{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPKLR encodes the liver and red blood cell isoforms of pyruvate kinase, the key glycolytic enzyme that catalyzes the conversion of phosphoenolpyruvate to pyruvate with generation of ATP. This activity is central to maintaining energy homeostasis in hepatocytes and erythrocytes, and mutations disrupting PKLR function are a major cause of hereditary nonspherocytic hemolytic anemia. In addition, reduced PKLR activity appears to confer a degree of protection against Plasmodium infection by impairing the parasite’s ability to utilize host cell metabolism, while its altered function has also been linked to conditions such as congenital insensitivity to pain and virus‐triggered liver dysfunction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in glycolysis, PKLR has emerged as an important modulator of metabolic reprogramming in a spectrum of diseases. Aberrant expression or mutation of PKLR is associated with conditions ranging from type 2 diabetes and nonalcoholic fatty liver disease to certain malignancies, where changes in enzyme activity affect oxidative stress responses and glutathione homeostasis that, in turn, support cell survival and metastatic progression. In some instances, PKLR interacts directly with viral proteins to diminish its activity, thereby contributing to hepatocyte dysfunction; genomic studies further reveal copy number variations and a diverse mutational spectrum in PKLR that correlate with altered clinical phenotypes across different populations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent structural and mutational analyses have further refined our understanding of PKLR regulation. High‐resolution crystallography, alanine‐scanning mutagenesis, and phylogenetic studies have identified critical residues and regulatory loops that govern effector binding, allosteric transitions, and enzyme stability. Such insights not only improve the prediction of genotype–phenotype correlations in pyruvate kinase deficiency but also point to emerging roles for PKLR in modulating cellular signaling—for example, influencing neuroendocrine differentiation in therapy‐resistant prostate cancer and affecting the frequency of acute pain episodes in sickle cell disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "38", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Y Indo, S Mardy, Y Miura, et al. 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