Important Peptides

An exopeptidase that sequentially releases an amino acid from the N-terminus of a protein or peptide. Examples include cystinyl aminopeptidase (MEROPS M01.011), which removes a terminal cysteine from the biologically important peptides oxytocin and vasopressin, and methionyl aminopeptidase (M24.001), which removes the initiating methionine from cytosolic... 

Intracellular pathways after escape from the endolysosomal system into the cytosol are less clear. Obvious bottlenecks include, in the case of gene transfer (pDNA delivery), cytosolic transport to the perinuclear area, nuclear uptake, and nuclear presentation of the pDNA to the transcriptional machinery in bioactive form. In the case of siRNA (or mRNA and some other nucleic acids such as oligonucleotides), cytosolic accessibility for the required function is essential. Besides cytosolic transport [176, 177] and the nuclear import of large nucleic acid molecules [178-180], incorporation of functional nuclear import peptide domains has been evaluated [181-186]. Another bottleneck, nucleic acid unpackaging [187], i.e., partial or complete dissociation from the polymeric carrier, which is required for biological accessibility of the delivered nucleic acid, will be discussed in Sect. 3.3. 

Once released from the cell of origin, the signal ligand must travel to its site of action. For the classical endocrine hormones this means via the bloodstream. Given that blood plasma is approximately 94% water, the physical nature of the hormone is important. Peptides are hydrophilic and so circulate unbound to any other molecule whereas... 

There are several biologically important peptides which contain tyrosine but not tryptophan. These include small molecules with molecular weights of about 1000 or less. Molecules such as oxytocin, vasopressin, and tyrocidine A are cyclic, while others such as angiotensin II and enkephalin are linear. Schiller 19) has reviewed the literature up through 1984 on fluorescence of these and several other peptides. One major finding that has been reported recently is that the anisotropy and fluorescence intensity decays of many peptides are complex. This is especially evident in some of the tyrosine-containing peptides, and we expect that there will be considerable effort made over the next few years toward understanding the physical basis for these complex kinetics. 

Figure 8.19 The formation of glutathione. Glutathione is an important peptide especially in removal of free radicals (i.e. as an antioxidant). It is synthesised in the intestine from glutamate, cysteine and glycine (see Appendix 8.4 for details).

Use of Proteases in Peptide Synthesis. Typically peptides are synthesized the standard solid or liquid phase methodologies (56, 57). However, both of these techniques require harsh chemical reactions which are detrimental to certain amino acids. Furthermore, in practical terms most peptide syntheses are limited to the range of 30 to 50 amino acid residues. Hence, peptide synthesis is still somewhat problematic in many cases. In certain situations, the alternative method of peptide synthesis using proteases is an attractive choice. With this form of synthesis, one can avoid the use of the noxious and hazardous chemicals used in solid or liquid phase peptide synthesis. Since the reactions are enzyme catalyzed, racemization of the peptide bond does not occur. This technique has been used with success in the synthesis and semisynthesis of several important peptides including human insulin (55,59). 

Vancomycin acts by inhibiting the correct synthesis of cell walls in gram-positive bacteria by specifically inhibiting the incorporation of V-acetylmuramic acid (NAM) and A-acetylglucosamine (NAG), two important peptide subunits that are present in the peptidoglycan layer of these types of bacteria. 

Alternatively, alkylation of 4-benzyl-2-(trifluoromethyl)-5(2//)-oxazolone 16 in the presence of mild base using active alkyl halides as electrophiles occurs at C-4 " Subsequent aminolysis of a 4,4-dialkyl-5(4f/)-oxazolone like 17 gave an Al-(trifluoroacetyl)-a,a-dialkylglycine amide 18 that was used to prepare important peptides incorporating an a,a-dibenzylglycine unit (Scheme 7.5). 

Alternatively, if the dehydroamino acid is C-terminal or is central in the peptide chain, then the oxazolone precursor to the dehydropeptide must be in position two in order to apply this methodology (Scheme 7.165). The requisite unsaturated 5(4//)-oxazolone intermediate 518 is obtained from the appropriate precursors following standard cyclization procedures and avoiding experimental conditions that would epimerize the chiral center. This methodology has been applied to access analogues of important peptides including dehydroaspartame, somatostatin, and dermorphin. In these cases, a dehydroamino acid was incorporated into the peptide backbone to study the relationship between conformational restriction and biological properties of the modified peptide. 

