosyl residues incorporated into polypeptide structures. The mechanism of dityrosine formation utilizes a relatively long-lived phenoxyl radical that cross-links to dimeric and polymeric structures by formation of carbon-carbon bonds between the aromatic moieties of phenolic tyrosine residues (H14) (Fig. 9). 

Rao P E, Kroon D J (1993). Orthoclone OKT3 Chemical mechanisms and functional effects of degradation of a therapeutic monoclonal antibody. In Y J Wang, R Pearlman, (eds.). Stability and Characterization of Protein and Peptide Drugs Case Histories Plenum Publishing Corporation, New York, pp. 135-158. 

An important first step in the hepatic metabolism of proteins and peptides is the uptake into hepatocytes. Small peptides may cross the hepatocyte membrane via passive diffusion if they have sufficient hydrophobicity. Uptake of larger peptides and proteins is facilitated via various carrier-mediated, energy-dependent transport processes. Receptor-mediated endocytosis is an additional mechanism for uptake into hepatocytes (see Sect. 8.3.4.5) [28]. In addition, peptides such as metkephamid can already be metabolized on the surface of hepatocytes or endothelial cells [41]. 

Several classes of nanomaterials, including carbon nanotubes (CNTs), have the ability to translocate molecules, such as DNA and proteins, into the interior of cells. These CNTs have been functionalized giving them the required solubility and ability to deliver molecules across cell membranes. While the toxicity of CNTs in these applications is not well characterized, initial stndies suggest that at low doses and at timescales of days, merely functionalized CNTs were not toxic to cells. Nanombes have also been nsed as a delivery mechanism for protein and peptide... 

To investigate in more details the mechanisms of the interaction of proteins and peptides with membranes, Scheidt et al. discussed the advantages and disadvantages of using lipid modified pseudopeptides to study their interactions with lipid membranes and the aid of solid-state NMR. In the same direction go developments of defined transmembrane peptides with covalently modified acyl chains to investigate interactions of proteins and lipids at the lipid-protein interface as reviewed by Nyholm et al. ... 

The importance of hydrophobic interactions in determining the spatial conformation of proteins and minimizing the free energy of their aqueous solutions has been stressed above. Formation and disruption of internal hydrophobic bonds is also essential for understanding denaturation phenomena of proteins and the mechanisms of their biological activity. The hydrophobicity of proteins and peptides affects their physicochemical behavior and may be of great value for their cosmetic effects and properties. 

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