Discovery of mycotoxin alternariol as a potential lead compound targeting xanthine oxidase
Discovery of mycotoxin alternariol as a potential lead compound targeting xanthine oxidase
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DOI：
10.1016/j.cbi.2022.109948
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发表时间：
2022-04-16
影响因子：
5.1
通讯作者：
Wang, Wei
中科院分区：
文献类型：
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作者：
Fan, Jiahe;Sun, Shiwei;Wang, Wei
黄嘌呤氧化酶（XO）催化次黄嘌呤氧化为黄嘌呤，黄嘌呤进一步转化为尿酸。嘌呤末端代谢物的过量产生或排泄减少可导致高尿酸血症。为了寻找新的黄嘌呤氧化酶抑制剂，我们首次从药用植物光tungensis Chun中分离到14种内生真菌，并对其培养滤液的乙酸乙酯提取物进行了XO抑制活性筛选。内生真菌alternnaria alternata GDZZ-J6提取物对XO的抑制作用最强。进一步分离其次生代谢物，分离出6个化合物。其中，二苯并α -吡啶酮衍生物霉毒素alternariol （AOH）对XO具有较强的抑制活性，IC50值为0.23 +/- 0.01 μ M，与临床使用的XO抑制剂别嘌呤醇（2.98 +/- 0.07 μ M）相比，AOH对XO的抑制效力提高了50倍。进一步比较了从鞣花酸、尿石素A、B和C的肠道微生物代谢产物中提取的三种二苯并α -吡咯酮对XO的IC50值，并讨论了它们的构效关系。双互易Lineweaver-Burk图的抑制动力学分析表明，AOH是一种非竞争性抑制剂。后续对接研究表明，Gln957、Lys1257和Phe1153通过与AOH形成氢键发挥重要作用。我们的研究结果表明，AOH可以作为进一步修饰的先导化合物来开发治疗高尿酸血症的药物。
Xanthine oxidase (XO) catalyzes the oxidation of hypoxanthine to xanthine, which is further converted to uric acid. The excessive production or reduced excretion of the purine terminal metabolite may lead to hyperuricemia. In our ongoing search for new xanthine oxidase inhibitors, 14 endophytic fungi were isolated for the first time from a medicinal plant Callicarpa kwangtungensis Chun, and the ethyl acetate extracts of their culture filtrates were screened for XO inhibitory activity. The extract from an endophytic fungus, characterized as Alternaria alternata GDZZ-J6, exhibited the most potent inhibition of XO. Further fractionation of its secondary metabolites led to the isolation of six compounds. Among them, mycotoxin alternariol (AOH), a dibenzo-alpha-pyrone derivative, had strong inhibitory activity on XO, and the IC50 value was 0.23 +/- 0.01 mu M. The potency of XO inhibition by AOH was > 12-fold higher as compared to allopurinol (2.98 +/- 0.07 mu M), a XO inhibitor that has been used clinically. The IC50 values of three dibenzo-alpha-pyrones from gut microbial metabolites of ellagic acid, urolithins A, B, and C, against XO were further compared, and their structure-activity relationships were discussed. Inhibition kinetic analysis by double-reciprocal Lineweaver-Burk plots demonstrated that AOH was an uncompetitive inhibitor. Follow-up docking studies showed that Gln957, Lys1257, and Phe1153 played an important role by forming hydrogen bonds with AOH. Our findings suggest that AOH may be used as a lead compound for further modification to develop future drug for treating hyperuricemia.