Single-step production of the simvastatin precursor monacolin J by engineering of an industrial strain of Aspergillus terreus
Single-step production of the simvastatin precursor monacolin J by engineering of an industrial strain of Aspergillus terreus
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通过土曲霉工业菌株的工程化一步生产辛伐他汀前体莫纳可林 J
DOI：
10.1016/j.ymben.2017.06.005
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发表时间：
2017-07-01
影响因子：
8.4
通讯作者：
Lu, Xuefeng
中科院分区：
文献类型：
--
作者：
Huang, Xuenian;Liang, Yajing;Lu, Xuefeng
莫那可林J是合成辛伐他汀（舒降之）的关键前体，辛伐他汀是治疗高胆固醇血症的重要药物。在工业上，莫那可林J是通过碱性水解洛伐他汀（一种由土曲霉产生的真菌聚酮化合物）来生产的。用于将洛伐他汀转化为辛伐他汀的多步化学方法是费力的、成本昂贵的和环境不友好的。以monacolin J为原料，采用生物催化法合成辛伐他汀。然而，monacolin J的直接生物生产尚未实现。在这里，我们确定了洛伐他汀水解酶产黄青霉，它显示了232倍的催化效率高，在体外水解洛伐他汀相比，以前的专利水解酶，但没有活性的辛伐他汀。此外，我们还证明了工业A.异源表达该洛伐他汀水解酶的terreus菌株可通过一步发酵高效生产monacolin J，约95%的生物合成的洛伐他汀被水解为monacolin J。我们的研究结果为生产monacolin J提供了一条简单、绿色的技术路线，这使得降胆固醇药物辛伐他汀的完全生物生产成为可能和有前途的。
Monacolin J is a key precursor for the synthesis of simvastatin (Zocor), an important drug for treating hypercholesterolemia. Industrially, monacolin J is manufactured through alkaline hydrolysis of lovastatin, a fungal polyketide produced by Aspergillus terreus. Multistep chemical processes for the conversion of lovastatin to simvastatin are laborious, cost expensive and environmentally unfriendly. A biocatalysis process for monacolin J conversion to simvastatin has been developed. However, direct bioproduction of monacolin J has not yet been achieved. Here, we identified a lovastatin hydrolase from Penicillium chrysogenum, which displays a 232-fold higher catalytic efficiency for the in vitro hydrolysis of lovastatin compared to a previously patented hydrolase, but no activity for simvastatin. Furthermore, we showed that an industrial A. terreus strain heterologously expressing this lovastatin hydrolase can produce monacolin J through single-step fermentation with high efficiency, approximately 95% of the biosynthesized lovastatin was hydrolyzed to monacolin J. Our results demonstrate a simple and green technical route for the production of monacolin J, which makes complete bioproduction of the cholesterol-lowering drug simvastatin feasible and promising.