NDH-2

NDH-2, also known as type II NADH:quinone oxidoreductase or alternative NADH dehydrogenase, is an enzyme which catalyzes the electron transfer from NADH to a quinone, being part of the electron transport chain. NDH-2 are peripheral membrane protein, functioning as dimers in vivo, with approximately 45 KDa per subunit and a single FAD as their cofactor.
NDH-2 are the only enzymes, with NADH dehydrogenase activity, expressed in the respiratory chain of some pathogenic organisms, and for that they have been proposed as new targets for rational drug design.

Structure

The structure/fold from these proteins may be divided into three domains: first dinucleotide binding domain, second dinucleotide binding domain and C-terminal domain.
The first domain is responsible for the noncovalent binding of FAD, while the second dinucleotide binding domain binds NADH. Both these domain are structurally organized in Rossmann folds, with the characteristic GxGxxG motif present.
The third domain, C-terminal, is responsible for the protein-membrane interaction. Upon expression of a C-terminal truncated version of NDH-2, it was observed an intracellular delocalization from the membrane to the cytoplasm. The third domain, together with part of the first domain, is also partially responsible for the binding of the electron acceptor.
There are currently crystallographic structures for NDH-2 from four different organisms:Staphylococcus aureus Caldalkalibacillus thermarum Saccharomyces cerevisiae

Plasmodium falciparum

Reaction

The enzymatic oxidoreduction reaction catalyzed by NDH-2 may be described as follows:
NADH + Q + H⁺ -----> NAD⁺ + QH₂
In this case, the electron donor is NADH and the electron acceptor is the quinone. Depending on the organism, the reduced quinone changes between menaquinone, ubiquinone or plastoquinone. The mechanism of the reaction may be divided in two half-reactions: 1stHR and 2ndHR.
In the 1stHR, 2 electrons and 1 proton from NADH are transferred to the prosthetic group, giving rise to its protonated form FADH₂. In this phase, an Enzyme-Substrate complex is established, characterized by the appearance of a "Charge-transfer complex".
Na 2stHR, the quinone binds and the 2 electrons and one of the FAD protons are transferred for this second substrate, forming the product quinol.
It is now accepted that the overall mechanism occurs by a ternary complex, instead of the previously proposed.

Phylogenetic distribution

The presence of NDH-2 in organisms which genome as already been fully sequenced was studied by Bioinformatics. In this study, NDH-2 were identified in 83% of Eukaryotes, 60% of bacteria and 32% of Archaeas. It was also observed the absence of NDH-2 in phyla composed of anaerobic organisms.
Despite being considered absent, in this same study, the presence of a gene coding for a NDH-2 homolog was observed in the human genome.