Abstract

The pentose-phosphate pathway (PPP) promotes the oxidative decarboxylation of glucose-6-phosphate (G6P) in two consecutive steps, catalyzed by glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD), yielding ribulose-5-phosphate (Ru5P) (Figure 1) (Wamelink et al., 2008). These steps constitute the so-called oxidative PPP branch, where the redox energy of G6P is conserved as NADPH(H +). Together with other NADPH(H +) regenerating systems, such as NADP-dependent isocitrate dehydrogenase and malic enzyme (ME), the oxidative PPP branch represents the most important source of reducing equivalents for (i) antioxidant enzymes, such as glutathione peroxidases and thioredoxin reductases, and (ii) fatty acid synthase (Dringen et al., 2007). Ru5P is isomerized into ribose-5-phosphate (R5P), which serves either as the precursor for nucleotide biosynthesis, or it continues metabolism through the non-oxidative PPP branch. In the latter, R5P epimerize into xylulose-5-phosphate (Xu5P), with which it transketolases producing sedoheptulose-7-phosphate (S7P) plus glyceraldehyde-3-phosphate (G3P). In turn, S7P and G3P transaldolase to form fructose-6-phosphate (F6P) and erythrose-4-phosphate (E4P). E4P is then transketolated with Xu5P forming F6P and G3P. Thus, through the PPP, three moles of G6P yield three CO 2 , two F6P, and one G3P. Since PPP-derived F6P and G3P are glycolytic intermediates too, they can follow conversion into pyruvate. Thus, glycolysis and PPP are two different pathways that share common pools of F6P and G3P intermediates. Accordingly, G6P converted into pyruvate through the PPP conserves both the redox and the energetic values of glucose, highlighting a yet unrecognized high impact of PPP flux activity in redox/energy conservation.

Highlights

  • The pentose-phosphate pathway (PPP) promotes the oxidative decarboxylation of glucose-6phosphate (G6P) in two consecutive steps, catalyzed by glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD), yielding ribulose-5-phosphate (Ru5P) (Figure 1) (Wamelink et al, 2008)

  • Labeling pattern in 13C-pyruvate originated from glycolysis ([2-13C]pyruvate) differs from that originated from a first round of PPP ([3-13C]- and [1,3-13C2]pyruvate), helping to estimate the contribution of both pathways in glucose utilization

  • A parallel incubation under identical conditions needs to be performed to quantify 14CO2 collected from [614C]glucose, since C6-G6P is exclusively decarboxylated in the tricarboxylic acid (TCA) after G6P is converted into pyruvate both through glycolysis and PPP

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Summary

The Impact of PPP in Redox and Energy Conservation

The pentose-phosphate pathway (PPP) promotes the oxidative decarboxylation of glucose-6phosphate (G6P) in two consecutive steps, catalyzed by glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD), yielding ribulose-5-phosphate (Ru5P) (Figure 1) (Wamelink et al, 2008) These steps constitute the so-called oxidative PPP branch, where the redox energy of G6P is conserved as NADPH(H+). Some cell types, such as neurons, express high PGI activity responsible for high equilibration rate of F6P with G6P, leading to a recycling-like PPP (PPP – second and third rounds) Identification of these recycling-PPP 13C-labeled intermediates (black carbons) identifies a more complex pattern of 13C-pyruvate labeling ([1-13C]-, [2-13C]-, and [1,2-13C2]pyruvate after the second PPP round; pattern after a third PPP round is omitted for simplicity) that overestimates glycolysis, underestimating the contribution of PPP to glucose utilization. Labeling in 13C-Ru5P and 13C-R5P ([2-13C]-, [1,2-13C2]-, [1,2,3-13C3]-, etc.) after the second PPP round can be used for an accurate estimation of PPP in highly recycling cells

Radioactive PPP Assessment Ex Vivo
Occurrence of Recycling PPP
PPP Assessment is Intrinsically Underestimated
Overestimation of Glycolysis
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