Polyketide antibiotics biosynthesis

Bibb, M.J., S. Biro, H. Motamedi, J.F. Coilins and C.R. Hutchinson (1989). Analysis of the deduced nucleotide sequence of the Streptomyces glaucescens tcml genes provide key information about the enzymology of polyketide antibiotic biosynthesis. EMBO J. 8 2727-2736. 

In animals, the breakdown of lipids involves conversion of propionyl-CoA to succinyl-CoA. Methylmalonyl-CoA is a metabolic intermediate in this process. In vivo, it is necessary to convert the 2-(S)-form of methylmalonyl-CoA to the 2-(R)-form, for reaction with methylmalonyl-CoA mutase. This reaction is catalyzed by methylmalonyl-CoA epimerase (MMCE) [4, 66-68]. Methylmalonate is also employed in polyketide antibiotic biosynthesis, in the form of methylmalonate units, although less is known about the stereochemical requirements of these processes [69, 70]. 

Keywords. Polyketide, Antibiotics, Biosynthesis, Bioprocess development. Metabolic engineering... 

Vrilbloed JW, Zerbe-Brnkhardt K, Ratnatilleke A, Grubelnik-Leiser A, Robinson JA (1999) Insertional inactivation of methylmalonyl coenzyme A (CoA) mutase and isobutyryl-CoA mutase genes in Streptomyces cinnamonensis-. influence on polyketide antibiotic biosynthesis. J Bacteriol 181 5600 - 5605... 

Bibb MJ, Biro S. Motamedi H, Collins JF, Hutchinson CR. Analysis of the nucleotide sequence of the Sne omyces glaucescens ccml genes provides key infiannation about the enzy mology of tetracencMaycin C polyketide antibiotic biosynthesis. EMBO J 1989 8 2727-2736,... 

Schneider, G., Enzymes in the biosynthesis of aromatic polyketide antibiotics, Curr. Opin. Struct. Biol., 15, 629, 2005. 

Keating, T. A., and Walsh, C. T. (1999). Initiation, elongation, and termination strategies in polyketide and polypeptide antibiotic biosynthesis. Curr. Opin. Chem. Biol., 3, 598-606. 

Gatto et al m characterized the mechanism of L-pipecolic acid formation by cyclodeaminase RapL from L-lysine within rapamycin biosynthesis, which is a hybrid NRP—polyketide antibiotic (Figure 25(a)). RapL was characterized by biochemical assays to require cofactor nicotinamide adenine dinucleotide (NAD+) and an oxidative cyclodeamination reaction mechanism corresponding to ornithine cyclodeamination was proposed based on ESI-FTMS analysis of RapL reaction products (Figure 25(b)). 

An mCyN unit is also present in the core of the polyketide antibiotic asukamycin from Streptomyces nodosas subsp. asukaensis [96]. This has been shown to arise not from a variant of the shikimate pathway, but from the condensation of a C4 unit from the TCA cycle, closely related to succinate, with a C3 unit, possibly dihydroxyacetone phosphate, from the triose pool. Related studies concerning 3-amino-4-hydroxybenzoic acid biosynthesis in Streptomyces murayamaensis mutants MC2 and MC3 support this hypothesis [97]. 

Biosynthesis of the Antifungal Polyketide Antibiotic Soraphen A in Sorangium cellulosum and Streptomyces lividans... 

El-Sayed, A.K., Hothersall, J., and Thomas, C.M. Quorum sensing-dependent regnlation of the biosynthesis of the polyketide antibiotic mupirocin in Pseudomonas fluorescens. Microbiology, 147, 2127-2139, 2001. 

Besides MMCM and GM, two other coenzyme B -dependent carbon skeleton mutases are known. These are (1) methylene glutarate mutase (MGM) from the anaerobe Eubacterium (Clostridium) barkeri, which catalyzes the equilibration of 2-methylene-glutarate with (R)-3-methylitaconate as part of a degradative path of nicotinic acid [175,199] and (2) isobutyryl-CoA mutase (ICM), which is observed in species of gram-positive bacteria Strep-tomyces and catalyzes the reversible rearrangement of iso-butyryl-CoA and n-butyryl-CoA [177]. The isomerization of iso-butyryl-CoA and n-butyryl-CoA in ICM is relevant in the biosynthesis of polyketide antibiotics [177]. 

There are many examples of important biologically active molecules formed by polyketide biosynthesis. Aureomycin and terramycin (Section 21.2) are examples of other aromatic polyketide antibiotics. Erythromycin (Section 17.7C) and aflatoxin, a carcinogen (see Why do these topics matter in Chapter 14), are polyketides from other pathways. 

Reactions of the Benzene Ring of Phenols 953 THE CHEMISTRY OF... Polyketide Anticancer Antibiotic Biosynthesis 954... 

Polyketide Anticancer Antibiotic Biosynthesis 954 The Bombardier Beetle s Noxious Spray 958 Bacterial Dehalogenation of a PCB Derivative 961... 

Malpartida F, Hallam SE, Kieser HM, Motamedi H, Hmehinson CR, Butler MJ. Sugden DA, Warren M, McKillop C, Bailey CR, Humphreys GO, Hopwood DA. Homology between Streptomyces genes coding for synthesis of different polyketides used to clone antibiotic biosynthesis genes. Nature 1987 325 818-821. 

Bibb MJ, Sherman DH, Omura S, Hopwood DA. Cloning, sequencing and deduced functions of a cluster of Streptomyces genes probably encoding biosynthesis of the polyketide antibiotic frenolicin. Gene 1994 142 31-39. 

In the study of biosynthesis of polyketide antibiotics. Cane and Luo applied the Evans aldol reaction to prepare a key intermediate 41 from aldehyde 40 and Evans reagent 20. °... 

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