Abstract
Targeting metabolic enzymes is believed to provide new therapeutic opportunities for cancer therapy. Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that importantly coordinates glycolysis, pentose phosphate pathway (PPP) flux and serine biosynthesis in cancer cells and hence gains increasing interest of inhibitor discovery. Only few PGAM1 inhibitors have been reported and the molecular potency remains very limited. In an effort to discover new PGAM1 inhibitors, we carried out a biochemical assay-based screen that was focused on natural products derived small molecule compounds. (-)-Epigallocatechin-3-gallate (EGCG), the major natural catechins of green tea extract, was identified as a PGAM1 inhibitor that was tremendously more potent than known PGAM1 inhibitors. Further studies combining molecular docking and site-specific mutagenesis revealed that EGCG inhibited PGAM1 enzymatic activity in a manner independent of substrate competition. EGCG modulated the intracellular level of 2-phosphoglycerate, impaired glycolysis and PPP and inhibited proliferation of cancer cells. This study suggested EGCG as a chemical scaffold for the discovery of potent PGAM1 inhibitors and gained mechanistic insights to understand the previously appreciated anticancer properties of EGCG.
Highlights
Metabolic reprogramming has been recognized as a hallmark of cancer (Hsu and Sabatini, 2008; Kroemer and Pouyssegur, 2008; Vander Heiden et al, 2009; Ward and Thompson, 2012)
To discover new Phosphoglycerate mutase 1 (PGAM1) inhibitors, we focused on natural products that are believed to provide rich chemical resources for drug discovery
To identify new PGAM1 inhibitors, we utilized a coupled PGAM1 and pyruvate kinase isozymes M1 (PKM1)/enolase biochemical assay followed by a counter screen to exclude compounds with activity toward PKM1 or enolase
Summary
Metabolic reprogramming has been recognized as a hallmark of cancer (Hsu and Sabatini, 2008; Kroemer and Pouyssegur, 2008; Vander Heiden et al, 2009; Ward and Thompson, 2012). Aerobic glycolysis confers a significant growth advantage of cancer cells by supplying essential ATP production, generating precursors for EGCG Inhibits PGAM1 biosynthesis, and providing reducing equivalents for antioxidant defense. In this process, glycolytic enzymes play a fundamental role in maintaining the metabolite flux, and in the converging the oncogenic signals to modulate metabolic profile (Mankoff et al, 2007). Downregulation of PGAM1 expression or inhibition of its metabolic activity leads to attenuated cell proliferation and tumor growth (Durany et al, 1997; Yeh et al, 2008; Ren et al, 2010; Hitosugi et al, 2012)
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