Peptides, antibiotic biosynthesis

SuzukcOce, K., Hori, H., Hayashi, H., Unezawa, H., "Peptide Antibiotics - Biosynthesis eind Functions , p. 325, Walter de Gruyte euid Co., 1982. 

Ristow H, Russo J, Stochaj E, Paulus H (1982) In Kleinkauf H, von Dohren H (eds) Peptide antibiotics - biosynthesis and functions. Walter de Gruyter, Berlin, p 381... 

D. J. Hook, R.P. Elander, R.B. Morin, Recent developments with cell free extracts on the enzymic biosynthesis of penicillins and cephalosporins in Peptide-antibiotics . Biosynthesis and Function, H. Kleinkauf, H. von Dohren eds. de Gruyter, Berlin 1982, pp 84-100... 

A similar approach is employed in the formation of peptides such as peptide antibiotics (see Box 13.11). In marked contrast to the ribosomal biosynthesis of proteins, where a biological production line interprets the genetic... 

Bacitracin (Fig. 4) is a cyclic peptide antibiotic. The lipid II molecule involved in the bacterial cell wall biosynthesis has a C55 isoprenyl pyrophosphate moiety that must be dephosphorylated so that it can reparticipate in another round of lipid II transfer. Bacitracin binds to the isoprenyl pyrophosphate and prevents the dephosphorylation which, in turn, blocks cell wall growth by interfering with the release of the muropeptide subunits to the outside of the bacterial cell membrane. Bacitracin inhibits similar reactions in eukaryotic cells. So, it is systemically toxic but is an effective and widely used topical antibiotic. 

Rajendran N and Marahiel MA (1999) Multifunctional peptide synthetases required for nonribosomal biosynthesis of peptide antibiotics. Comprehensive Natural Products Chemistry, Vol 4. Elsevier, Amsterdam, pp 195-200. 

H Kleinkauf, H von Dohren. Nonribosomal biosynthesis of peptide antibiotics. Eur J Biochem 192 1-15, 1990. 

DJ Smith, AJ Earl, G Turner. The multifunctional peptide synthetase performing the first step of penicillin biosynthesis in Penicillium chrysogenum is a 421,073 dalton protein similar to Bacillus brevis peptide antibiotic synthetases. EMBO J 9 2743-2750, 1990. 

Tyr substructures are, moreover, found within several peptidic antibiotics, for example the edeines 57 from Bacillus brevis, or within cyclodepsipeptides that have been isolated from marine sponges, for example jaspamides A-C 59 [106] or geo-diamolides H-I 58 [107] (Scheme 1.5.9). The chondramides 60 are closely related antibiotics that have been obtained from the myxobacterium Chondromyces croca-tus. Within the edeine biosynthesis D-/ -Tyr 9 seems to be a real precursor [89]. The biosynthesis of the jaspamides, the geodiamolides, or the chondramides has not yet been investigated. 

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. 

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. 

Some antibiotics that have been derived from peptides were mentioned in Chapter l. The biosynthesis of penicillins was discussed in Chapter 8. Many peptide antibiotics are known. Some find clinical applications but others such as gramicidin S (9.7), tyrocidine A (9.8) and polymyxins (9.9) are too toxic for use in humans. Cyclosporin A (Figure 1.4), however, has immunosuppressive properties and it has been used in transplant surgery for this reason rather than for its antibiotic properties. Peptide antibiotics have some non-standard structural features and these may explain in part their antibiotic properties. First, cyclic peptides are not found in animal cells. Secondly, peptide antibiotics usually contain some unusual amino acids they may have the d configuration, be A-methylated or have other non-standard structural features. Clearly, these features are not compatible with direct ribo-somal synthesis. 

Bacillussubtilis produces the cyclic peptide antibiotic surfactin (82).This is an acyl-pep-tidolactone composed of a p-hydroxy fatty acid side chain and seven amino acid residues, including a leucine at position 7. The biosynthesis of surfactin is catalyzed by a peptide synthetase consisting of three modules. The first and second modules are carrying three domains, the last module just one domain. The last domain catalyzes the activation and... 

Even in the case it should be possible to separate ribozyme activity from the ribosome or to isolate an in vitro selected ribozyme that can catalyze the same type of peptide bond formation as a ribosome, however such a biocatalyst seem does not to be suitable for simple practical use rather than using a chemical coupling reagent. In principle, this conclusion is also valid for the nonribosomal poly- or multienzymes which are involved in the biosynthesis of peptide antibiotics[7Z. Up to now, they have only found application in the synthesis field of cyclosporin, gramicidin S, special P-lactam antibiotics and analogs. 

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. 

In non-i ibosomal biosynthesis of peptide antibiotics by multimodular synthetases, amino acid monomers ai e activated by the adenylation domains of the synthetase and loaded onto the adjacent canier protein domains as thioesters, then the formation of peptide bonds and translocation of the growing chain are effected by the synthetase s condensation domains. Whether the condensation domains have any editing function has been unknown. Synthesis of aminoacyl-CoA molecules and direct enzymatic transfer of aminoacyl-phospho-pantetheine to the caiiier domains allow the adenylation domain editing function to be bypassed. This method was used to demonstrate that the first condensation domain of tyroci-dine synthetase shows low selectivity at the donor residue (D-phenyManine) and higher selectivity at the acceptor residue (L-proline) in the formation of the chain-initiating D-Phe-L-Pro dipeptidyl-enzyme intermediate. 

Tlie sequential reactions in elongating acyl transfers in the synthesis of polyketide natural products and non-ribosomal peptide antibiotics such as erythromycin, rapamycin, epotliilone, lovastatin, penicillins, cyclosporin and vancomycin resemble molecular solid-state assembly lines. Such multimodular enzymes may be utilized in combinatorial biosynthesis by way of reprogramming for the manufacture of unnaUiral analogs of natural products. 

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