Citrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation

Abstract Chromodomain helicase DNA binding protein 4 (CHD4) is an ATPase subunit of the Nucleosome Remodelling and Deacetylation (NuRD) complex that regulates gene expression. CHD4 essential for growth multiple patient derived melanoma xenografts breast cancer. Here we show expression PADI1 (Protein Arginine Deiminase 1) PADI3 in cancer cell types modulating citrullination arginine residues allosterically-regulated glycolytic enzyme pyruvate kinase M2 (PKM2). Citrullination PKM2 R106 reprogrammes cross-talk between ligands lowering its sensitivity to inhibitors Tryptophan, Alanine Phenylalanine promoting activation by Serine. thus bypasses normal physiological regulation low Serine levels promote excessive glycolysis reduced proliferation. We further up-regulated hypoxia where contributes increased glycolysis. provide insight as how conversion arginines citrulline impacts key interactions within act concert reprogramme activity additional mechanism regulating this important enzyme.