Which pathway produces nadph

In the skeletal muscle, FFAs reduce insulin-stimulated glucose intake, resulting in skeletal muscle insulin resistance On the other hand, lipolysis in adipose tissues increases hepatic acetyl CoA levels and pyruvate carboxylase activity which further promotes hepatic glucose production.

Both hepatic glucose production and pro-inflammatory cytokines contribute to hepatic insulin resistance 8 , 17 , Recent studies suggest that the PPP might serve as a novel and promising target for modulating obesity-induced inflammation and insulin sensitivity in different tissues.

Pro-inflammatory cytokines also increase G6PD expression in adipocytes. This vicious cycle promotes obesity-related insulin resistance, resulting in severe T2DM. The non-oxidative PPP in adipose tissues also plays an important role in regulating insulin sensitivity. Therefore, loss of TKT in adipose tissues alleviates high fat diet HFD -induced obesity, leading to reduced hepatic steatosis and improved insulin sensitivity Furthermore, G6PD in skeletal muscle regulates glucose uptake and insulin sensitivity It is reasonable to assume that regulating CARKL may reduce obesity-induced inflammation, leading to increased insulin sensitivity.

Figure 2. The role of the PPP in insulin resistance. M2 macrophages release anti-inflammatory mediators including IL and arginase 1 to maintain insulin sensitivity. Decreased G6PD in adipocytes suppresses inflammation and ameliorates insulin resistance. The amplifying pathway accounts for the majority of glucose-stimulated insulin secretion GSIS. Decreased insulin secretion in the amplifying pathway is often observed in patients with T2DM.

Therefore, how to simulate insulin secretion during the amplifying pathway is important for the prevention and treatment of T2DM. Patients with G6PD deficiency show decreased insulin secretion Figure 3.

The role of the PPP in insulin secretion. Diabetes can lead to diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, diabetic macroangiopathy and other chronic complications.

Oxidative stress can cause these complications by activating the hexosamine pathway, the advanced glycation end products AGEs pathway and the diacylglycerol DAG -protein kinase C PKC pathway Hyperglycemia decreases G6PD activity through the activation of protein kinase A PKA and increase of intracellular oxidative stress, leading to chronic kidney injury, and diabetic kidney disease DKD 43 — Moreover, overexpression of G6PD in endothelial cells prevents diabetic cardiomyopathy by decreasing ROS accumulation and increasing endothelial cell viability TKT plays an important role in preventing hyperglycemia-induced vascular cell dysfunction Thiamine deficiency and decreased TKT activity has been reported to contribute to diabetic complications Low plasma thiamine was found in patients with DKD and diabetic rats.

After high-dose thiamine therapy, the progression of proteinuria and microalbuminuria was reversed in both patients and animal models, indicating that regulating the activity of TKT may be a promising therapy in treating DKD 47 , 49 , Benfotiamine, a lipid-soluble thiamine derivative, can prevent diabetic retinopathy and cardiomyopathy as well as accelerate the healing of diabetic limbs by activating TKT 51 — However, benfotiamine did not show promising efficacy in phase II and IV trials for the treatment of DKD or diabetic peripheral nerve function 54 , Therefore, other transketolase activators await further investigation.

Various enzymes in the PPP have been shown to be potential targets in cancer therapy. These proteins not only function as metabolic enzymes, but also participate in the regulation of other cellular activities. Therefore, we will summarize recent findings in upstream signaling pathways regulating PPP enzymes in cancer initiation and progression Table 1.

Up-regulation of the G6PD level or activity is often observed in many kinds of cancer 79 — Several signaling pathways have been identified to be responsible for promoting G6PD expression or activity in cancer cells Figure 4.

TAp73, a member of the p53 family which is often overexpressed in cancers, supports tumor growth by inducing G6PD expression 56 , Nuclear factor E2-related factor 2 NRF2 is a transcription factor regulated by oxidative stress. In addition, some post-translational modifications such as phosphorylation, acetylation, O-GlcNAcylation and ubiquitination affect the activity of G6PD 59 , 67 , 69 , Figure 4. Regulation of G6PD in cancers. Several signaling pathways have been identified to be responsible for promoting G6PD expression or activity in cancer cells.

