Department of Chemical and Biomolecular Engineering and Energy Biosciences Institute, University of California, Berkeley, 2151 Berkeley Way, Berkeley, CA 94704 (USA).
Angew Chem Int Ed Engl. 2014 Jan 3;53(1):136-9. doi: 10.1002/anie.201308069. Epub 2013 Nov 13.
Physostigmine is a parasympathomimetic drug used to treat a variety of neurological disorders, including Alzheimer's disease and glaucoma. Because of its potent biological activity and unique pyrroloindole skeleton, physostigmine has been the target of many organic syntheses. However, the biosynthesis of physostigmine has been relatively understudied. In this study, we identified a biosynthetic gene cluster for physostigmine by genome mining. The 8.5 kb gene cluster encodes eight proteins (PsmA-H), seven of which are required for the synthesis of physostigmine from 5-hydroxytryptophan, as shown by in vitro total reconstitution. Further genetic and enzymatic studies enabled us to delineate the biosynthetic pathway for physostigmine. The pathway features an unusual reaction cascade consisting of highly coordinated methylation and acetylation/deacetylation reactions.
毒扁豆碱是一种拟副交感神经药物，用于治疗多种神经紊乱，包括阿尔茨海默病和青光眼。由于其强大的生物活性和独特的吡咯并吲哚骨架，毒扁豆碱一直是许多有机合成的目标。然而，毒扁豆碱的生物合成相对研究较少。在这项研究中，我们通过基因组挖掘鉴定了毒扁豆碱的生物合成基因簇。该 8.5kb 的基因簇编码 8 种蛋白（PsmA-H），其中 7 种蛋白需要从 5-羟色氨酸合成毒扁豆碱，这一点通过体外全重组得到了证实。进一步的遗传和酶学研究使我们能够描绘毒扁豆碱的生物合成途径。该途径的特点是一个不寻常的反应级联，包括高度协调的甲基化和乙酰化/去乙酰化反应。
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