Thienamycin biosynthesis

Figure 4.19 Early biosynthetic pathway for thienamycin biosynthesis and assignment of functions to the different genes.

Figure 4.21 Latest biosynthetic pathway for thienamycin biosynthesis.

Occurrence, Fermentation, and Biosynthesis. Although a large number of Streptomjces species have been shown to produce carbapenems, only S. cattkja (2) and S. penemfaciens (11) have been reported to give thienamycin (2). Generally the antibiotics occur as a mixture of analogues or isomers and are often co-produced with penicillin N and cephamycin C. Yields are low compared to other P-lactams produced by streptomycetes, and titres are of the order of 1—20 p-g sohdusmL despite, in many cases, a great deal of effort on the optimization of the media and fermentation conditions. The rather poor stabiUty of the compounds also contributes to a low recovery in the isolation procedures. The fermentation and isolation processes for thienamycin and the olivanic acids has been reviewed in some detail (12). 

Occurrence, Fermentation, and Biosynthesis. Although a large number of Streptomyces species have been shown to produce carbapenems. only S. cattleya and S. penemfaciens have been reported to give thienamycin. Generally the antibiotics occur as a mixture of analogues or isomers and are often coproduced with penicillin N and cephaniycin C. 

Little has been published on the biosynthesis of the carbapenem antibiotics. Albers-Schonberg et al. 281) reported that the carbapenem nucleus in thienamycin is derived from glutamate and acetate as shown in Fig. 6, but so far no detailed account of this work has been published. Box... 

M. Sanada, t. Miyano, S. Iwadare, I.M. Williamson, B.H. Arison, I.L. Smith, A.W. Douglas, I.M. Liesch, E. Inamine, Biosynthesis of fluorothreonine and fluoroacetic acid by the Thienamycin producer, Streptomyces-catdeYa, J. Antibiot. 39 (1986) 259-265. 

Fluorothreonine. In 1986 a second Streptomyces species capable of the biosynthesis of fluorinated compounds was identified (24). In the course of studies with Streptomyces cattleya to improve the yield of the 6-lactam antibiotic, thienamycin, it was discovered that when fluoride was present in tiie culture medium both fluoroacetate 1 and 4-fluorothreonine 6 accumulated in millimolar concentrations during fermentation. 4-fluorothreonine is the only naturally ocurring fluorinated amino acid known. When 4-fluorothreonine was initially isolated (24) the absolute stereochemistry of 4-fluorothreonine was predicted to be analogous to L-threonine. We have recently confirmed this by asymmetric synthesis (25) and demonstrated that natural 4-fluorothreonine has the (25, 3S) configuration. The... 

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