Peptides, antibiotics enzymic

The natural amino acids are mainly a-amino acids, in contrast to (3-amino acids such as p-alanine and taurine. Most a-amino acids have four different substituents at C-2 (Ca). The a atom therefore represents a chiral center—I e., there are two different enantiomers (L- and D-amino acids see p. 8). Among the proteinogenic amino acids, only glycine is not chiral (R = H). In nature, it is almost exclusively L-amino acids that are found. D-Amino acids occur in bacteria—e. g., in murein (see p.40)—and in peptide antibiotics. In animal metabolism, D-Amino acids would disturb the enzymatic reactions of L-amino acids and they are therefore broken down in the liver by the enzyme D-amino add oxidase. 

T Although D-amino acids do not generally occur in proteins, they do serve some special functions in the structure of bacterial cell walls and peptide antibiotics. Bacterial peptidoglycans (see Fig. 20-23) contain both D-alanine and D-glutamate. D-Amino acids arise directly from the l isomers by the action of amino acid racemases, which have pyridoxal phosphate as cofactor (see Fig. 18-6). Amino acid racemization is uniquely important to bacterial metabolism, and enzymes such as... 

A second enzyme (of mass 100 kDa) is needed for activation of phenylalanine. It is apparently the activated phenylalanine (which at some point in the process is isomerized from l- to D-phenylalanine) that initiates polymer formation in a manner analogous to that of fatty acid elongation (Fig. 17-12). Initiation occurs when the amino group of the activated phenylalanine (on the second enzyme) attacks the acyl group of the aminoacyl thioester by which the activated proline is held. Next, the freed imino group of proline attacks the activated valine, etc., to form the pentapeptide. Then two pentapeptides are joined and cyclized to give the antibiotic. The sequence is absolutely specific, and it is remarkable that this relatively small enzyme system is able to carry out each step in the proper sequence. Many other peptide antibiotics, such as the bacitracins, tyrocidines,215 and enniatins, are synthesized in a similar way,213 216 217 as are depsipeptides and the immunosuppresant cyclosporin. A virtually identical pattern is observed for formation of polyketides,218 219 whose chemistry is considered in Chapter 21. 

While peptide antibiotics are synthesized according to enzyme-controlled polymerization patterns, both proteins and nucleic acids are made by template mechanisms. Tire sequence of their monomer emits is determined by genetically encoded information. A key reaction in the formation of proteins is the transfer of activated aminoacyl groups to molecules of tRNA (Eq. 17-36). Tire tRNAs act as carriers or adapters as explained in detail in Chapter 29. Each aminoacyl-tRNA synthetase must recognize the correct tRNA and attach the correct amino acid to it. The tRNA then carries the activated amino acid to a ribosome, where it is placed, at the correct moment, in the active site. Peptidyltransferase, using a transacylation reaction, in an insertion mechanism transfers the C terminus of the growing peptide chain onto the amino group of... 

How do antibiotics act Some, like penicillin, block specific enzymes. Peptide antibiotics often form complexes with metal ions (Fig. 8-22) and disrupt the control of ion permeability in bacterial membranes. Polyene antibiotics interfere with proton and ion transport in fungal membranes. Tetracyclines and many other antibiotics interfere directly with protein synthesis (Box 29-B). Others intercalate into DNA molecules (Fig. 5-23 Box 28-A). There is no single mode of action. The search for suitable antibiotics for human use consists in finding compounds highly toxic to infective organisms but with low toxicity to human cells. 

Peptides - [ANTIBIOTICS - PEPTIDES] (Vol 3) - [TRACE AND RESIDUE ANALYSIS] (Vol 24) -m beer [BEER] (Vol 4) -as endogenous opioids [OPIOIDS, ENDOGENOUS] (Vol 17) -enzymatic synthesis of [ENZYMES IN ORGANIC SYNTHESIS] (Vol 9) -radiolabeling of [RADIOPHARMACEUTICALS] (Vol20)... 

EJ Vandamme. Peptide antibiotic production through immobilized biocatalyst technology. Enzyme Microb Technol 5 403-416, 1983. 

