Last update 19 Sep 2024

G6PC2

Last update 19 Sep 2024

Basic Info

Synonyms

G-6-Pase 2, G6Pase 2, G6PC2

+ [4]

Introduction

May hydrolyze glucose-6-phosphate to glucose in the endoplasmic reticulum. May be responsible for glucose production through glycogenolysis and gluconeogenesis (By similarity).

Drugs associated with G6PC2

GNTI-122

Target

G6PC2

Mechanism

G6PC2 inhibitors

Active Org.

GentiBio, Inc.Startup

Originator Org.

GentiBio, Inc.Startup

Active Indication

Diabetes Mellitus, Type 1

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with G6PC2

100 Translational Medicine associated with G6PC2

0 Patents (Medical) associated with G6PC2

233

Literatures (Medical) associated with G6PC2

31 Dec 2024·Journal of Immunotoxicology

HLA-A02 restricted T-cell cross-reactivity to a microbial antigen

Article

Author: Aints, Alar ; Šunina, Marina ; Uibo, Raivo

Molecular mimicry has been proposed to be a possible mechanism of induction of autoimmunity. In some cases, it is believed that such events could lead to a disease such as Type 1 diabetes (T1D). One of the primary MHC-I epitopes in the non-obese diabetic (NOD) mouse model of T1D has been identified as a peptide from the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) protein. In humans, the most common MHC-I model allele is HLA-A02; based on this, the study here identified a potential HLA-A0201-restricted human IGRP epitope as YLKTNLFLFL and also found a homologous A0201-restricted peptide in an Enterococcal protein. Using cells obtained from healthy human donors, it was seen that after a 2-week incubation with the synthetic bacterial protein, healthy A0201⁺ donor CD8⁺ cells displayed increased staining for human IGRP-peptide-dextramer. On the other hand, in control cultures, no significant levels of dextramer-staining CD8⁺ T-cells were detectable. From these outcomes, it is possible to conclude that certain bacterial proteins may initiate CD8⁺ T-cell-mediated immune reaction toward homologous human antigens.

01 Aug 2024·Journal of Molecular Endocrinology

Multiple promoter and enhancer differences likely contribute to augmented G6PC2 expression in human versus mouse pancreatic islet alpha cells

Article

Author: Martin, Cyrus C ; Flemming, Brian P ; Oeser, James K ; Wangmo, Tenzin ; Attie, Alan ; Keller, Mark P. ; O'Brien, Richard M

G6PC2 encodes a glucose-6-phosphatase catalytic subunit that opposes the action of glucokinase in pancreatic islets thereby modulating the sensitivity of insulin and glucagon secretion to glucose. In mice, G6pc2 is expressed at ~20-fold higher levels in β-cells versus α-cells, whereas in humans G6PC2 is expressed at only ~5-fold higher levels in β-cells. We therefore hypothesize that G6PC2 likely influences glucagon secretion to a greater degree in humans. With a view to generating a humanized mouse that re-capitulates augmented G6PC2 expression levels in α-cells, we sought to identify the genomic regions that confer differential mouse G6pc2 expression in α-cells versus β-cells as well as the evolutionary changes that have altered this ratio in humans. Studies in islet-derived cell lines suggest that the elevated G6pc2 expression in mouse β-cells versus α-cells is mainly due to a difference in the relative activity of the proximal G6pc2 promoter in these cell types. Similarly, the smaller difference in G6PC2 expression between α-cells versus β-cells in humans is potentially explained by a change in relative proximal G6PC2 promoter activity. However, we show that both glucocorticoid levels and multiple differences in the relative activity of eight transcriptional enhancers between mice and humans likely contribute to differential G6PC2 expression. Finally, we show that a mouse-specific non-coding RNA, Gm13613, whose expression is controlled by G6pc2 enhancer I, does not regulate G6pc2 expression, indicating that altered expression of Gm13613 in a humanized mouse that contains both the human promoter and enhancers, should not affect G6PC2 function.

01 Jul 2024·Biochimie

Biochemical and metabolic characterization of a G6PC2 inhibitor

Article

Author: Haratipour, Zeinab ; Rahim, Mohsin ; O'Rourke, Margaret L ; Blind, Ray D ; O'Brien, Richard M ; Young, Jamey D ; Kim, Kwangho ; Claxton, Derek P ; Oeser, James K ; Orun, Abigail R ; Hawes, Emily M

Three glucose-6-phosphatase catalytic subunits, that hydrolyze glucose-6-phosphate (G6P) to glucose and inorganic phosphate, have been identified, designated G6PC1-3, but only G6PC1 and G6PC2 have been implicated in the regulation of fasting blood glucose (FBG). Elevated FBG has been associated with multiple adverse clinical outcomes, including increased risk for type 2 diabetes and various cancers. Therefore, G6PC1 and G6PC2 inhibitors that lower FBG may be of prophylactic value for the prevention of multiple conditions. The studies described here characterize a G6PC2 inhibitor, designated VU0945627, previously identified as Compound 3. We show that VU0945627 preferentially inhibits human G6PC2 versus human G6PC1 but activates human G6PC3. VU0945627 is a mixed G6PC2 inhibitor, increasing the Km but reducing the Vmax for G6P hydrolysis. PyRx virtual docking to an AlphaFold2-derived G6PC2 structural model suggests VU0945627 binds two sites in human G6PC2. Mutation of residues in these sites reduces the inhibitory effect of VU0945627. VU0945627 does not inhibit mouse G6PC2 despite its 84% sequence identity with human G6PC2. Mutagenesis studies suggest this lack of inhibition of mouse G6PC2 is due, in part, to a change in residue 318 from histidine in human G6PC2 to proline in mouse G6PC2. Surprisingly, VU0945627 still inhibited glucose cycling in the mouse islet-derived βTC-3 cell line. Studies using intact mouse liver microsomes and PyRx docking suggest that this observation can be explained by an ability of VU0945627 to also inhibit the G6P transporter SLC37A4. These data will inform future computational modeling studies designed to identify G6PC isoform-specific inhibitors.

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G6PC2

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