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Last update 08 May 2025

GFAT

Last update 08 May 2025

Basic Info

Synonyms

D-fructose-6-phosphate amidotransferase 1, GFA, GFAT

+ [8]

Introduction

Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins. Regulates the circadian expression of clock genes BMAL1 and CRY1 (By similarity). Has a role in fine tuning the metabolic fluctuations of cytosolic UDP-GlcNAc and its effects on hyaluronan synthesis that occur during tissue remodeling (PubMed:26887390).

Drugs associated with GFAT

RO0509347

Target

GFAT

Mechanism

GFAT inhibitors

Active Org.-

Originator Org.

Hoffmann-La Roche, Inc.

Active Indication-

Inactive Indication

Diabetes Mellitus, Type 2

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GFAT

100 Translational Medicine associated with GFAT

0 Patents (Medical) associated with GFAT

738

Literatures (Medical) associated with GFAT

13 May 2025·Neurology

Causal Pathway and Mediation Analysis

Article

Author: Myserlis, Evangelos Pavlos ; Anderson, Christopher D. ; Rosand, Jonathan ; Mayerhofer, Ernst ; Banerjee, Chirantan ; Georgakis, Marios K. ; Omarov, Murad ; Parodi, Livia

BACKGROUND AND OBJECTIVESPrevious studies have shown that increased body fat is associated with stroke risk, with evidence suggesting that body fat distribution, rather than total body fat, exerts a more prominent role in cerebrovascular risk prediction. In this study, we explore causal associations between body mass index (BMI)-independent adipose tissue distribution profiles and cerebrovascular disease (CVD) risk, aiming to refine the association between body fat distribution and stroke.METHODSWe selected variants associated with BMI-independent visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), and gluteofemoral adipose tissue (GFAT) volumes in UK Biobank, and performed univariable and multivariable Mendelian randomization (MR) analyses with ischemic stroke (IS) and subtypes (large artery stroke [LAS], cardioembolic stroke [CES], and small vessel stroke [SVS]). We used coronary artery disease (CAD), carotid intima media thickness (cIMT), and MRI-confirmed lacunar stroke as positive controls. We explored the mediatory role of common cardiovascular (systolic blood pressure, diabetes, and low-density lipoprotein), insulin resistance, inflammatory (C-reactive protein), and adipose tissue-specific (adiponectin, leptin) factors by performing 2-step mediation MR analyses. Estimates were expressed per standard deviation increase in adjusted adipose tissue volume.RESULTSGenetic predisposition to higher GFAT volume was associated with lower risk of IS (odds ratio [OR] 0.92, 95% CI 0.86-0.98), LAS (OR 0.80, 95% CI 0.66-0.96), and SVS (OR 0.77, 95% CI 0.67-0.88), but not CES, consistent in multivariable analyses. Genetic predisposition to higher GFAT volume was also associated with lower risk of CAD (OR 0.82, 95% CI 0.76-0.88), lacunar stroke (OR 0.78, 95% CI 0.67-0.92), and mean cIMT (β = -0.073, 95% CI -0.114 to -0.031). Associations were largely consistent in sensitivity analyses. No association was observed between genetic predisposition to ASAT or VAT and IS risk. Although common vascular risk factors were the predominant mediators in the GFAT-CVD axis, adiponectin and leptin mediated a proportion of IS and CAD risk (∼15% (1.8%-57%) and ∼4.6% (0.8%-13.5%) mediated by adiponectin, respectively).DISCUSSIONThis study supports a protective role of gluteofemorally distributed fat volume in CVD risk. Although this role is predominantly mediated by common vascular risk factor modification, adipose tissue-specific factors may exert a mediatory effect, suggesting a possible novel target for attenuating adiposity-related CVD risk.