Biosynthesis of (S)-/ -Tyrosine in Bacillus brevis Vm4 //-Tyrosine 43 is a constituent of the peptide antibiotics edeine A and B [60] obtained from cultures of BaciUus brevis Vm4. //-Tyrosine is derived from a-tyrosine 42 by use of a tyrosine 2,3-aminomutase [61]. The purified enzyme has properties fundamentally different from those of all other aminomutases so far mentioned. It requires ATP and Mg2+ ions, but no other cofactors. 

A type I thioesterase domain is present at the NHj-terminal of the animal FAS and is responsible for catalyzing hydrolysis of the completed fatty acyl chain from the enzyme. The active site contains both conserved serine and histidine residues [87] and is thought to function via a mechanism similar to that of the serine proteases [50] however, no conserved acidic residue is present to complete the charge relay/transfer. A second variety of thioesterase (type II) is encoded as a separate protein and interacts with the multifunctional FAS to release medium chain fatty acids [88, 89]. This enzyme has a weak sequence similarity to the type I thioesterase, which includes the conserved active site serine and histidine residues. These enzymes are also homologous to proteins encoded by genes involved in the synthesis of peptide antibiotics [90,91] (see below). 

Quadri LE, Sello J, Keating TA, Weinreb PH, Walsh CT. Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin. Chem. Biol. 1998 5 631-645. Eppelmann K, Doekel S, Marahiel MA. Engineered biosynthesis of the peptide antibiotic bacitracin in the surrogate host Bacillus subtiUs. J. Biol. Chem. 2001 276 34824-34831. 

The high loading capability of large-volume CCC systems is commonly used in industry. Large amounts (gram to kilogram scale) of natural products with high added values are separated by CCC. Alkaloids, antibiotics, enzymes, macrolides, peptides, rare fatty acids, saponins, tannins, taxoids and/or precursors of Taxol , and other fine chemicals have been isolated, separated, and/or purified by preparative CCC [1]. 

New applications are envisaged in the near future, particularly in the emerging area of bio-separation such as purification of enzymes, peptides, antibiotics and natural extracts. Numerous companies offer SMB equipments for the pharmaceutical and the fine chemical industries [2,8]. This technology covers a broad range of production scales from the laboratory units, which use chromatographic... 

Cf-Aminophosphonates can act as peptide mimetics, enzyme inhibitors, antibiotic and pharmacological agents, and as herbicides, fungicides, insecticides, and plant growth regulators. Akbari et al. have demonstrated that a readily available, highly efficient, task-specific ionic liquid (TSIL) can be used as a recyclable catalyst for the synthesis of a-aminophosphonates from aldehydes and ketones in water (Fig. 12.44) [30]. This is the first report of a functionalized ionic liquid-catalyzed synthesis of a-aminophosphonates. 

Peptide biosynthesis may occur through two different systems. Most of cellular peptides and proteins are produced by the ribosomal machinery connecting 20 proteino-genic amino acids to the desired products. However, most of the bioactive peptides are produced non-ribosomally by large peptide synthetases. These peptides are used as antibiotics, enzyme inhibitors, toxins, and other medically useful drugs. The biosynthesis of... 

Although lantibiotics are not enzymes and do not contain cofactors they are included here and briefly discussed because they are proteins whose biosynthesis requires extensive and unusual posttranslational modifications. These modifications endow the gene product with a new function, in this case an antimicrobial activity, which would not exist in the absence of these covalent modifications to the protein. They are found in peptides of microbial origin. Their name derives from lanthionine, which is a nonproteinogenic amino acid composed of two alanine residues that are crosslinked on their /3-carbon atoms by a thioether linkage (Figure 15). The wide array of fascinating posttranslational modifications which are present in this class of peptide antibiotics is reminiscent of those seen in some protein-derived cofactors. 

The intensive studies on the genetic code and on the proteins in recent years have led to a fairly good understanding of the mechanism of protein biosynthesis . The biosynthetic mechanism involved in the formation of peptides has not yet been studied in equal detail. Some physiologically active peptides like bradykinin and angiotensin are known to be derived from proteins by a specific enzymatic hydrolysis. Other peptides, like glutathione - , ophthalmic acid , the nucleotide-pentapeptide from Staph, aureus and y-polyglutamic acid have been shown to require for their synthesis only a soluble enzyme system. Their biosynthetic mechanism is therefore entirely different from that of the proteins. Such a different type of mechanism has also been demonstrated lately to be involved in the synthesis of peptide antibiotics. 

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