Recent findings in the regulation of G6PD and its role in diseases

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) is the only rate-limiting enzyme in the pentose phosphate pathway (PPP). Rapidly proliferating cells require metabolites from PPP to synthesize ribonucleotides and maintain intracellular redox homeostasis. G6PD expression can be abnormally elevated in a variety of cancers. In addition, G6PD may act as a regulator of viral replication and vascular smooth muscle function. Therefore, G6PD-mediated activation of PPP may promote tumor and non-neoplastic disease progression. Recently, studies have identified post-translational modifications (PTMs) as an important mechanism for regulating G6PD function. Here, we provide a comprehensive review of various PTMs (e.g., phosphorylation, acetylation, glycosylation, ubiquitination, and glutarylation), which are identified in the regulation of G6PD structure, expression and enzymatic activity. In addition, we review signaling pathways that regulate G6PD and evaluate the role of oncogenic signals that lead to the reprogramming of PPP in tumor and non-neoplastic diseases as well as summarize the inhibitors that target G6PD.

Exploring the Multi-Faceted Role of Sirtuins in Glioblastoma Pathogenesis and Targeting Options

“…Moreover, SIRT5 regulates isocitrate to α-ketoglutarate (α-KG) by desuccinylating isocitrate dehydrogenase 2 (IDH2), thus supporting ROS scavenging activities. In addition, SIRT5, through deglutarylation, increases the activity of glucose 6-phosphate dehydrogenase (G6PD) via the pentose phosphate pathway (PPP) and promotes NADPH production [ 84 , 87 ]. Rapidly proliferating cells require metabolites from PPP to synthesize ribonucleotides and regulate gene expression.…”

“…Rapidly proliferating cells require metabolites from PPP to synthesize ribonucleotides and regulate gene expression. G6PD expression can be deregulated in a variety of cancers and act as a regulator of viral replication [ 87 ]. Recent studies have suggested that SIRT5 plays an important role as a proviral factor necessary for the efficient replication of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through its direct interaction with the viral Nsp14 protein [ 88 ].…”

The impact of the endocrine-disrupting chemicals on the glucose-6-phosphate dehydrogenase enzyme activity

“…Glucose-6-phosphate dehydrogenase (G6PD, glucose 6-phosphate: NADP (+) oxidoreductase, EC1.1.1.1.49) enzyme is the first and rate-limiting step in the pentose phosphate pathway (PPP). G6PD is an allosteric enzyme found in monomer, homodimer, and homotetramer forms and catalyzes the production of 6-phosphogluconolactone from glucose-6-phosphate (G6P) ( Meng et al, 2022 ). G6PD maintains the reduction of NADP + into coenzyme NADPH which is vital for various reductive biosynthetic reactions such as maintaining reduced glutathione (GSH), protection against reactive oxygen species (ROS), and detoxification of xenobiotics ( B Tandogan, 2011 ; Gao et al, 2019 ).…”

Human papillomavirus type 16 E6 promotes cervical cancer proliferation by upregulating transketolase enzymatic activity through the activation of protein kinase B

“…21,22 NADPH provides materials for tumor biosynthesis while reducing oxidative stress within tumor cells. [23][24][25] In some tumor cells, over 85% of the ribose produced in the PPP pathway for nucleotide synthesis is generated directly or indirectly by the nonoxidative PPP. 26 Thus, TKT, a key enzyme in the nonoxidative PPP, is essential for cancer cell survival and growth.…”

“…R5P serves as a precursor for the nucleic‐ and amino‐acid synthesis, influencing cancer cell metabolism and proliferation, and DNA damage response 21,22 . NADPH provides materials for tumor biosynthesis while reducing oxidative stress within tumor cells 23–25 . In some tumor cells, over 85% of the ribose produced in the PPP pathway for nucleotide synthesis is generated directly or indirectly by the nonoxidative PPP 26 .…”