PGK1

PGK1 catalyzes an ATP-producing step in glycolysis and supports tumor-cell metabolic fitness through glucose metabolism^[1]. Mechanistically, mitochondrial PGK1 phosphorylates PDHK1 Thr338, activates PDHK1, inhibits the PDH complex, reduces mitochondrial pyruvate utilization, increases lactate production, and promotes brain tumorigenesis^[2]. Under hypoxia or glutamine deprivation, PGK1 phosphorylates Beclin1 Ser30, enhances VPS34-Beclin1 activity, and drives stress-induced autophagy linked to glioblastoma prognosis^[3]. In liver cancer models, PGK1 depletion reduced proliferation and tumorigenesis, while PGK1 acetylation promoted liver cancer progression^[4]. Compared with PGK2, PGK1 represents the cytoplasmic isoform, whereas PGK2 is sperm-specific; PGK2 keeps an essentially identical active site but differs in C-terminal regions away from the active site^[5]. For experimental applications, NG52 inhibited PGK1 kinase activity, restored PDH activity, reversed the Warburg effect, and suppressed glioma xenograft growth^[1]. Ilicicolin H acted as a non-ATP-competitive PGK1 inhibitor that reduced glucose uptake, lactate production, and hepatocellular carcinoma proliferation^[6]. Structure-based screening also identified CHR-6494 and Z57346765 as PGK1-binding inhibitors that reduced PGK1 metabolic enzyme activity and inhibited kidney renal clear cell carcinoma growth^[7].- PGK1 connects glycolytic ATP production with PDHK1-PDH control and tumor metabolic remodeling^[1][2]. - PGK1 differs from sperm-specific PGK2 mainly by expression context and distal structural regions^[5]. - PGK1 inhibitors support mechanistic studies of glycolysis, autophagy, and cancer-cell proliferation^[1][6][7].