These signaling pathways interact with each other, adding complexity to the regulation of G6PD. The level of G6PD often negatively correlates to the prognosis of cancer patients Suppression of G6PD induces cellular senescence in hepatocellular carcinoma HCC cells and leads to intracellular oxidative stress, making cancer cells sensitive to chemotherapy 60 , Interestingly, elevated G6PD is not observed in liver cirrhosis which is a main cause of liver cancer, indicating that G6PD might play an important role in promoting malignant transformation However, the role of 6PGL in cancer remains to be elucidated.

In addition to its function as a metabolic enzyme, 6PGD also regulates cell metastasis by promoting phosphorylation of c-Met Post-translational modification of 6PGD is important for cancer cell proliferation and tumor growth. Acetylation of 6PGD plays a key role in coordinating redox homeostasis, lipogenesis and glycolysis Patients with lower levels of 6PGD Y phosphorylation have longer median survival time Aberrant expression of 6PGD can accelerate cancer cell proliferation and induce resistance to chemical or radical therapy 72 , 94 — All these findings suggest that inhibiting the expression or activity of 6PGD might be a promising therapeutic strategy for cancer.

Kras G12D regulates the non-oxidative but not oxidative PPP to provide cancer cells with sufficient R5P for nucleotide biosynthesis RPI promotes tumor growth and colony formation by negatively modulating protein phosphatase 2A PP2A to activate extracellular signal-regulated kinase ERK signaling pathways In zebrafish, overexpression of RPI contributes to fatty liver, liver cirrhosis and cell proliferation High level of RPI is reported to predict negative clinical outcomes of colorectal cancer patients.

The expression of TKT is elevated in many types of cancer 75 — 78 , 83 , Patients with pancreatic cancer have higher levels of serum fructose which induces TKT expression to drive nucleic acid synthesis in cancer cells Despite the accumulation of R5P, knockdown of TKT suppresses tumor growth and sensitizes cancer cells to chemotherapy Recent work suggests that TKT promotes genome instability by regulating nucleotide biosynthesis during liver injury and cancer initiation In addition, TKT can regulate cell cycle and promote the viability and proliferation of cancer cells independent of its enzyme activity.

Moreover, higher TALDO expression often indicates poorer clinical outcomes and more resistance to trastuzumab therapy in breast cancer. When human epidermal growth factor receptor 2 HER2 signaling is inhibited, breast cancer cells rely on the non-oxidative arm of the PPP to replenish the oxidative arm. NADPH, a key intracellular reductant, is required for glutathione system and other ROS scavengers to maintain the redox homeostasis Therefore, the PPP serves as an ideal target for regulating the redox homeostasis in metabolic diseases and cancer.

The PPP regulates insulin secretion. Insulin promoting the growth and proliferation of cells is one of the mechanisms underlying increased cancer risk in obese and diabetic patients , Chronic inflammation is a well-known hallmark of cancer and insulin resistance.

Obesity-related inflammation is believed to create a microenvironment contributing to the initiation and progression of cancer In turn, cancer cells secrete cytokines to recruit macrophages, leading to cancer-related inflammation, which plays an important role in cancer cell migration and invasion , The PPP plays a critical role in type 2 diabetes and cancer.

XT designed and revised the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor is currently co-organizing a Research Topic with one of the authors XT, and confirms the absence of any other collaboration. We would like to thank all members in the Tong laboratory for their helpful suggestions.

We apologize to those researchers whose work could not be cited or discussed in detail due to the space limitation. Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci. The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: a review. J Inherit Metab Dis. Redox Biol. Bradshaw PC. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol Rev Camb Philos Soc. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications.

