The regulation of the oxidative phase of the pentose phosphate pathway: New answers to old problems

Abstract

There is a paradox in the oxidizing phase of the phosphate pentose pathway that has not yet been solved. The flow through the pathway is reduced in basal conditions; however, it must rise notably when a NADPH supplement is required. The paradox consists of the strong inhibition that the NADPH exerts on the both dehydrogenases of the pathway, especially on the regulating enzyme glucose-6-phosphate dehydrogenase (G6PD). Theoretically, in anabolic situations, the increase of gene expression of G6PD and 6-phosphogluconate dehydrogenase can induce a rise in the production of NADPH, which would cause the immediate inhibition of the enzyme and a drastic flow reduction. However, increasing the flow through oxidative phase of the pentose phosphate pathway (OPPP) has been experimentally demonstrated in many physiological states. However, this situation will be resolved if the NADPH metabolized or otherwise sufficient NADPH is sequestered to relax the inhibition of the dehydrogenases of OPPP and to maintain high ratio of NADPH/NADP 1 needed to ensure the reducing environment of the cell cytoplasm and the contribution of NADPH for anabolic processes. In 1974, the presence of a protein capable of reversing the inhibition of G6PD by NADPH was detected; however, to date, this paradox remains undisclosed. This review deals with the possibility that such reverting action might be similar to the activity of a protein named HSCARG, which is responsible for the abduction of NADPH, thus keeping a portion of the coenzyme away from the catalytic action and, simultaneously, the immune response through the NF-jB (nuclear factor kappa light-chain enhancer of activated B cells) system. The model has many similarities with the hypothesis proposed some 40 years back on the reversion of G6PD inhibition by NADPH. V C 2014 IUBMB Life, 66(11):775-779, 2014

Synergistic Killing of Polymyxin B in Combination With the Antineoplastic Drug Mitotane Against Polymyxin-Susceptible and -Resistant Acinetobacter baumannii: A Metabolomic Study

“…Apart from its potential impact on membrane structure and the bacterial stress response, mitotane monotherapy also affected pentose phosphate pathway in FADDI-AB065 ( Figure 6 ). Pentose phosphate pathway is responsible for the production of NADPH during the oxidative phase and ribose during the non-oxidative phase, which are essential products for anabolic reactions and DNA/RNA synthesis, respectively ( Wamelink et al, 2008 ; Barcia-Vieitez and Ramos-Martinez, 2014 ). As the metabolites affected by mitotane in FADDI-AB065 are involved in the non-oxidative phase of pentose phosphate pathway, it is likely that mitotane also affects DNA/RNA synthesis in A. baumannii .…”

Redox state affects fecundity and insecticide susceptibility in Anopheles gambiae

“…However, little is known about how significant the NADPH dependent reducing power is to these defense mechanisms. NADPH is primarily produced through the oxidative phase of the pentose phosphate pathway (PPP) 19 , 20 . In this paper, we present the evidence that exposure to an oxidative stressor and metabolic inhibition of NADPH regeneration result in a redox shift, which leads to adverse effects on mosquito fecundity and insecticide detoxification.…”

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“…The activity of glucose-6-phosphate dehydrogenase plays a central role in cellular oxidative-reduction processes 24,25 . This enzyme plays a significant role in the regulation of oxidative stress through the initial regulation of NADPH as the main intracellular reductant.…”