{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSULT1A1 is a key phase II conjugating enzyme that catalyzes the transfer of a sulfonate group from the universal cofactor (3′-phosphoadenosine 5′-phosphosulfate) to a wide array of small, lipophilic phenolic and estrogenic compounds. In doing so, it modulates the biological activity of endogenous hormones (for example, by inactivating estrogens and catechol estrogens) as well as a range of xenobiotics—including environmental procarcinogens and dietary promutagens—thereby playing a dual role in detoxification and bioactivation. Functional studies have demonstrated that SULT1A1 is central in metabolizing active drug metabolites such as 4‑hydroxytamoxifen and naturally occurring polyphenols, and its activity is critical for effective chemical defense in the human body."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and kinetic investigations have revealed that the SULT1A1 active site is remarkably flexible, accommodating substrates of varying sizes and shapes. Intriguingly, the enzyme can bind two molecules of a xenobiotic substrate (as shown for p‑nitrophenol), leading to substrate inhibition when substrate concentrations are high. This adaptability explains not only the capacity of SULT1A1 to process diverse lipophilic compounds—including diiodothyronine and resveratrol—but also how subtle changes in active site architecture, as highlighted by comparative studies with SULT1A3, can affect substrate specificity and enzyme inhibition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic variability in SULT1A1—including coding single nucleotide polymorphisms, variations in gene copy number, and differences in regulatory 3′‐untranslated region sequences—introduces significant interindividual differences in enzyme activity and stability. These polymorphisms can alter the rate of sulfonation of both drugs and environmental chemicals, thereby impacting hormone regulation and modulating susceptibility to cancers associated with altered bioactivation of procarcinogens. For instance, variations that result in low activity or less thermostable forms of SULT1A1 have been linked to changes in drug efficacy (such as in tamoxifen therapy) and cancer risk; meanwhile, regulatory polymorphisms further fine‐tune overall enzyme expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "W Zheng, D Xie, J R Cerhan, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "A functional polymorphism in the SULT1A1 gene (G638A) is associated with risk of lung cancer in relation to tobacco smoking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgh053"}], "href": "https://doi.org/10.1093/carcin/bgh053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14688021"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14688021"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Amanda C Barnett, Sergey Tsvetanov, Niranjali Gamage, et al. 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An insight into active site plasticity and substrate inhibition with multi-ring substrates."}]}, {"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.M508289200"}], "href": "https://doi.org/10.1074/jbc.M508289200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16221673"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16221673"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "M Miksits, A Maier-Salamon, S Aust, et al. 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