Nat Rev Endocrinol. Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Front Physiol. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest. These compounds are used in a variety of different biological processes including production of nucleotides and nucleic acids ribosephosphate , as well as synthesis of aromatic amino acids erythrosephosphate.

Glucosephosphate dehydrogenase is the rate-controlling enzyme in this pathway. In mammals, the PPP occurs exclusively in the cytoplasm; it is found to be most active in the liver, mammary gland, and adrenal cortex.

While the PPP does involve oxidation of glucose, its primary role is anabolic rather than catabolic, using the energy stored in NADPH to synthesize large, complex molecules from small precursors. For example, erythrocytes generate a large amount of NADPH through the pentose phosphate pathway to use in the reduction of glutathione.

In addition to the synthesis of fatty acids, NADPH is also required for the biosynthesis of cholesterol , neurotransmitters, and nucleotides via phosphoribosyl-pyrophosphate PRPP. Furthermore, NADPH-dependent reductases are involved in tissue detoxification and are further used in the reduction of glutathione in erythrocytes. The pentose phosphate pathway can be divided into 2 distinct phases: a first oxidative and a second non-oxidative reductive phase.

Both processes occur exclusively in the cytoplasm. In the first oxidative phase of the pentose phosphate pathway, glucose is oxidized to generate 2 molecules of NADPH.

This step is essentially irreversible and the committing step , as the reactions are strongly exergonic. The oxidative phase starts with dehydrogenation at the C1 atom of glucosephosphate, a reaction catalyzed by glucosephosphate dehydrogenase G6PD. The reaction product is 6-phosphogluconolactone. The oxidative decarboxylation of 6-phosphogluconate by gluconatephosphate dehydrogenase yields 3-ketophosphogluconate , which is converted to ribulosephosphate , a substrate for non-oxidative reactions, and NADPH.

This second, non-oxidative phase is reversible and reductive. It yields pentoses used in the synthesis of nucleotides and catalyzes the interconversion of 3, 4, 5, 6, and 7-carbon sugars.

This, in turn, may result in intermediates, which, for example, may enter glycolysis. Ribulosephosphate generated in the oxidative phase is partly converted to xylulosephosphate, catalyzed by ribulosephosphate epimerase , and partly isomerized by the enzyme phosphopentose isomerase ribosephosphate isomerase to ribosephosphate. The 2 resulting C 5 carbohydrates are now required for the next step: xylulosephosphate serves as a C 2 donor.

The enzyme transketolase transfers 2 carbon fragments to the pentose ribosephosphate, which yields glyceraldehydephosphate and sedoheptulosephosphate. The 2 products of the previous step continue to transfer carbon fragments: The enzyme transaldolase transfers 3 carbon atoms of sedoheptulosephosphate to glyceraldehydephosphate; thus, 2 new carbohydrates are generated: erythrosephosphate and fructosephosphate.

This step is also catalyzed by a transketolase ; together with erythrosephosphate, generated in the third reaction, another xylulosephosphate is used to generate another fructosephosphate and an additional glyceraldehydephosphate. Ultimately, this means that 3 molecules of ribosephosphate can generate 2 molecules of fructosephosphate and 1 molecule of glyceraldehydephosphate, which may be fed into the glycolytic pathway. Furthermore, fructosephosphate can be converted back into glucosephosphate and enter into a new pentose phosphate pathway.

The demand and availability of different reaction products, intermediates, and substrates starting reactants of the pathway determine which part of the pentose phosphate pathway is operative and how fast the part is. Only when NADPH is required for reductive biosynthesis reactions, is the first phase of the pentose phosphate pathway active.

It is assumed that insulin upregulates the transcription rate of glyceraldehydephosphate dehydrogenase, which amplifies the first step of the pentose phosphate pathway. As the pentose phosphate pathway and the glycolytic pathway are directly connected and defined by a coordinated interplay or exchange of various molecules between them, the output of the pentose phosphate pathway is determined by the needs of the cell.

Four different metabolic situations are described as follows:.