Last update 01 Nov 2024

GSS

Last update 01 Nov 2024

Basic Info

Synonyms

Glutathione synthase, Glutathione synthetase, GSH synthetase

+ [3]

Introduction

Catalyzes the production of glutathione from gamma-glutamylcysteine and glycine in an ATP-dependent manner (PubMed:7646467, PubMed:9215686). Glutathione (gamma-glutamylcysteinylglycine, GSH) is the most abundant intracellular thiol in living aerobic cells and is required for numerous processes including the protection of cells against oxidative damage, amino acid transport, the detoxification of foreign compounds, the maintenance of protein sulfhydryl groups in a reduced state and acts as a cofactor for a number of enzymes (PubMed:10369661). Participates in ophthalmate biosynthesis in hepatocytes (By similarity).

Drugs associated with GSS

Cysteamine Hydrochloride

Target

GSS

Mechanism

GSS stimulants

Active Org.

Recordati Rare Diseases, Inc. [+3]

Originator Org.

Leadiant Biosciences, Inc.

Active Indication

Cystinosis [+1]

Inactive Indication

Corneal Diseases

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date02 Oct 2012

Procysteine

Target

GSS

Mechanism

GSS stimulants

Active Org.-

Originator Org.

Addition Technology, Inc.

Active Indication-

Inactive Indication

Amyotrophic Lateral Sclerosis [+2]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with GSS

NCT04125927 / CompletedPhase 3

Open-label, Single-arm, Multicenter Study to Assess the Safety of Cystadrops® in Pediatric Cystinosis Patients From 6 Months to Less Than 2 Years Old

Cystadrops® is currently indicated in adults and children from 2 years of age diagnosed with cystinosis with corneal crystal accumulation observed.
However administration of Cystadrops® in patients below 2 years old could be of value for these patients and prevent the crystal deposit. It is the reason why as part of the Cystadrops® pediatric investigational plan (PIP), RECORDATI Rare Diseases committed to conduct a clinical study to assess Cystadrops® safety and efficacy in the pediatric population from 6 months to less than 2 years old.

Start Date01 Sep 2020

Sponsor / Collaborator

Recordati Rare Diseases

EUCTR2009-012564-13-FR / Not yet recruitingNot Applicable

Cysteamine Hydrochloride for nephropathic Cystinosis, open-label Phase III pivotal study - CYSTADROPS CHOC study

Start Date03 Jan 2013

Sponsor / Collaborator

Orphan Europe SARL

JPRN-UMIN000005844 / CompletedNot ApplicableIIT

Clinical multi-center study of OTC periodontal ointment-containing applicator with brush (MC2) for reducing risk of relapse of chronic periodontitis during supportive periodontal therapy - Clinical multi-center study of OTC periodontal ointment-containing applicator with brush (MC2)

Start Date01 Aug 2011

Sponsor / Collaborator

Okayama University

100 Clinical Results associated with GSS

100 Translational Medicine associated with GSS

0 Patents (Medical) associated with GSS

1,117

Literatures (Medical) associated with GSS

01 Dec 2024·Journal of Structural Biology

Arabidopsis thaliana argininosuccinate lyase structure uncovers the role of serine as the catalytic base

Article

Author: Pietrzyk-Brzezinska, Agnieszka J. ; Nielipinski, Maciej ; Krzeszewska, Dominika ; Pietrzyk-Brzezinska, Agnieszka J ; Sekula, Bartosz

Arginine is an important amino acid in plants, as it not only plays a structural role and serves as nitrogen storage but is also a precursor for various molecules, including polyamines and proline. Arginine is produced by argininosuccinate lyase (ASL) which catalyzes the cleavage of argininosuccinate to arginine and fumarate. ASL belongs to the fumarate lyase family and while many members of this family were well-characterized, little is known about plant ASLs. Here we present the first crystal structures of ASL from the model plant, Arabidopsis thaliana (AtASL). One of the structures represents the unliganded form of the AtASL homotetramer. The other structure, obtained from a crystal soaked in argininosuccinate, accommodates the substrate or the reaction products in one of four active sites of the AtASL tetramer. Each active site is located at the interface of three neighboring protomers. The AtASL structure with ligands allowed us to analyze the enzyme-substrate and the enzyme-product interactions in detail. Furthermore, based on our analyses, we describe residues of AtASL crucial for catalysis. The structure of AtASL gives the rationale for the open-to-close transition of the GSS mobile loop and indicates the importance of serine 333 from this loop for the enzymatic action of the enzyme. Finally, we supplemented the structural data with the identification of sequence motifs characteristic for ASLs.

