{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nFAD‐dependent polyamine oxidase (PAOX) is a key enzyme in the catabolic pathway of polyamines, oxidizing acetylated derivatives such as N1‑acetylspermidine and N1‑acetylspermine to yield hydrogen peroxide, corresponding aminoaldehydes, and ammonia. However, its role in mediating cytotoxic responses is context dependent. In breast cancer cells treated with the polyamine analogue BENSpm, for example, neither PAOX mRNA nor activity was induced, and the generation of H₂O₂ was attributed solely to the inducible spermine oxidase SMO (PAOh1), indicating a minimal role for PAOX in this antitumor response."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its conventional substrate oxidation, PAOX exhibits stereospecific behavior that can be modulated by its microenvironment. Biochemical studies have shown that while PAOX normally oxidizes achiral substrates, its substrate preference can be shifted by exogenous aldehydes – for instance, benzaldehyde can favor the oxidation of the (R)-isomer of certain polyamine analogues, whereas pyridoxal reverses this selectivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Such regulatory mechanisms highlight the dynamic nature of PAOX in polyamine metabolism."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn pathological contexts, PAOX activity has significant implications. In type 1 diabetes mellitus, elevated plasma PAOX activity correlates with increased oxidative stress and higher levels of malondialdehyde, suggesting that PAOX‐mediated generation of reactive aldehydes and H₂O₂ may contribute to diabetic complications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Furthermore, in primary myelofibrosis, a copy number gain at the PAOX gene locus leads to its transcriptional up‐regulation, and targeted inhibition of PAOX selectively induces cell death in malignant progenitor cells, pointing to a potential therapeutic strategy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRegulation of PAOX expression is also influenced by hormonal factors. In estrogen receptor–positive breast cancer cells, 17β‑estradiol, through estrogen receptor 2 (ERβ/ESR2) interaction with activator protein‑1 (AP‑1) sites on the promoter, represses PAOX transcription. This estrogen‐mediated downregulation may account for altered polyamine levels observed post‑menopause."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLastly, genetic diversity in the PAOX gene, such as the rs1046175 polymorphism, appears to influence the diagnostic performance of plasma biomarkers in non‑small‑cell lung carcinoma, underscoring the potential impact of PAOX genetic variants on disease diagnostics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Allison Pledgie, Yi Huang, Amy Hacker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Spermine oxidase SMO(PAOh1), Not N1-acetylpolyamine oxidase PAO, is the primary source of cytotoxic H2O2 in polyamine analogue-treated human breast cancer cell lines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M508177200"}], "href": "https://doi.org/10.1074/jbc.M508177200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16207710"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16207710"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Aki Järvinen, Tuomo A Keinänen, Nikolay A Grigorenko, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Gene polymorphisms of SFTPB rs7316, rs9752 and PAOX rs1046175 affect the diagnostic value of plasma Pro-SFTPB and DAS in Chinese Han non-small-cell lung cancer patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.28741"}], "href": "https://doi.org/10.1002/jcb.28741"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31016788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31016788"}]}]}]}