Last update 01 Nov 2024

GLUD1

Last update 01 Nov 2024

Basic Info

Synonyms

GDH, GDH 1, GLUD

+ [3]

Introduction

Mitochondrial glutamate dehydrogenase that catalyzes the conversion of L-glutamate into alpha-ketoglutarate. Plays a key role in glutamine anaplerosis by producing alpha-ketoglutarate, an important intermediate in the tricarboxylic acid cycle (PubMed:11032875, PubMed:16959573, PubMed:11254391, PubMed:16023112). Plays a role in insulin homeostasis (PubMed:9571255, PubMed:11297618). May be involved in learning and memory reactions by increasing the turnover of the excitatory neurotransmitter glutamate (By similarity).

Drugs associated with GLUD1

GLUD1 inhibitor (CD3)

Target

GLUD1

Mechanism

GLUD1 inhibitors

Active Org.

Centre for Drug Design & Discovery

Originator Org.

Centre for Drug Design & Discovery

Active Indication

Muscular Atrophy

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GLUD1 inhibitors (CD3)

Target

GLUD1

Mechanism

GLUD1 inhibitors

Active Org.

Centre for Drug Design & Discovery

Originator Org.

Centre for Drug Design & Discovery

Active Indication

Muscular Atrophy

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GLUD1

100 Translational Medicine associated with GLUD1

0 Patents (Medical) associated with GLUD1

736

Literatures (Medical) associated with GLUD1

01 Oct 2024·Cell Insight

Deacetylation of GLUD1 maintains the survival of lung adenocarcinoma cells under glucose starvation by inhibiting autophagic cell death

Article

Author: Wang, Lei ; Cheng, Zhujun ; Hu, Qifan ; Wang, Keru ; Wan, Xiaorui ; Han, Tianyu ; Wang, Zuorui ; Xu, Jing ; Yuan, Yi ; Sun, Longhua ; Cheng, Junyao

Enhanced glutamine catabolism is one of the main metabolic features of cancer, providing energy and intermediate metabolites for cancer progression. However, the functions of glutamine catabolism in cancer under nutrient deprivation need to be further clarified. Here, we discovered that deacetylation of glutamate dehydrogenase 1 (GLUD1), one of the key enzymes in glutamine catabolism, maintains the survival of lung adenocarcinoma (LUAD) cells under glucose starvation by inhibiting autophagic cell death. We found that glucose starvation increased GLUD1 activity by reducing its acetylation on Lys84 and promoted its active hexamer formation. Besides, deacetylation of GLUD1 induced its cytoplasmic localization, where GLUD1 was ubiquitinated in K63-linkage by TRIM21, leading to the binding of GLUD1 with cytoplasmic glutaminase KGA. These two effects enhanced glutamine metabolism both in mitochondria and cytoplasm, increased the production of alpha-ketoglutarate (α-KG). Meanwhile, cytoplasmic GLUD1 also interacted with p62 and prevented its acetylation, leading to the inhibition of p62 body formation. All these effects blocked autophagic cell death of LUAD cells under glucose starvation. Taken together, our results reveal a novel function of GLUD1 under glucose deprivation in LUAD cells and provide new insights into the functions of glutamine catabolism during cancer progression.

01 Oct 2024·The FEBS Journal

GDH1 exacerbates renal fibrosis by inhibiting the transcriptional activity of peroxisome proliferator‐activated receptor gamma

Article

Author: Yu, Xiaowen ; Li, Shumin ; Huang, Songming ; Liu, Qianqi ; Zhao, Yingying ; Qin, Jun

Renal fibrosis is the common outcome of practically all progressive forms of chronic kidney disease (CKD), a significant societal health concern. Glutamate dehydrogenase (GDH) 1 is one of key enzymes in glutamine metabolism to catalyze the reversible conversion of glutamate to α‐ketoglutarate and ammonia. However, its function in renal fibrosis has not yet been proven. In this study, GDH1 expression was significantly downregulated in kidney tissues of both children with kidney disease and animal models of CKD. In vivo, the use of R162 (a GDH1 inhibitor) significantly improved renal fibrosis, as indicated by Sirius red and Masson trichrome staining. These findings are consistent with the impaired expression of fibrosis indicators in kidneys from both the unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (5/6 Nx) models. In vitro, silencing GDH1 or pretreatment with R162 inhibited the induction of fibrosis indicators in tissue kidney proximal tubular cells (TKPTS) treated with Transforming growth factor Beta 1 (TGF‐β1), whereas activating GDH1 worsened TGF‐β1's induction impact. Using RNA‐sequence, luciferase reporter assays and Biacore analysis, we demonstrated that GDH1 interacts with Peroxisome proliferator‐activated receptor gamma (PPARγ) and blocks its transcriptional activity, independent of the protein's expression. Additionally, R162 treatment boosted PPARγ transcriptional activity, and blocking of this signaling pathway reversed R162's protective effect. Finally, we discovered that R162 treatment or silencing GDH1 greatly lowered reactive oxygen species (ROS) and lipid accumulation. These findings concluded that suppressing GDH1 or R162 treatment could prevent renal fibrosis by augmenting PPARγ transcriptional activity to control lipid accumulation and redox balance.

30 Sep 2024·Journal of Molecular Cell Biology

Inhibition of GLUD1 mediated by LASP1 and SYVN1 contributes to hepatitis B virus X protein-induced hepatocarcinogenesis

Article

Author: Zheng, Kui-Yang ; Ma, Li-Hong ; Liu, Xiang-Ye ; Wang, Xing ; Zhong, Yu-Jie ; Zhang, Huan-Yang ; Wang, Yu-Xin ; Kong, De-Long ; You, Hong-Juan ; Bao, En-Si ; Kong, Fan-Yun ; Li, Qi ; Tang, Ren-Xian

AbstractGlutamate dehydrogenase 1 (GLUD1) is implicated in oncogenesis. However, little is known about the relationship between GLUD1 and hepatocellular carcinoma (HCC). In the present study, we demonstrated that the expression levels of GLUD1 significantly decreased in tumors, which was relevant to the poor prognosis of HCC. Functionally, GLUD1 silencing enhanced the growth and migration of HCC cells. Mechanistically, the upregulation of interleukin-32 through AKT activation contributes to GLUD1 silencing-facilitated hepatocarcinogenesis. The interaction between GLUD1 and AKT, as well as α-ketoglutarate regulated by GLUD1, can suppress AKT activation. In addition, LIM and SH3 protein 1 (LASP1) interacts with GLUD1 and induces GLUD1 degradation via the ubiquitin–proteasome pathway, which relies on the E3 ubiquitin ligase synoviolin (SYVN1), whose interaction with GLUD1 is enhanced by LASP1. In hepatitis B virus (HBV)-related HCC, the HBV X protein (HBX) can suppress GLUD1 with the participation of LASP1 and SYVN1. Collectively, our data suggest that GLUD1 silencing is significantly associated with HCC development, and LASP1 and SYVN1 mediate the inhibition of GLUD1 in HCC, especially in HBV-related tumors.

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GLUD1

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