Conversion of NO2 to NO by reduced coenzyme F420 protects mycobacteria from nitrosative damage

In mycobacteria, F-420, a deazaflavin derivative, acts as a hydride transfer coenzyme for an F-420-specific glucose-6-phosphate dehydrogenase (Fgd). Physiologically relevant reactions in the mycobacteria that use Fgd-generated reduced F-420 (F420H2) are unknown. In this work, F420H2 was found to be oxidized by NO only in the presence of oxygen. Further analysis demonstrated that NO2, produced from NO and O-2, was the oxidant. UV-visible spectroscopic and NO-sensor-based analyses proved that F420H2 reduced NO2 to NO. This reaction could serve as a defense system for Mycobacterium tuberculosis, which is more sensitive to NO2 than NO under aerobic conditions. Activated macrophages produce NO, which in acidified phagosomes is converted to NO2. Hence, by converting NO2 back to NO with F420H2, M. tuberculosis could decrease the effectiveness of antibacterial action of macrophages; such defense would correspond to active tuberculosis conditions where the bacterium grows aerobically. This hypothesis was consistent with the observation that a mutant strain of Mycobacterium smegmatis, a nonpathogenic relative of M. tuberculosis, which either did not produce or could not reduce F-420, was approximate to 4-fold more sensitive to NO2 than the wild-type strain. The phenomenon is reminiscent of the anticancer activity of gamma-tocopherol, which reduces NO2 to NO and protects human cells from NO2-induced carcinogenesis.