Macrolide antibiotics, biosynthesis

A Arisawa, N Kawamura, K Takeda, H Tsunekawa, K Okamura, R Okamoto. Cloning of the macrolide antibiotic biosynthesis gene acyA, which encodes 3-0-acyltransferase, from Streptomyces thermotolerans and its use for direct fermentative production of a hybrid macrolide antibiotic. Appl Environ Microbiol 60 2657-2660, 1994. 

Y Xue, L Zhao, HW Liu, DH Sherman. A gene cluster for macrolide antibiotic biosynthesis in Streptomyces venezuelae. Architecture of metabolic diversity. Proc Natl Acad Sci (USA) 95 12111-12116, 1998. 

Shafiee, A. Hutchinson, C. R. Macrolide antibiotic biosynthesis isolation and properties of two forms of 6-deoxyerythronolide B hydroxylase from Saccharopolyspora erythraea (Streptomyces erythreus). Biochemistry 26, 6204-6210 (1987). 

Borisova, S., Zhao, L., Melancon, C.E. et al. (2004) Characterization of the glycosyltransferase activity of desVII analysis of and implications for the biosynthesis of macrolide antibiotics. Journal of the American Chemical... 

This is a complex molecule, made up of an adenine nucleotide (ADP-3 -phosphate), pantothenic acid (vitamin B5), and cysteamine (2-mercaptoethylamine), but for mechanism purposes can be thought of as a simple thiol, HSCoA. Pre-eminent amongst the biochemical thioesters is the thioester of acetic acid, acetyl-coenzyme A (acetyl-CoA). This compound plays a key role in the biosynthesis and metabolism of fatty acids (see Sections 15.4 and 15.5), as well as being a building block for the biosynthesis of a wide range of natural products, such as phenols and macrolide antibiotics (see Box 10.4). 

Macrolide antibiotics target the bacterial ribosome and inhibit the bacterial protein biosynthesis. Many gram-negative bacteria are inherently resistant to mac-rolides because their outer membrane is impermeable to macrolides. Several mechanisms of acquired resistance have been reported. In some cases, resistance is conferred by methylation of ribosomes by methylase enzymes, the genes of... 

Martin JF (1984) Biosynthesis, regulation, and genetics of polyene macrolide antibiotics. In Omura S (ed) Macrolide antibiotics Chemistry Biology, and Practice Academic Press, Orlando, 405... 

Kreuzman AJ, Turner JR, Yeh WK (1988) Two distinctive O-methyltransferases catalyzing penultimate and terminal reactions of macrolide antibiotic (tylosin) biosynthesis. Substrate specificity, enzyme inhibition, and kinetic mechanism. J Biol Chem 263 15626-15633... 

SE Fishman, K Cox, JL Larson, PA Reynolds, ET Seno, W-K Yeh, R Van Frank, CL Hershberger. Cloning genes for the biosynthesis of a macrolide antibiotic. Proc Natl Acad Sci (USA) 84 8248-8252, 1987. 

S. antibioticus produces another unusual macrolide antibiotic [45] called chlorothricin (57) containing, in addition to the aglycone (modified methylsalicylic acid), saccharides, dideoxyhexoses in the first place. Their biosynthesis was investigated by the incorporation of stable isotopes [45-47]. The compounds were only active in a synthetic medium and inactive in a complex one [48]. Compounds designated MC031-034 (58-61) are similar to chlorothricin mentioned above and were isolated from the cultivation broth of Streptomyces sp. collected in Japan. Another compound, 2-hydroxychlorothricin (62), with antitumor activity, was isolated [66] from Streptomyces K818. 

D-Desosamine (51) and D-mycaminose (52) occur in macrolide antibiotics.2 Early studies with tracers showed that the hexose portion of these sugars can be derived from D-glucose without inversion or breakdown of the sugar chain.82,83 The N- methyl groups are derived from methionine.82,84 No further work on the biosynthesis of these sugars has been reported. 

More than 500 different representatives of the macrolide antibiotics are known, most of which are biologically active against Gram-positive bacteria, displaying a relatively low toxicity. Clinically used are erythromycin, oleandomycin, carbomycin and leucomycin (O Fig. 5). They act as inhibitors of the bacterial protein biosynthesis by binding to the 50S-ribosomal subunit. The synthesis of the two clinically important 16-membered ring macrolide antibiotics leucomycin A3 and carbomycin B could be started from D-glucose, which was chosen because it contained three of the required stereocenters [40]. 

At least two unusual features characterize this biosynthesis. One is the origin of the methyl branches in the polyketide chain from the methyl group of methionine. This is in contrast to the biosynthesis of most macrolide antibiotics in which chain branches are formed by utilization of the appropriate homologs in place of acetate chain extension units, i.e., propionate units. The second unusual feature of this biosynthesis is the mode of incorporation of glycerol and particularly the fact that it is a specific precursor of the three-carbon polyketide chain starter unit [50 ]. 

Tylosin 33 from Streptomyces fradiae is a representative member of the large family of 16-membered macrolide antibiotics commonly utilised in veterinary medicine. The aglycone core, tylactone 34 is constructed from two acetate, five propionate and one butyrate units [68, 69]. The processive mechanism for its biosynthesis was demonstrated by the pioneering contributions of Hutchinson... 

In summary, the enzymes responsible for pikromycin biosynthesis represent powerful tools for the generation of novel macrolide antibiotic compounds with the unique biosynthetic capabilities of the pikromycin PKS and the substrate flexibility of the respective tailoring enzymes. In the next section, we highlight work directed at investigating and exploiting the biosynthetic enzymes encoded by pikA, des, and pikC for the production of ketolide compounds through chemoenzymatic approaches. 

Vazquez, D. (1979). Macrolide antibiotics of the spiramycin and carbomycin groups. In Molecular Biology, Biochemistry and Biophysics—Inhibitors of Protein Biosynthesis (A. Kleinzller, G. F. Springer, and H. G. Wittmann, Eds.), Vol. 30, pp. 120-126. Springer-Verlag, Berlin. 

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