9p0j | pdb_00009p0j
Human liver phosphofructokinase-1 bound to XJ-4-85
Structural highlights
FunctionPFKAL_HUMAN Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis (PubMed:22923583). Negatively regulates the phagocyte oxidative burst in response to bacterial infection by controlling cellular NADPH biosynthesis and NADPH oxidase-derived reactive oxygen species. Upon macrophage activation, drives the metabolic switch toward glycolysis, thus preventing glucose turnover that produces NADPH via pentose phosphate pathway (By similarity).[UniProtKB:P12382][HAMAP-Rule:MF_03184][1] Publication Abstract from PubMedGlycolysis fuels vital cellular functions, and its dysregulation has been implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, represents a key vulnerability for development of targeted anticancer agents; however, the development of such agents remains challenging owing to metabolic heterogeneity and resistance. Here we developed a covalent phosphofructokinase-1 liver type (PFKL) activator that couples glycolytic activation with delivery of a cytotoxic carnitine palmitoyltransferase 2 (CPT2)-targeting payload to cancer cells in vitro and in vivo. The electrophile-drug conjugate site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL, while concomitantly releasing a CPT2-selective inhibitor to destabilize cell metabolism. The delivery mechanism of electrophile-drug conjugates is analogous to that of antibody-drug conjugates, but differentiated by their selective covalent targeting of intracellular proteins. A covalent PFKL activator suppresses tumor growth.,Jiang X, Lynch EM, Lyu C, Wilson CN, Salay LE, Hess HT, Lyons SN, Lu MJ, Luo S, Kim G, Chan HR, Wolfe WJ, Zacharias LG, Mathews TP, Lin YC, Webb BA, Kollman JM, Cambronne XA, Hsu KL Nat Chem Biol. 2026 Aug 5. doi: 10.1038/s41589-026-02289-9. PMID:42557312[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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