Type II NADH:quinone oxidoreductase family: phylogenetic distribution, structural diversity and evolutionary divergences

Abstract

Type II NADH:quinone oxidoreductases (NDH-2s) are membrane proteins, crucial for the catabolic metabolism, because they contribute to the maintenance of the NADH/NAD balance. In several pathogenic bacteria and protists, NDH-2s are the only enzymes performing respiratory NADH:quinone oxidoreductase activity. For this reason and for being considered absent in mammals, NDH-2s were proposed as suitable targets for novel antimicrobial therapies. We selected all sequences of genes encoding NDH-2s from fully sequenced genomes present in the KEGG database. These genes were present in 61% of the 1805 species belonging to Eukarya (83%), Bacteria (60%) and Archaea (32%). Notably sequences from mammal species including humans were retrieved in our selection as NDH-2s. The data obtained and the already available information allowed systematizing several properties of NDH-2s: (i) the existence of additional sequence motifs with putative regulatory functions, (ii) specificity towards NADH or NADPH and (iii) the type of quinone binding motif. We observed that NDH-2 family distribution is not congruent with the taxonomic tree, suggesting different origins for the eukaryotic sequences and possible lateral gene transfer among prokaryotes. We note the absence of genes coding for NDH-2 in anaerobic phyla and the presence of multiple copies in several genomes, specifically in cyanobacteria. These observations inspired us to propose a metabolic hypothesis for the appearance of NDH-2s.

Genomes of ubiquitous marine and hypersaline Hydrogenovibrio, Thiomicrorhabdus and Thiomicrospira spp. encode a diversity of mechanisms to sustain chemolithoautotrophy in heterogeneous environments

“…All of these organisms carry genes encoding complex I (NADH:ubiquinone reductase, EC 1.6.5.3). Some members of Hydrogenovibrio carry genes encoding alternative (type II) NADH:ubiquinone reductase (EC 1.6.5.9), which is common among ‘Proteobacteria’ (Marreiros et al ., ), though not among the autotrophic organisms surveyed here (Supporting Information Table S4). Type II NADH:ubiquinone reductase oxidizes NADH without directly contributing to proton potential, which may function to maintain cellular NADH/NAD + ratios (Kerscher et al ., ).…”

The mechanism of catalysis by type-II NADH:quinone oxidoreductases

“…The low NADP + /NADPH affinity can be explained by the structure of NDH-2 with NAD + /NADH bound (discussed later), by unfavorable interactions between the side chain of E198 and the adenine nucleotide phosphate. Indeed, sequence analyses suggests that the majority of NDH-2 variants contain Glu or Asp at this position and so react only with NADH2, and the corresponding Glu to Gln mutation in Agrobacterium tumefaciens NDH-2 was demonstrated to change its specificity towards NADPH23.…”

“…Unlike in NDH-1 (respiratory complex I, which catalyzes the same reaction in animals and many other species) catalysis by NDH-2 is not used to support the proton motive force that drives ATP synthesis, so its catalysis is highly exergonic and essentially irreversible. NDH-2 is also much smaller and simpler in structure than complex I – it comprises only a single subunit and one flavin redox cofactor12. Consequently, it has been explored as a gene therapy for human complex I disorders, to relieve the accumulation of NADH and decrease reactive oxygen species (ROS) production3456.…”

Alternative NAD(P)H dehydrogenase and alternative oxidase: Proposed physiological roles in animals

“…1B) is a non-classical RS enzyme which uses reductants (sulphide, sulphite, or cyanide) which are not normally formed under aerobic metabolism in typical eukaryotes (Hildebrandt and Grieshaber, 2008). Some distant homology is observed between NDH2s and apoptosis-inducing factor (AIF), and apoptosis-inducing factor-like proteins (Elguindy and Nakamaru-Ogiso, 2015;Marreiros et al, 2016). Moreover, it was shown that NDH2 from the budding yeast Saccharomyces cerevisiae is able to promote apoptosis (Li et al, 2006;Cui et al, 2012), while AIF can operate as a NADH dehydrogenase (Elguindy and Nakamaru-Ogiso, 2015).…”