{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n3′‐Phosphoadenosine‐5′‐phosphosulfate synthase 1 (PAPSS1) is a bifunctional enzyme that plays an essential role in cellular sulfonation by catalyzing the synthesis of the high‐energy sulfate donor PAPS from ATP and inorganic sulfate. PAPSS1 contains an N‐terminal APS kinase domain and a C‐terminal ATP sulfurylase domain that work sequentially to generate PAPS, a cofactor required by numerous sulfotransferases for modifying hormones, extracellular matrix components, drugs, and other molecules. Detailed biochemical studies have demonstrated its catalytic efficiency, kinetic properties (including substrate inhibition by APS), and structural features such as a dimeric, asymmetric architecture with dynamic inter‐domain interactions. Furthermore, tissue‐specific expression and subcellular localization analyses reveal that PAPSS1 is predominantly expressed in tissues like brain and skin, and that distinct nuclear localization signals allow it to function in both the nucleus and cytoplasm"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n\n<br><br>\nBeyond its classical role in sulfation, PAPSS1 has emerged as a multifunctional regulator in diverse cellular processes with direct implications in disease. For instance, modulation of cellular sulfonation through PAPSS1 influences estrogen metabolism in hormone‐sensitive tumors, thereby affecting cell proliferation and apoptosis. Moreover, genetic studies have linked polymorphisms and altered expression of PAPSS1 to hepatocellular carcinoma susceptibility, while functional screening has implicated the enzyme as a critical host factor during retroviral replication by affecting provirus establishment and viral gene expression"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n\n<br><br>\nRecent preclinical findings further underline the therapeutic potential of targeting PAPSS1 in cancer. Inhibition or knockdown of PAPSS1 has been shown to enhance the sensitivity of cancer cells—such as those in lung adenocarcinoma and epithelial ovarian cancer—to DNA‐damaging agents like cisplatin, possibly by perturbing sulfonation‐dependent regulation of DNA repair and apoptotic pathways. Complementary studies in hepatic cell models also reveal compensatory changes in drug‐metabolizing enzyme expression upon PAPSS suppression. Collectively, these insights suggest that low PAPSS1 expression may serve as a prognostic biomarker for improved response to platinum‐based chemotherapy, and that PAPSS1 itself represents a promising target for therapeutic intervention in various malignancies including esophageal squamous cell carcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "K V Venkatachalam "}, {"type": "b", "children": [{"type": "t", "text": "Human 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase: biochemistry, molecular biology and genetic deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "IUBMB Life (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/1521654031000072148"}], "href": "https://doi.org/10.1080/1521654031000072148"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12716056"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12716056"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hirotoshi Fuda, Chikara Shimizu, Young C Lee, et al. 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