Nikkomycins are peptidyl
nucleoside antibiotics that act as therapeutic
antifungal agents in humans and easily degraded
insecticides in agriculture. The
nikkomycin peptidyl moiety contains a pyridyl residue derived from
L-lysine. The first step in peptidyl biosynthesis is an
aminotransferase-catalyzed reaction that converts
L-lysine to Delta(1)- or
Delta(2)-piperideine-2-carboxylate (P2C). Spectral, chromatographic, and kinetic analyses show that the aerobic reaction of nikD with P2C results in the stoichiometric formation of
picolinate, accompanied by the reduction of 2 mol of
oxygen to
hydrogen peroxide. A high resolution HPLC method, capable of separating
picolinate,
nicotinate and isonicotinate, was developed and used in product identification. NikD contains 1 mol of covalently bound
FAD and exists as a monomer in
solution. Reductive and oxidative titrations with
dithionite and
potassium ferricyanide, respectively, show that
FAD is the only redox-active group in nikD. Anaerobic reaction of nikD with 1 mol of P2C results in immediate reduction of
enzyme-bound
FAD. Because nikD is an obligate 2-electron acceptor, it is proposed that the observed 4-electron oxidation of P2C to
picolinate occurs via a mechanism involving two successive nikD-catalyzed 2-electron oxidation steps. In addition to nikkomycins, a nikD-like reaction is implicated in the biosynthesis of an
L-lysine-derived pyridyl moiety found in
streptogramin group B antibiotics that are used as part of a last resort treatment for severe
infections due to gram positive bacteria.