Biosynthetic Modifications

Genetic engineering of biosynthetic pathways to create specific modifications in chemical structure of secondary metabolites is now a practical reality in bacterial systems. In the simplest cases, a single enzymatic function is eliminated by inactivating the respective gene, resulting in an altered product. One such example is shown in Figure 6.10 from the work of scientists at Biotica Technologies, Cambridge, U.K., where the oxidation state of the aromatic ring in the ansamycin antibiotic macbecin is reduced from quinone to phenol. This was accomplished by inactivation of the gene macM that was found through genetic analysis to code for the specific enzyme responsible for addition of the para oxygen to the phenol ring that is further oxidized to the quinone.

Macbecin

Nonquinone analogs of macbecin

FIGURE 6.10 Macbecin and nonquinone analogs derived from the knock out of a key oxidative function.

Macbecin

Nonquinone analogs of macbecin

FIGURE 6.10 Macbecin and nonquinone analogs derived from the knock out of a key oxidative function.

The macbecins are promising HSP-90 inhibitors with potential in cancer chemotherapy whose off-target effects have been linked to the reactive quinone moiety. The new products lack this reactive unit and are expected to have reduced side effects. This precise alteration in the structure was made possible by the identification of the functions associated with the key genes found in the macbecin biosynthetic gene cluster.

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