In view of the large diversity of structures listed in Tables 1 and 2, only the synthetic methods developed for the most common and biologically most important peptide derivatives will be discussed in the following sections. Additional attention will be paid to the often-ingenious design of artificial modifications capable of mimicking the native peptide transformations in an efficient and biologically competent manner. 

However, it was not until 1971, when Gross and Morrell reported the structure elucidation of the purified nisin peptide, 12 that it became clear that nisin contained Lan and MeLan residues. Since nisin is an important peptide antibiotic, regularly used in the food production industry as a preservative (preservative EC 234), it has attracted a great deal of attention. Nisin is produced by fermentation, however, partly because of its intriguing structure, it also became the target for the only complete synthesis of a lantibiotic reported to date in the literature. This work has been reviewed. 13 14 ... 

Large peptides of biologieal signifieanee are known by their trivial names e.g., insulin is an important peptide eomposed of 51 amino aeid residues. 

While no further development of FK 33-824, Biphalin, Important peptidic tool DPDPE or other prominent opioid peptides has been compounds for opioid... 

The complex structure of peplide antibiotics adds considerably to (he problems of synthesis, but more recent efforts toward improved peptide antibiotics are encouraging. Methods of hioassay and other laboratory use of economic antibiotics are available. Table 1 is a list of important peptide antibiotics. More extensive listings of minor peptide antibiotics have been published. 

The names and structures of the twenty natural amino acids are given in Table 1.13. The International Union of Pure and Applied Chemistry (IUPAC) uses the three-letter abbreviations shown in the second column of Table 1.13 to describe amino acids. These are widely used in biological circles as well but are inappropriate when long peptide or protein sequences need to be described. For example, when proinsulin is cleaved, it forms the biologically important peptide insulin and another peptide usually called C-peptide. The human peptide consists of a linear chain of 31 amino acids that have the sequence, from amino to carboxyl, H2N-Glu-Ala-Glu-Asp-Leu-Gln-Val-Glu-Gln-Glu-Leu-Gly-Gly-Gly-Pro-Gly-Ala-Gly-Ser-Leu-Gln-Pro-Leu-Ala-Leu-Glu-Gly-Ser-Leu-Gln-OH. This is readily comprehensible to most chemists because the abbreviations are typically the first three letters of the amino acid. Thus, alanine is Ala and arginine is Arg. Aspartic acid and asparagine cannot both be named Asp so the latter is distinguished as Asn. 

Sawamura, D., Li, K., Chu, M.-L., and Uitto, J. (1991). Human bullous pemphigoid antigen (BPAG1). Amino acid sequences deduced from cloned cDNAs predict biologically important peptide segments and protein domains. J. Biol. Chem. 266, 17784-17790. 

Anterior Lobe. The anterior pituitary, or adenohypophysis, secretes six important peptide hormones. The anterior pituitary releases growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), and prolactin (Pr). The physiologic effects of these hormones are listed in Table 28-1. 

Total synthesis of peptides is rarely an economical method for their commercial production. Important peptides are usually derived from biological sources. For example, insulin for diabetics was originally taken from pork pancreas. Now, recombinant DNA techniques have improved the quality and availability of peptide pharmaceuticals. It is possible to extract the piece of DNA that contains the code for a particular protein, insert it into a bacterium, and induce the bacterium to produce the protein. Strains of Escherichia coli have been developed to produce human insulin that avoids dangerous reactions in people who are allergic to pork products. 

Nonmodified small oligopeptides are reimported into responder cells after the secretion. The imported peptides directly bind to intracellular receptors that regulate transcription of target genes directly or indirectly. 

Importantly, peptides and proteins are assembled from amino acids on the basis of genetic coding (gene-nucleotide sequence), or can be synthesized in the laboratory. 

The current worldwide supply for custom-made peptides is estimated to be around 10 billion (this amount includes pharmaceutically important peptides). Principal components of the market are peptides for studies of protein-protein interactions, finding antibody epitopes, and analogs of biologically active peptides and potential drugs. Added to this market is a significant business in peptide synthesizers, reagents, and supports. Large-scale proteomics research is... 

In Table V are collected the most important peptides isolated by Heyns et al. (1951), Schroeder et al. (1953), 1954), and Kroner et al. (1953, 1955), following acid hydrolysis of steer hide collagen and gelatin. The peptide fractions were separated on ion exchange columns, and individual peptides resolved on celite, followed by sequence studies carried out by the methods of Sanger. 

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