The generation of reducing equivalent NADPH via glucose-6-phosphate dehydrogenase (G6PD) is critical for the maintenance of redox homeostasis and reductive biosynthesis in cells. NADPH also plays key roles in cellular processes mediated by redox signaling. Insufficient G6PD activity predisposes cells to growth retardation and demise. Severely lacking G6PD impairs embryonic development and delays organismal growth. Altered G6PD activity is associated with pathophysiology, such as autophagy, insulin resistance, infection, inflammation, as well as diabetes and hypertension. Aberrant activation of G6PD leads to enhanced cell proliferation and adaptation in many types of cancers. The present review aims to update the existing knowledge concerning G6PD and emphasizes how G6PD modulates redox signaling and affects cell survival and demise, particularly in diseases such as cancer. Exploiting G6PD as a potential drug target against cancer is also discussed.

We report a novel pathway for arsenic detoxification in the legume symbiont Sinorhizobium meliloti. Although a majority of ars operons consist of three genes, arsR (transcriptional regulator), arsB [As(OH) 3 /H ؉ antiporter], and arsC (arsenate reductase), the S. meliloti ars operon includes an aquaglyceroporin (aqpS) in place of arsB. The presence of AqpS in an arsenic resistance operon is interesting, since aquaglyceroporin channels have previously been shown to adventitiously facilitate uptake of arsenite into cells, rendering them sensitive to arsenite. To understand the role of aqpS in arsenic resistance, S. meliloti aqpS and arsC were disrupted individually. Disruption of aqpS resulted in increased tolerance to arsenite but not arsenate, while cells with an arsC disruption showed selective sensitivity to arsenate. The results of transport experiments in intact cells suggest that AqpS is the only protein of the S. meliloti ars operon that facilitates transport of arsenite. Coexpression of S. meliloti aqpS and arsC in a strain of E. coli lacking the ars operon complemented arsenate but not arsenite sensitivity. These results imply that, when S. meliloti is exposed to environmental arsenate, arsenate enters the cell through phosphate transport systems and is reduced to arsenite by ArsC. Internally generated arsenite flows out of the cell by downhill movement through AqpS. Thus, AqpS confers arsenate resistance together with ArsC-catalyzed reduction. This is the first report of an aquaglyceroporin with a physiological function in arsenic resistance.Arsenic compounds are widespread in the biosphere, arising from both natural and anthropomorphic sources. The two biologically relevant oxidation states of inorganic arsenic are arsenite [As(III)] and arsenate [As(V)], the former being more toxic than the later. The primary mechanism of arsenite toxicity is due to its ability to react with protein sulfhydryl groups, thereby affecting their function. By itself, arsenate has low toxicity as a phosphate analogue, and its main toxicity is the result of its conversion to arsenite.In response to toxicity, microorganisms have evolved mechanisms for arsenic resistance. Arsenic resistance (ars) genes are common in microbes and are localized to ars operons on either the chromosome or plasmid (11). Many, if not most, ars operons consist of three genes: arsR, arsB, and arsC. ArsR is a trans-acting repressor (23, 25) that senses environmental As(III) and controls the expression of ArsB and ArsC. ArsC is a reductase that reduces As(V) to As(III) (14), while ArsB extrudes As(III) out of the cells by functioning as an As(OH) 3 /H ϩ antiporter (10). Therefore, expression of both ArsB and ArsC provides resistance to both As(III) and As(V). In addition to the three-gene chromosomal ars operon, some ars operons such as those carried by Escherichia coli plasmids R773 and R46 have five genes, arsRDABC, that encode two additional proteins, ArsD and ArsA. ArsD exhibits weak As(III)-responsive transcriptional repressor activity (4), andArsA...

Arsenic is the most pervasive environmental substance and is classified by the International Agency for Research on Cancer as a Group 1 human carcinogen. Nearly every organism has resistance pathways for inorganic arsenic, and in bacteria, their genes are found in arsenic resistance (ars) operons. Recently, a parallel pathway for organic arsenicals has been identified. The ars genes responsible for the organoarsenical detoxification includes arsM, which encodes an As(III) S-adenosylmethionine methyltransferase, arsI, which encodes a C–As bond lyase, and arsH, which encodes a methylarsenite oxidase. The identification and properties of arsM, arsI and arsH are described in this review.

Purified ArsH from Sinorhizobium meliloti exhibits NADPH:FMN-dependent reduction of molecular O 2 to hydrogen peroxide and catalyzes reduction of azo dyes. The structure of ArsH was determined at 1.8 Å resolution. ArsH crystallizes with eight molecules in the asymmetric unit forming two tetramers. Each monomer has a core domain with a central fivestranded parallel b-sheet and two monomers interact to form a classical flavodoxin-like dimer. The N-and C-terminal extensions of ArsH are involved in interactions between subunits and tetramer formation. The structure may provide insight in how ArsH participates in arsenic detoxification.

G6PD deficiency has been the most pervasive inherited disorder in the world since having been discovered. G6PD has an antioxidant role by functioning as a major nicotinamide adenine dinucleotide phosphate (NADPH) provider to reduce excessive oxidative stress. NADPH can produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) mediated by NADPH oxidase (NOX) and nitric oxide synthase (NOS), respectively. Hence, G6PD also has a pro-oxidant role. Research in the past has focused on the enhanced susceptibility of G6PD-deficient cells or individuals to oxidative challenge. The cytoregulatory role of G6PD has largely been overlooked. By using a metabolomic approach, it is noted that upon oxidant challenge, G6PD-deficient cells will reprogram the GSH metabolism from regeneration to synthesis with exhaustive energy consumption. Recently, new cellular/physiologic roles of G6PD have been discovered. By using a proteomic approach, it has been found that G6PD plays a regulatory role in xenobiotic metabolism possibly via NOX and the redox-sensitive Nrf2-signaling pathway to modulate the expression of xenobiotic-metabolizing enzymes. Since G6PD is a key regulator responsible for intracellular redox homeostasis, G6PD deficiency can alter redox balance leading to many abnormal cellular effects such as the cellular inflammatory and immune response against viral infection. G6PD may play an important role in embryogenesis as G6PD-knockdown mouse cannot produce offspring and G6PD-deficient C. elegans with defective egg production and hatching. This array of findings indicates that the cellular and physiologic roles of G6PD, other than the classical role as an antioxidant enzyme, deserve further attention.