01 Dec 2024·Molecular Biology Reports

Metformin-induced oxidative stress inhibits LNCaP prostate cancer cell survival

Article

Author: Tran, Alice ; Dixon, Sashana ; Trivedi, Malav S ; Schrier, Matthew S ; Deth, Richard C ; Castejon, Ana ; Dong, Jianan

BACKGROUNDPreclinical and clinical studies over the past several decades have indicated the potential value of metformin, a widely utilized treatment for Type 2 diabetes, in prostate cancer therapy. Notably, these studies demonstrated metformin's pleiotropic effects on several molecular and metabolic pathways, such as androgen signaling, cell cycle, and cellular bioenergetics. In this study we investigated the role of metformin in regulating intracellular redox status and cell survival in LNCaP prostate cancer cells.METHODS AND RESULTSThe cytotoxic effects of metformin with or without the presence of SBI0206965 (AMPK inhibitor) on LNCaP cells were determined using MTT and trypan blue exclusion assays. Seahorse XP extracellular analysis, Liquid Chromatography/ Mass Spectrophotometry (LC/MS), and 2,7- and Dichlorofluoresin diacetate (DCFDA) assay were used to assess the effects of metformin on cellular bioenergetics, redox status, and redox-related metabolites. mRNA expression and protein concentration of redox-related enzymes were measured using Real Time-qPCR and ELISA assay, respectively. Independently of AMP-activated protein kinase, metformin exhibited a dose- and time-dependent inhibition of LNCaP cell survival, a response mitigated by glutathione or N-acetylcysteine (ROS scavengers) treatment. Notably, these findings were concomitant with a decline in ATP levels and the inhibition of oxidative phosphorylation. The results further indicated metformin's induction of reactive oxygen species, which significantly decreased glutathione levels and the ratio of reduced to oxidized glutathione, as well as the transsulfuration metabolite, cystathionine. Consistent with an induction of oxidative stress condition, metformin increased mRNA levels of the master redox transcription factor Nrf-2 (nuclear factor erythroid-derived 2-like), as well as transsulfuration enzymes cystathionine beta-synthase and cystathionase and GSH synthesis enzymes γ-glutamylcysteine synthetase and glutathione synthetase.CONCLUSIONOur findings highlight multiple mechanisms by which metformin-induced formation of reactive oxygen species may contribute to its efficacy in prostate cancer treatment, including promotion of oxidative stress, Nrf2 activation, and modulation of redox-related pathways, leading to its anti-survival action.

01 Dec 2024·Phytomedicine

Corosolic acid inhibits EMT in lung cancer cells by promoting YAP-mediated ferroptosis

Article

Author: Gao, Lingli ; Zhao, Wenyu ; Zhang, Congcong ; Wang, Mengyu ; Zhang, Yinghui ; Chen, Yulong ; Wang, Qianna ; Zhang, Yanyu ; Ma, Liangliang ; Jin, Xiaoqin ; Liu, Yaru ; Zhang, Yasu ; Wu, Nan

BACKGROUNDCorosolic acid (CA), a naturally occurring pentacyclic triterpenoid is renowned for its anticancer attributes. Previous studies have predominantly centered on the anticancer properties of CA in lung cancer, specifically its role in inducing apoptosis, however, investigations regarding its involvement in ferroptosis have been scarce.METHODSThe apoptotic and proliferative effects were evaluated by CCK8 and colony formation assay. Cell death and ROS generation were measured to assess the response of CA to iron death induction. Scratch and invasion assays were performed to verify the effect of CA on the invasive ability of lung cancer cells. Protein and mRNA expression were analyzed using Western blotting and qPCR. The CHX assay was carried out to detect protein half-life. Metabolite levels were measured with appropriate kits. Protein expression was detected through IF and IHC. A xenograft tumor model was established to investigate the inhibitory effect of CA on lung cancer in vivo.RESULTSThe current findings revealed that CA exerts its anticancer effect by inducing cell death, accompanied by the accumulation of lipid reactive oxygen species (ROS), hinting at the possible involvement of ferroptosis. Our experimental results further substantiated the significance of ferroptosis in the CA anticancer mechanism, as ferroptosis inhibitors were found to effectively rescue CA-induced cell death. Significantly, we demonstrated for the first time that CA could induce ferroptosis further by suppressing EMT in lung cancer cells. Additionally, CA could regulate GPX4 to induce ferroptosis, interestingly, CA downregulated GSH synthetase by inhibiting YAP rather than GPX4, thereby reducing GSH, inducing ferroptosis, and further suppressing EMT in lung cancer cells.We also discovered that GSS is a crucial downstream target of YAP in regulating GSH. Moreover, a xenograft mouse model indicated that CA could trigger ferroptosis in lung cancer cells by regulating YAP expression and GSH levels.CONCLUSIONCA inhibited lung cancer cell metastasis by inducing ferroptosis. Our data offer the first evidence that CA induces ferroptosis in lung cancer cells by regulating YAP/GSS to modulate GSH, thereby further suppressing EMT. These results imply the potential of CA as an inducer of ferroptosis to inhibit lung cancer metastasis.

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