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HOME> Products> Natural and Chemical compound> Enzyme inhibitor> Pro-GA ＜Cell-Permeable GGCT Inhibitor＞

Pro-drug type gamma-Glutamylcyclotransferase (GGCT) inhibitor Pro-GA ＜Cell-Permeable GGCT Inhibitor＞

Date：April 11 2018Web Page No：81020

Funakoshi Co.,Ltd.

GGCT (γ-glutamyl cyclotransferase, also known as C7orf24) is one of the recently identified glutathione metabolism-related enzymes that is highly expressed in cancer cells and is attracting attention as a novel cancer marker. Pro-GA is a compound that imparts cell membrane permeability to N-glutaryl-alanine (GA), a GGCT inhibitor, and is the world's first prodrug GGCT inhibitor that can be used in cell experiments. It is useful for functional analysis of GGCT in cancer cells and analysis of downstream signals.

Principle of pro-drug type inhibitor Pro-GA for GGCT

Inhibition of proliferation in normal cells

Inhibition of proliferation in cancer cells

Pro-GA inhibits GGCT and examples of cancer cell-specific growth inhibition

Pro-GA passes through cell membrane, is internalized into cytoplasm, and is converted to a GGCT inhibitor GA by intracellular esterase, which inhibits GGCT activity. GGCT is highly expressed in cancer cells, and Pro-GA markedly inhibited the growth of cancer cells (for details, please refer to ☞ Example of Use).

What is GGCT
What is Pro-GA
Features
Example of Use
Webinar Movie
Product Information

What is GGCT

γ-Glutamyl cyclotransferase (GGCT) is an enzyme that cleaves γ-glutamyl dipeptide (γ-Glu-Xaa, where Xaa is any amino acid) into 5-oxoproline and free amino acid Xaa. It has been known to exist as an enzyme related to glutathione metabolism since the 1950s, but its gene was not identified until 2008, and its function in cells has not been fully analyzed.
Biochemical analysis by Oakley et al. in 2008 revealed that C7orf24, a protein of unknown function that is highly expressed in cancer cells, exhibits GGCT activity. Since then, GGCT has attracted attention as a marker protein specific to cancer cells, but the physiological function of GGCT is still unknown.

GGCT cycle — **Simple diagram of glutathione cycle**

Although the expression level of GGCT in normal cells is low, overexpression of GGCT significantly promotes cell proliferation. On the other hand, in cancer cells with high expression of GGCT, knockdown of GGCT by RNAi suppresses cell proliferation and migration. These findings suggest that GGCT greatly contributes to the proliferation of cancer cells, and the development of specific inhibitors is expected to analyze how the enzyme activity of GGCT contributes to the proliferation of cancer cells. Several compounds that exhibit GGCT inhibitory activity in vitro, including N-glutaryl-alanine (GA), have been developed, but none of them is permeable to cell membranes and can be used in cell experiments.
Pro-GA is a prodrug of GA and is the world's first GGCT inhibitor that can be used in cell and animal experiments.

References

Oakley, et al., J. Biol. Chem., 283, 22031 (2008).
Kageyama, et al., Proteomics Clin. Appl., 1, 192 (2007).

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What is Pro-GA

Pro-GA is the world's first prodrug-type membrane-permeable GGCT inhibitor. It exhibits high membrane permeation activity and intracellular GA release activity, and inhibits cancer cell-specific growth.

Original paper

Ii, et al., ChemMedChem, 13, 155 (2018). "A Novel Prodrug of a γ-Glutamyl cyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer."

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Features

GGCT inhibitor N-glutaryl alanine (GA) is diesterified with methyl and acetoxymethyl groups. It is permeable to cell membrane. After internalization, methyl ester and acetoxymethyl ester are hydrolyzed by intracellular esterase, and functions as inhibitor GA.
GA is a reversible inhibitor and transiently inhibits the enzymatic activity of GGCT.
It has also inhibited tumor formation in xenograft experiments in vivo.

【Reference】GGCT inhibitory activity of GA

Lysates of NIH3T3 cells with low expression of GGCT and NIH3T3 cells with overexpression of GGCT were prepared and GGCT activity was evaluated. The GGCT activity, which was enhanced by overexpression, was markedly suppressed by the addition of GA (100 μM).
※ This data indicates the GGCT inhibitory activity of GA, not that of Pro-GA. Because Pro-GA is a prodrug of GA, it exhibits GGCT inhibitory activity only when it is converted to GA by intracellular esterase.

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Example of Use

Pro-GA inhibits cancer cell-specific growth

Normal cells and cancer cells were cultured in the absence or presence of Pro-GA (80 or 100 μM) for mammary cells, hematopoietic cells, and prostate cells, respectively. The proliferation of each cell was quantitatively observed by cell proliferation assay using WST-8. In the absence of Pro-GA, specific proliferation was observed in various cancer cells, but Pro-GA significantly suppressed the proliferation. The addition of GA without prodrug did not inhibit the proliferation.
※ For mammary cells, hematopoietic cells, and prostate cells, HMEC/MCF7, PBMC/HL-60, and PrEC/PC3 were used as normal cells and cancer cells, respectively.

	Mammary gland	Hematopoietic	Postate gland
Normal cells
Cancer cells

Tumor suppression by Pro-GA in vivo xenograft model

Intracellular GA release activity

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Webinar Movie

Please down load the movie from here.

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Product Information

[Date : April 25 2025 00:06]

Detail Product Name Product Code Supplier Size Price

Pro-GA, Cell-permeable GGCT inhibitor
DatasheetThis may not be the latest data sheet. FDV-0019 FNAFunakoshi Co.,Ltd. 2 mg $400

Contact

Description	Cell-Permeable GGCT Inhibitor. GGCT is one of the recently identified glutathione metabolism-related enzymes that is highly expressed in cancer cells.
Storage	-20°C	CAS
Link

[Date : April 25 2025 00:06]

Pro-GA, Cell-permeable GGCT inhibitor

DatasheetThis may not be the latest data sheet.

Product Code: FDV-0019
Supplier: FNA
Size: 2mg
Price: $400

Description	Cell-Permeable GGCT Inhibitor. GGCT is one of the recently identified glutathione metabolism-related enzymes that is highly expressed in cancer cells.
Storage	-20°C	CAS
Link

Contact

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