{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent genetic association studies have implicated PNMT in a variety of clinical conditions. For example, investigations in neurodevelopmental disorders have revealed an association between PNMT genetic variation and attention‐deficit/hyperactivity disorder ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]. In addition, PNMT resides within chromosomal regions that are frequently amplified in cancers ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "], and linkage studies have positioned its locus as a candidate region for blood pressure regulation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "]. PNMT’s potential influence on energy balance and weight loss has also been explored ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "], while biochemical evidence suggests that beyond its canonical role, PNMT can methylate beta‐carbolines – a reaction that may contribute to Parkinsonian toxicity ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "]."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiochemically, PNMT is the terminal enzyme in catecholamine biosynthesis that catalyzes the S-adenosyl-L-methionine–dependent methylation of norepinephrine to form epinephrine. Its activity is reportedly reduced in specific neuronal populations in Alzheimer’s disease ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "]. Detailed structural studies have characterized its substrate specificity and revealed that key catalytic residues – notably Glu185 – organize an SN2-type methyl transfer reaction ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": "]. Kinetic analyses support an ordered sequential mechanism in which AdoMet binds first, a finding that aligns with the enzyme’s biochemical behavior ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "]. Moreover, investigations into its quaternary structure have demonstrated that human PNMT can form disulfide-linked dimers without a loss in catalytic efficiency ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "]."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its enzymatic function, PNMT expression and genetic polymorphisms have significant regulatory and clinical implications. Variants in the PNMT gene have been associated with adverse outcomes in acute kidney injury ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "], as well as with dimensions of temperament ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "] and multiple sclerosis susceptibility, likely through effects on innate immune responses mediated by catecholamines ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "]. Its locus further appears to contribute to blood pressure phenotypes ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "] and may be linked to asthma-related symptoms ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "]. Altered PNMT gene expression has been observed in the transplanted heart ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "], and its transcription is regulated by nicotinic stimuli via a specific promoter element ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "]. In the realm of tumor biology, reduced PNMT expression correlates with malignancy in pheochromocytomas and paragangliomas ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "25"}]}, {"type": "t", "text": "]. Furthermore, promoter polymorphisms in PNMT have been implicated in essential hypertension ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "] and in modulating circulating epinephrine levels during exercise ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": "]. Recent experiments have begun to unravel the cis/trans regulatory mechanisms underlying these associations ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": "], and work in related contexts suggests that PNMT activity may also interact with sympathetic responses following alcohol intake ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": "]. 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