Type II NADH dehydrogenase (NDH-2) (NDH-2)

Type II NADH dehydrogenase (NDH-2) is a membrane-bound flavoenzyme that serves as the primary entry point for electrons into the mycobacterial respiratory chain (UniProt P9WIV3). It catalyzes the oxidation of NADH to NAD+ and the concomitant reduction of menaquinone to menaquinol (Yano et al., 2011). Because humans lack NDH-2 and instead utilize the structurally distinct Complex I (NDH-1), this enzyme represents a high-value target for selective antitubercular drug development (Cook et al., 2014). NDH-2 is essential for the survival of Mycobacterium tuberculosis in both replicating and non-replicating states, as it maintains the proton motive force required for ATP synthesis. Pharmacological inhibition of NDH-2, or its subversion to produce reactive oxygen species (as seen with clofazimine), leads to metabolic collapse and bactericidal effects (Heikal et al., 2016). Current research focuses on identifying potent NDH-2 inhibitors to combat multi-drug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis strains. The enzyme's role in maintaining redox balance makes it particularly vulnerable to small molecule interference. Associated membrane targets in the respiratory chain, such as cytochrome bc1 and ATP synthase, work in tandem with NDH-2 to sustain the energy needs of the pathogen.

Other names

NADH:menaquinone oxidoreductaseNdhNdhANon-proton-pumping NADH dehydrogenaseNDH-IIType II NADH:quinone oxidoreductase

Inhibition of NADH oxidation and electron transfer to the menaquinone pool, leading to ATP depletion and increased production of reactive oxygen species (ROS).