Biosynthesis of microbial metabolites

Colchidne.— C Labels have been used with great success in the study of the biosynthesis of microbial metabolites.Application to plant alkaloid biosynthesis is limited in general by low incorporations of precursor and dilution of label by... 

Bechthold, A. and Fernandez, J.A.S., Combinatorial biosynthesis of microbial metabolites, in Combinatorial Chemistry Synthesis, Analysis, Screening Jung, G., Ed., Wiley-VCH, Weinheim, 1999 chap. 12. 

Thiericke, R. and Rohr, J. (1993) Biological variation of microbial metabolites by precursor-directed biosynthesis. Natural Product Reports, 10 (3), 265-289. 

The established practice of including references to earlier Reports in this series for background information is continued. Two comprehensive reviews are also cited.1,2 An authoritative account of the biosynthesis of fungal metabolites has been published,3 as has an introductory text which includes a survey of the biosynthesis of alkaloids and nitrogenous microbial metabolites.4... 

In the first part of this chapter, we deal with insecticides including miticides and nematocides, which include very useful compounds such as avermectins and milbemycins, produced by bacteria and fungi. We list out microbial insecticides of importance and review the works mainly on the mode of action and biosynthesis of each metabolite. In the next part, major mycotoxins are listed and recent topics on them, especially on their biosynthesis, are described. Since contamination of two major mycotoxin groups, aflatoxins (AFs) and trichothecenes, in food and feed is a worldwide problem, they are treated in detail in the last part of this chapter. Recent studies on their biosynthesis, regulatory mechanism for their production, and inhibitors of their production are described. 

Van Pee KH (2001) Microbial biosynthesis of halo-metabolites. Arch. Microbiol 175 250-258. 

A number of microbial metabolites whose biosynthesis has been studied are (at least formally) derived from a di- (or tri-)peptide echinulin and benzodiazepine alkaloids (both referred to already), gliotoxin, mycelianamide/ sporidesmin, and the /3-lactam antibiotics. In the case of the last mentioned, in spite of extensive work and the accumulation of a wealth of detail on the fates of the individual atoms in the precursor amino-acids, the mechanism of ring formation remains obscure. 

A feature of the biosynthesis of a number of microbial metabolites is the fracture of aromatic rings in the precursor amino-acids pyrrolnitrin (see this Report, p. 23), anthramycin, tomaymycin, and streptonigrin (see this Report, p. 23). This is only observed rarely in the biosynthesis of plant bases, a notable example being the betalains, which are pigments in plants of the order Centro-spermae. ... 

Tryptophan (7.25) serves as a precursor for a number of microbial metabolites. A notable example is the ergot alkaloids (Section 7.5.1). Other aromatic amino acids are involved in the biosynthesis of various metabolites. Their origins are through shikimic acid 7,78) (see Section 5.1). Shikimic acid itself, or a close metabolic relative, serves as a source for some metabolites, e.g. phenazines (Section 7.5.5) and the ansamycins (Section 7.6.1). For compounds like the latter, acetate and propionate are also important starting materials for biosynthesis. Another important part source for many metabolites is mevalonate, invariably as a C5 (dimethylallyl) unit. 

Zhang, D., Zhang, H., Aranibar, N. et al. (2006) Structural elucidation of human oxidative metabolites of muraglitazar use of microbial bioreactors in the biosynthesis of metabolite standards. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34, 267-280. 

Recently, a new polyketide biosynthetic pathway in bacteria that parallels the well studied plant PKSs has been discovered that can assemble small aromatic metabolites.8,9 These type III PKSs10 are members of the chalcone synthase (CHS) and stilbene synthase (STS) family of PKSs previously thought to be restricted to plants.11 The best studied type III PKS is CHS. Physiologically, CHS catalyzes the biosynthesis of 4,2, 4, 6 -tetrahydroxychalcone (chalcone). Moreover, in some organisms CHS works in concert with chalcone reductase (CHR) to produce 4,2 ,4 -trihydroxychalcone (deoxychalcone) (Fig. 12.1). Both natural products constitute plant secondary metabolites that are used as precursors for the biosynthesis of anthocyanin pigments, anti-microbial phytoalexins, and chemical inducers of Rhizobium nodulation genes.12... 

Herbert, R. B. 2001. The biosynthesis of plant alkaloids and nitrogenous microbial metabolites. Nature Product Reports, 18 50-65. 

A large number of a, 3-didehydro-a-amino acids have been identified as constituents of relatively low molecular weight cyclic compounds from microbial sources. However, the presence of a,p-didehydroalanine in bacterial as well as in mammalian histidine ammonia lyase and in phenylalanine ammonia lyase shows that the occurrence of a,p-didehydro-a-amino acids is not limited to small molecules alone 8 These residues are incorporated in natural sequences by posttranslation modification. a,p-Didehydro-a-amino acids have also been postulated to be precursors in the biosynthesis of several heterocyclic metabolites including penicillin and cephalosporin 9 Other well-known compounds containing ,( -di-dehydro-a-amino acids are nisin 10,11 (a food preservative112 ), subtilin (a broad spectrum antibiotic) 13 and some of the metabolites isolated from Streptomyces strains such as gri-seoviridin 14 ... 

Arene oxides and their oxepin tautomers play a role in the biosynthesis of some microbial metabolites, e.g., the sulfur-containing antibiotics gliotoxin (345),188 dehydrogliotoxin (346),189 apoarontin (347),190 aranotin (348),191... 

Ghisalba O (1985) Biosynthesis of Rifamycins (Ansamycins) and Microbial Production of Shikimate Pathway Precursors, Intermediates, and Metabolites. Chimia 39 79... 

Metabolites from cyanobacteria are generally of amino acid or polyketide origin and frequently show potent biological activity. The series of dolastatin metabolites, exemplified by dolastatin-10 (Structure 2.18), are linear peptides which show potent cytotoxic activity and are of clinical interest as anti-tumour agents. Originally isolated in very low yield from the Indian Ocean sea hare Dolabella auricularia, dolastatins are now known to be cyanobacterial products.43,44 The discovery of a microbial source for these pharmaceutically important compounds will facilitate study of their biosynthesis and could potentially lead to the production of structural analogues by provision of modified biosynthetic precursors to the cultivar. As discussed below and in Section VI, toxic secondary metabolites from cyanobacteria have often been implicated in the chemical defenses of sea hares.45"17... 

Piericidins are the first compounds obtained by the screening search for insecticidal natural products among microbial metabolites.10 They were isolated from Streptomyces mobaraensis in 1963,11 and many piericidin derivatives have been found in microbial metabolites until now.12 Piericidins are not used as insecticides practically, but are important biological reagents because they have specific inhibitory activity toward the mitochondrial electron transport chain protein nicotinamide adenine dinucleotide (NADH)-ubiquinone reductase (complex I).13 Piericidin Ax (1 in Figure 1) is biosynthesized as a polyketide,14 but genes responsible for its biosynthesis are not yet identified. Total synthesis of piericidins A (1) was reported recently.15... 

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