Polypeptides Antibiotics

Our approach has been essentially empirical in nature with less emphasis on the theoretical. We have isolated single substances, proved their purity, and determined their covalent structure by classical methods of organic chemistry we have then used these substances of molecular weight ranging from 1,000 to 14,000 as model solutes for the study of conformation and intermolecular interaction. Solutes of special interest have been gramicidin SA (2), bacitracin A (3), polymyxin B, and the tyrocidines A, B, and C (4). All are cyclic antibiotic polypeptides. The first three behave in aqueous solution as reasonably ideal solutes and do not associate, but the tyrocidines associate strongly and are interesting models for the study of association phenomena. Other model solutes of... 

Bacitracin. Altracin Ayfivin Fortracin Penitra-cin Topitracin Zutracin. Antibiotic polypeptide complex produced by Bacillus subfilis and licheniformis Johnson et al, Science 102, 376 (1945) Anker et at. J. Bacterial 55, 249 (1948). Commercial bacitracin is a mixture of at least nine bacitracins. Purification of bacitracin by carrier displacement method Porath, Acta Chem. Stand. 6, 1237 (1952). Purification with ion exchange resin Chaiet, Cochrane, U.S, pat. 2,915,432 (1959 to Merck Co.). Production Johnson, Meleney, U.S. pat- 2,498,165 (1950 to the U.S. Secy, of War) Freaney, Allen, U.S, pat. 2,828,246 (1958 to Commercial Solvents). Solubilities Weiss et al, Antibiot. Che-mother. 7, 374 (1957). Preliminary structure studies Haus-mann et at, J. Am. Chem. Soc. 77, 723 (1955) Lockhart et of, Biochem. J. 61, 534 (1955) St off el, Craig, J. Am. Chem. Soc. 83, 145 (1961), Structure of bacitracin A Ressler,... 

Most channels behave as simple resistors to current flow when the channel is open, the current through the channel varies linearly with membrane potential (AF — IR). The antibiotic polypeptide gramicidin A forms a cylindrical channel by end-to-end dimerization of two peptides, one in each of the bilayer leaflets. Individual gramicidin channels exhibit a resistance of 8 x 10 over... 

It has been known for some time that certain antibiotic polypeptides exert a rather specific effect upon natural membranes . Recent observations by Pressman , however, have led to the discovery by Chappell and Crofts that certain polypeptides of the valinomycin and gramicidin group are specific cation conductors. 

Purine antibiotics purine derivatives with antibiotic activity. They occur as nucleosides (see Nucleoside antibiotics), polypeptides (see Viomycin), or free bases (see 8-Araguanidine). 

Lipmann F. Bacterial production of antibiotic polypeptides by ihiol linked synthesis on pro tein templates. Adv Microb Phys 1980 21 227-260. 

Mach, B., E. Reich, and E. L. Tatum Separation of the biosynthesis of the antibiotic polypeptide tyrocidine from protein biosynthesis. Proc. Natl. Acad. Sci. U.S. 50,... 

Relationship of actinomycin formation to the synthesis of structurally similar polypeptide antibiotics such as etamycin, echinomycin, polymyxin, bacitracin, gramicidin and the relationship of antibiotic polypeptide formation to protein synthesis. 

Antibiotic A201A. Antibiotic A201A (23), produced by S. capreolus is an /V -dimethyladenine nucleoside stmcturaHy similar to puromycin (19). Compound (23) which contains an aromatic acid and monosaccharide residues (1,4), inhibits the incorporation of amino acids into proteins but has no effect on RNA or DNA synthesis. Compound (23) does not accept polypeptides as does (19), and does appear to block formation of the initiation complex of the SOS subunit. It may block formation of a puromycin-reactive ribosome. 

Aminohexose Nucleosides. The 4-aminohexose nucleosides (128—140) are Hsted in Table 7 (1—4,240—242). A biosynthetic relationship between the 4-aminohexose peptidyl nucleoside antibiotics and the pentopyranines has been proposed (1). The 4-aminohexose pyrimidine nucleoside antibiotics block peptidyl transferase activity and inhibit transfer of amino acids from aminoacyl-tRNA to polypeptides. Hikizimycin, gougerotin, amicetin, and blasticidin S bind to the peptidyl transferase center at overlapping sites (243). 

The amide linkage between monomer units in a protein is called a peptide bond. Peptides and polypeptides, which often exhibit biological activity (see Antibiotics, peptides Neuroregulators), are smaller than proteins. Although the differentiation between polypeptide and protein is somewhat arbitrary, the usual distinction is drawn around 100 monomer units. Proteins are also characterized by higher levels of stmcture resulting from internal interactions. 

The phleomycin, bleomycin and related families are widespectrum antibiotics containing the pyrimidine (987) in addition, they have antineoplastic activity and bleomycin is already in clinical use for certain tumours. They were isolated about 1956 from Streptomyces verticillus, and in addition to the pyrimidine portion the molecules contain an amide part (R ) and a complicated part (R ) consisting of polypeptide, an imidazole, two sugars, a bithiazole and a polybasic side chain which can vary widely phleomycin and bleomycin differ by only one double bond in the bithiazole section (78MI21303). The activity of such antibiotics is increased by the addition of simple heterocycles (including inter alia pyrimidines and fused pyrimidines) and other amplifiers (82MI21300). 

Therapeutic Function Antitubercular Chemical Name Cyclic polypeptide antibiotic Common Name Caprolin Structural Formula ... 

Other antibiotics inhibit protein synthesis on all ribosomes (puromycin) or only on those of eukaryotic cells (cycloheximide). Puromycin (Figure 38—11) is a structural analog of tyrosinyl-tRNA. Puromycin is incorporated via the A site on the ribosome into the carboxyl terminal position of a peptide but causes the premature release of the polypeptide. Puromycin, as a tyrosinyl-tRNA analog, effectively inhibits protein synthesis in both prokaryotes and eukaryotes. Cycloheximide inhibits peptidyltransferase in the 60S ribosomal subunit in eukaryotes, presumably by binding to an rRNA component. 

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