01 May 2025·Hepatology

Tumor suppressive role of the antimicrobial lectin REG3A targeting the O-GlcNAc glycosylation pathway

Article

Author: R Vivès, Romain ; Darnaud, Marion ; Geoffre, Nicolas ; Deshayes, Alice ; Lacoste, Claire ; Bréchot, Christian ; Purhonen, Janne ; Moniaux, Nicolas ; Amouyal, Paul ; Amouyal, Gilles ; Buendia, Marie Annick ; Friedel-Arboleas, Mélanie ; Faivre, Jamila ; Guettier, Catherine ; Nguyen, Tung-Son ; Dos Santos, Alexandre ; Kallijärvi, Jukka ; Job, Sylvie ; Issad, Tarik ; Vivès, Romain R.

Background and Aims:Antimicrobial proteins of the regenerating family member 3 alpha (REG3A) family provide a first line of protection against infections and transformed cells. Their expression is inducible by inflammation, which makes their role in cancer biology less clear since an immune-inflammatory context may preexist or coexist with cancer, as occurs in HCC. The aim of this study is to clarify the role of REG3A in liver carcinogenesis and to determine whether its carbohydrate-binding functions are involved.Approach and Results:This study provides evidence for a suppressive role of REG3A in HCC by reducing O-GlcNAcylation in 2 mouse models of HCC, in vitro cell studies, and clinical samples. REG3A expression in hepatocytes significantly reduced global O-GlcNAcylation and O-GlcNAcylation of c-MYC in preneoplastic and tumor livers and markedly inhibited HCC development in REG3A-c-MYC double transgenic mice and mice exposed to diethylnitrosamine. REG3A modified O-GlcNAcylation without altering the expression or activity of O-linked N-acetylglucosaminyltransferase, O-linked N-acetylglucosaminyl hydrolase, or glutamine fructose-6-phosphate amidotransferase. Reduced O-GlcNAcylation was consistent with decreased levels of UDP-GlcNAc in precancerous and cancerous livers. This effect was linked to the ability of REG3A to bind glucose and glucose-6 phosphate, suggested by a REG3A mutant unable to bind glucose and glucose-6 phosphate and alter O-GlcNAcylation. Importantly, patients with cirrhosis with high hepatic REG3A expression had lower levels of O-GlcNAcylation and longer cancer-free survival than REG3A-negative cirrhotic livers.Conclusions:REG3A helps fight liver cancer by reducing O-GlcNAcylation. This study suggests a new paradigm for the regulation of O-GlcNAc signaling in cancer-related pathways through interactions with the carbohydrate-binding function of REG3A.

18 Apr 2025·Science Advances

Targeting PGM3 abolishes SREBP-1 activation-hexosamine synthesis feedback regulation to effectively suppress brain tumor growth

Article

Author: Mo, Xiaokui ; Fan, Yunzhou ; Su, Huali ; Guo, Deliang ; Liu, Yanwei ; Chiang, Cheng-Yao ; Magaki, Shino ; Yin, Xinmin ; Wang, Qiang ; Yong, William H ; Zhong, Yaogang ; Kou, Yongjun ; Zhang, Xiang ; Cloughesy, Timothy F. ; He, Liqing ; Geng, Feng ; Chakravarti, Arnab ; Lefai, Etienne

Elevated hexosamine biosynthesis fuels tumor growth by facilitating protein and lipid glycosylation. But which enzyme in this pathway is better to serve as an antitumor target remains unclear. Here, we revealed that targeting GFAT1, the rate-limiting enzyme in hexosamine synthesis, exhibits limited inhibitory effects on glioblastoma (GBM), the most lethal brain tumor. This outcome is due to the compensation of NAGK-mediated hexosamine salvage pathway. Unexpectedly, inhibiting PGM3, which controls the flux of both de novo hexosamine synthesis and salvage pathways, down-regulates the expression of other enzymes in this pathway and suppresses SREBP-1, a critical lipogenic transcription factor, effectively inhibiting GBM growth. Unexpectedly, SREBP-1 transcriptionally up-regulates the expression of hexosamine synthesis enzymes, while inhibition of these enzymes in turn down-regulates SREBP-1 activation via reducing N-glycosylation of its transporter, SCAP. Our study identified PGM3 as a promising target for treating GBM. Its inhibition disrupts the SREBP-1 activation-hexosamine synthesis positive feedback regulation to effectively eliminate GBM cells.

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