Chloramphenicol biosynthesis

Gross F, Lewis EA, Piraee M, van Pee K-H, Vining LC, White RL (2002) Isolation of 3 -O-Acetylchloramphenicol A Possible Intermediate in Chloramphenicol Biosynthesis. Bioorg Med Chem Lett 12 283... 

Chloramphenicol.—A synthetase which converts chorismic acid into p-amino-phenylalanine (an intermediate in chloramphenicol biosynthesis) has been partly characterized it requires an aminotransferase and pyridoxal phosphate for activity.58... 

To illustrate mechanisms by which complex halogenated secondary metabolites are elaborated, the haloperoxidase-mediated biosynthesis of selected halometabolites elaborated by marine microorganisms will be described. The discussion given by Neidleman20 of chloramphenicol biosynthesis provides an example of bacterial halometabolite biosynthesis, while fungal halometabolite biosynthetic schemes are found in the monograph by Turner21. 

The pyruvate derivative (159) is a likely intermediate in the formation of the amino-acid (160) in chloramphenicol biosynthesis. A search for an enzyme in cultures of a Streptomyces species which produces (161) has led only to the isolation of a non-specific amino-transferase. ... 

The biosynthesis of many secondary metabolites is inhibited by processes resembling feedback inhibition. The end-product repression of arylamine synthase, an enzyme catalyzing the amination of chorismic acid to an aromatic amine which serves as an intermediate in chloramphenicol biosynthesis, was described (29). 

An example is probably the regulation of chloramphenicol biosynthesis (D 8.2) in Strcptomyces venezuelae. Structural genes are located on the chromosome but genes whose mutation represses chloramphenicol formation by 90 % fail to map on it. A plasmid which may carry these genes can be demonstrated after cell disintegration, but it has not yet been characterized. 

PodzeUnska K, Latimer R, Bhattacharya A, Vining LC, Zechel DL, Jia ZC. Chloramphenicol biosynthesis the structure of CmlS, a flavin-dependent halogenase showing a covalent flavin-aspartate bond. J. Mol. Biol. 2010 397(1) 316-331. 

Aminoglycosides Tetracyclines Chloramphenicol Erythromycin Clindamycin Spectinomycin Mupirodn Fusldfc add Inhibition of protein biosynthesis... 

As a group, the protein biosynthesis inhibitors comprise the second largest class of antibiotics available for clinical use. Natural product classes of antibiotics that inhibit the protein biosynthesis are aminoglycosides, tetracyclines, chloramphenicol, macrolides, lincosamides, fusidic acid, streptogramins and mupirocin (Fig. 7). 

Chloramphenicol. Only chloramphenicol and a few closely related analogues fall into this group, Chloramphenicol, a nitro benzene derivative of dichloioacetic acid, inhibits piotein biosynthesis,... 

Piraee M, White RL, Vining LC (2004) Biosynthesis of the Dichloroacetyl Component of Chloramphenicol in Streptomyces venezuelae ISP5230 Genes Required for Halogenation. Microbiology 150 85... 

Thus for instance its biosynthesis [5] was investigated with the aid of stable isotopes (2H, 13C), in experiments in which acetic acid or dichloroacetic acid served as precursors. In streptomyces it was found that the addition of amino acids such as phenylalanine, or P-nitrophenylserine increases the chloramphenicol production. In further experiments NaCl was replaced with NaBr and bromo and chloroderivatives could be isolated from the cultivation broth [6]. 

Although chloramphenicol inhibits carotenoid synthesis, it also inactivates photo-chemically responsive membranes in which carotenoids are located, and hence previous conclusions that the enzymes involved in carotenoid biosynthesis are themselves synthesized in the cytoplasm are not strictly valid. However, the demonstration367 that dark-grown Euglena gracilis, which has carotenoids localized in the proplastids, can synthesize carotenoids in the presence of chloramphenicol indicates that such synthesis is not dependent on protein synthesis in the proplastid. 

Inhibitions of protein synthesis were subsequently confirmed by chemical analyses for protein in growing bacterial cultures38, 39. Figure 439 shows the specific inhibition of protein biosynthesis by chloramphenicol in E. coli and the continuation of RNA ( ribose ) and DNA biosynthesis for an experimental period of 50 minutes. Similar results have been typically obtained with other inhibitors of protein biosynthesis. 

Park and Strominger noticed the accumulation of a C3didine derivative in cultures of Staphylococcus aureus which had been inhibited by chloramphenicol, penicillin, or Crystal Violet. This cytidine derivative has been identified by Baddiley s group as cytidine ribitol pyrophosphate. Since these inhibitors affect the cell-wall synthesis, the data lend support to the belief that the cytidine compound is involved in the biosynthesis of a cell-wall constituent, and a likely candidate would be ribitol teichoic acid. 

Several studies of the biosynthesis of chloramphenicol have led to the conclusion that it is formed via the shikimic acid pathway, specifically from chorismic acid. An arylamine synthetase promotes formation of p-amino-L-phenyl alanine (1 ) 50>51. This product is converted to chloramphenicol (15) by oxidation of the amine function to a nitro group, by hy-droxylation of the benzylic methylene group, reduction of the carboxyl... 

Mach, Reich and Tatum were able to demonstrate an inhibition of the biosynthesis of protein in cells of B. brevis by chloramphenicol and puromycin without affecting the synthesis of tyrocidine . Several analogues of amino acids were found, which inhibited the biosynthesis of tyrocidine without affecting that of protein and vice versa. In contrast to protein synthesis, the production of tyrocidine did not depend on the continuous synthesis of RNA. Furthermore, environmental factors were able to control the relative amounts of the different tyrocidines synthesized by genetically homogeneous cultures . Addition of phenylalanine to the culture medium resulted in the almost exclusive synthesis of tyrocidine A, whereas the unsupplemented culture produced tyrocidine A, B and C. In the presence of tryptophan, a new form of tyrocidine, called tyrocidine D, containing three tryptophan in place of three phenylalanine residues, was produced. This lack of absolute requirement for specific amino acids in the formation of a peptide bond is in contrast to the strict specificity of sequential incorporation of amino acids... 

There are also a large number of antibiotics structurally unrelated to penicillins and cephalosporins. These compounds exert their antimicrobial activity by inhibiting protein biosynthesis. In 1947 chloramphenicol (see Figure 3) was isolated from cultures of Streptomyces venezuelae. It is a broad-spectrum bacteriostatic agent that interferes with protein synthesis by binding to bacterial ribosomes. The use of chloramphenicol in humans is hmited because of the drug s toxicity. It inhibits liver enzymes and suppresses red blood cell formation. 

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