<scp>SIRT</scp>
            2 controls the pentose phosphate switch

Wu, Lindsay E.; Sinclair, David A.

doi:10.15252/embj.201488713

Cited by 13 publications

(15 citation statements)

References 10 publications

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“…Post-translationally, G6PD is modified by lysine acetylation, phosphorylation, ubiquitination and O-GlcNAcylation 34 35 36 37 . We previously found that G6PD is deacetylated and activated by SIRT2 38 , which led us to explore the possibility of targeting SIRT2 to suppress G6PD and leukaemia 39 40 41 . SIRT2-mediated deacetylation of G6PD sustained NADPH production and promoted cell proliferation across different subtypes of AML.…”

Section: Discussionmentioning

confidence: 99%

SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

Wang

et al. 2016

Sci Rep

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Like most other types of cancer cells, leukaemia cells undergo metabolic reprogramming to support rapid proliferation through enhancing biosynthetic processes. Pentose phosphate pathway (PPP) plays a pivotal role in meeting the anabolic demands for cancer cells. However, the molecular mechanism by which PPP contributes to leukaemia remains elusive. Here, we report that leukaemia cell proliferation is dependent on the oxidative branch of PPP, in particular the first and rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of G6PD reduces NADPH level in acute myeloid leukaemia (AML) cell lines. Exogenous lipid supplements partially restore the proliferation of G6PD-depleted cells. Deacetylase SIRT2 promotes NADPH production through deacetylating G6PD at lysine 403 (K403). Activation of G6PD by SIRT2 supports the proliferation and clonogenic activity of leukaemia cells. Chemical inhibitors against SIRT2 suppress G6PD activity, leading to reduced cell proliferation of leukaemia cells, but not normal hematopoietic stem and progenitor cells. Importantly, SIRT2 is overexpressed in clinical AML samples, while K403 acetylation is downregulated and G6PD catalytic activity is increased comparing to that of normal control. Together, our study reveals that acetylation regulation of G6PD is involved in the metabolic reprogramming of AML, and SIRT2 serves as a promising target for further therapeutic investigations.

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Section: Discussionmentioning

confidence: 99%

SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

Wang

et al. 2016

Sci Rep

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“…The rate-limiting step of the salvage pathway is catalyzed by NAMPT and requires PRPP as a cosubstrate, which is mostly supplied by the PPP pathway in cancer cells. 3 , 190 – 192 NAMPT was originally called pre-B-cell colony-enhancing factor (PBEF), a cytokine secreted by early B cells to promote maturation and proliferation. The NAMPT structure presents intracellular and extracellular forms (referred to as iNAMPT and eNAMPT, respectively).…”

Section: Nampt In Cancermentioning

confidence: 99%

NAD+ metabolism, stemness, the immune response, and cancer

Navas

Carnero

2021

Sig Transduct Target Ther

212

171

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NAD+ was discovered during yeast fermentation, and since its discovery, its important roles in redox metabolism, aging, and longevity, the immune system and DNA repair have been highlighted. A deregulation of the NAD+ levels has been associated with metabolic diseases and aging-related diseases, including neurodegeneration, defective immune responses, and cancer. NAD+ acts as a cofactor through its interplay with NADH, playing an essential role in many enzymatic reactions of energy metabolism, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, and the TCA cycle. NAD+ also plays a role in deacetylation by sirtuins and ADP ribosylation during DNA damage/repair by PARP proteins. Finally, different NAD hydrolase proteins also consume NAD+ while converting it into ADP-ribose or its cyclic counterpart. Some of these proteins, such as CD38, seem to be extensively involved in the immune response. Since NAD cannot be taken directly from food, NAD metabolism is essential, and NAMPT is the key enzyme recovering NAD from nicotinamide and generating most of the NAD cellular pools. Because of the complex network of pathways in which NAD+ is essential, the important role of NAD+ and its key generating enzyme, NAMPT, in cancer is understandable. In the present work, we review the role of NAD+ and NAMPT in the ways that they may influence cancer metabolism, the immune system, stemness, aging, and cancer. Finally, we review some ongoing research on therapeutic approaches.

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“…Furthermore, in the pentose phosphate pathway (PPP), glucose-6-phosphate (G6P) dehydrogenase (G6PD) converts G6P to 6-p-gluconate, when the NAD + -dependent SIRT2 deacetylates and activates G6PD. The PPP pathway converts NADP + to NADPH and regenerates the antioxidant glutathione (GSH), thus promoting cell survival during oxidative stress (Wu and Sinclair, 2014). A schematic representation of the subcellular NAD + balance is shown in Figure 2.…”

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confidence: 99%

NAD+ in Brain Aging and Neurodegenerative Disorders

et al. 2019

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NAD + is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD + -dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD + and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer's, Parkinson's, and Huntington diseases, and amyotrophic lateral sclerosis. Advances in understanding the molecular and cellular mechanisms of NAD + -based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders.

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SIRT 2 controls the pentose phosphate switch

Cited by 13 publications

References 10 publications

SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

NAD+ metabolism, stemness, the immune response, and cancer

NAD+ in Brain Aging and Neurodegenerative Disorders

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