{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHMG‐CoA lyase (HMGCL) is a pivotal mitochondrial enzyme that catalyzes the divalent cation–dependent cleavage of HMG‐CoA into acetoacetate and acetyl‐CoA, thereby furnishing the essential substrates for ketone body production and L‐leucine catabolism. Detailed structural studies have revealed that HMGCL adopts a (β/α)8 TIM barrel conformation and functions as a dimer, with critical active site residues—such as Arg41, Asp42, His233, His235, Cys266, and key C-terminal amino acids—being indispensable for proper substrate orientation and catalytic turnover."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlternative splicing and the existence of isoforms further underscore the complexity of HMGCL regulation. In human tissues, alternative transcripts—including those with exon deletions—have been identified for HMGCL, and a related HMGCL‐like protein (HMGCLL1) has been characterized as an extramitochondrial enzyme with comparable catalytic properties. In addition, the peroxisomal form of HMGCL has been isolated, suggesting that tissue‐specific posttranscriptional modifications and subcellular distribution may coordinate ketone‐body synthesis according to metabolic demand."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nInherited mutations in the HMGCL gene are responsible for a life‐threatening metabolic disorder marked by hypoketotic hypoglycemia, metabolic acidosis, and neurological compromise. Numerous missense, nonsense, small deletion, and splicing mutations affecting HMGCL undermine its catalytic efficiency by disrupting active site geometry or destabilizing protein structure. Clinical studies in diverse populations—from Spanish to Saudi Arabian and Taiwanese patients—have correlated these mutations with variable degrees of enzyme deficiency and disease severity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical metabolic role, HMGCL is implicated in oncogenic processes and cellular regulation. In BRAFV600E‐positive cancers, up‐regulation of HMGCL fosters acetoacetate production that in turn selectively sustains MEK1 activation, thereby contributing to tumor cell proliferation. Conversely, in nasopharyngeal carcinoma HMGCL suppression leads to decreased intracellular β‐hydroxybutyrate and reactive oxygen species generation, facilitating enhanced cell migration, invasion, and tumorigenicity. Moreover, aberrant HMGCL function has been linked to glioblastoma progression and even indirectly to benign prostatic hyperplasia via targeting by specific microRNAs (miR-1202), thereby influencing epithelial–mesenchymal transition and Wnt/β‐catenin signaling cascades."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, metabolic diversity among individuals and tissues extends to the broader network of lipid homeostasis. While genetic variations in metabolic determinants can affect cholesterol metabolism and dietary lipid responsiveness, it is noteworthy that HMGCL’s role in ketogenesis remains distinct from that of HMG‐CoA reductase, the rate‐limiting enzyme in cholesterol biosynthesis. In this context, sex-specific differences in triglyceride metabolism may reflect, in part, the intricate interplay among various enzymes of energy metabolism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Zhuji Fu, Jennifer A Runquist, Farhad Forouhar, et al. 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