Biosynthesis of the antituberculous agent caprazamycin

Caprazamycins, produced by Streptomyces sp. MK730-62F2, are liponucleoside antibiotics displaying potent antituberculous activity in vitro against multi drug-resistant Mycobacterium tuberculosis strains. Therefore, they are expected to be promising compounds for the development of antituberculous drugs. All of the cpz genes required for caprazamycin biosynthesis have been identified.¹ However, the biosynthetic pathway of caprazamycin is not fully understood. It has been proposed that the cpz23 gene is essential for caprazamycin biosynthesis and is involved in β-hydroxyacyl transfer during the biosynthesis of β-hydroxyacylated caprazol. To confirm this hypothesis, we constructed the cpz23-deleted mutants (Δcpz23) and identified a novel metabolite that accumulated in the mutant. NMR and HRMS analyses unequivocally established the structure of the unknown metabolite as caprazol 3′′-phosphate, which has a core skeleton of caprazamycin with a phosphate group at the 3′′ position but lacks the acyl moiety attached to the 3′′′-hydroxy group. This result suggests that Cpz23 may catalyze the acylation of the 3′′′-hydroxy group in caprazol 3′′-phosphate. To test this hypothesis, we are investigating the Cpz23-catalyzed reaction. The characterization of Cpz23 may lead to the production of promising caprazamycin derivatives, because the acyl group is critically important for the antibacterial properties of caprazamycin.

1) Kaysser, L. et al. J. Biol. Chem. 284: 14987-14996 (2009).