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.

Keywords: glucose-6-phosphate dehydrogenase; metabolic reprogramming; pentose phosphate pathway; post-translational modifications; tumorigenesis.

FIGURE 1

Transcriptional regulation of G6PD. The cartoon diagram on display consists of three main parts. On the left, activation of NF-ĸB in response to cellular stresses or the PIEKA-FYN complex leads to the phosphorylation and activation of STAT3, which results in the translocation of p-STAT3 to the nucleus and binding to the G6PD promoter enhancing transcription. In the middle section, signals regulate the expression of HMGA1 to promote G6PD transcription. On the right side, HBV protein forms a complex with intracellular protein p62 and KEAP1, resulting in translocation of NRF2 into the nucleus to promote G6PD expression. At the bottom, methylation and acetylation of histones are involved in transcriptional regulation of G6PD.

FIGURE 2

G6PD post-translational modifications. Phosphorylation, glycosylation, acetylation and glutarylation modifications regulate G6PD enzyme activity and specific sites identified are shown in the central circle. Ubiquitination and SUMOylation are synergistically involved in the regulation of G6PD protein stability. Acetylation and methylation of histones H3K27 and H3K9 regulate G6PD transcriptional expression, respectively.

FIGURE 3

Schematic diagram of G6PD (PDB: 2BH9) dimer. A dimer consisting of two G6PD monomers, each of which includes a catalytic NADP⁺ and structural NADP⁺, respectively. The G6PD K403, Y401 and T406 sites are located close to the structural NADP⁺.