The efflux pump MlcE from the Penicillium solitum compactin biosynthetic gene cluster increases Saccharomyces cerevisiae resistance to natural statins

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    Abstract

    The use of statins as cholesterol-lowering drugs is based on their ability to inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), the key
    enzyme in the mevalonate pathway, which is responsible for the production of ergosterol in fungi and cholesterol in human. Industrial scale production
    of natural statins (i.e. compactin and lovastatin) and their semi-synthetic derivatives (i.e. pravastatin and simvastatin) is based on fermentation of
    statin-producing filamentous fungi, such as Aspergillus terreus and Penicillium solitum, however, the unique physiology and morphology make these
    natural producers difficult to culture in bioreactors. The production limitations associated with the use of natural producers can be overcome by
    heterologous expression of the biosynthetic pathway in Saccharomyces cerevisiae (1), however, it is crucial to establish a nondestructive resistance
    mechanism in yeast, which would overcome the undesirable effects of statins. One possible mechanism is an active export of statins, a mechanism
    that does not just provide the resistance but can also significantly ease the purification of the produced compounds. In order to establish export of
    statins from yeast we integrated a putative efflux pump-encoding gene mlcE from the P. solitum compactin biosynthetic gene cluster into S. cerevisiae
    genome. The resulting strain was tested for susceptibility to statins by growing the strain on media containing statins. The constructed strain showed
    an increased resistance to both natural statins (compactin and lovastatin), and also to a semi-synthetic statin simvastatin, when compared to the wild
    type strain. Expression of a mRFP-tagged MlcE show that MlcE is localized in the yeast plasma membrane. In conclusion we provide evidence indicating
    that MlcE is a transmembrane efflux pump, capable of exporting natural and semi-natural statins from yeast, and overexpression of MlcE in a statinproducing
    yeast could therefore greatly improve the commercial production of natural and semi-natural statins. Reference: (1) Xu W. et al., (2013),
    “LovG: The Thioesterase Required for Dihydromonacolin”, Angew. Chem. Int. Ed. 2013, 52, 6472 –6475.
    Original languageEnglish
    Publication date2014
    Publication statusPublished - 2014
    EventYeast Genetics Meeting - Seattle, Washington, United States
    Duration: 29 Jul 20143 Aug 2014

    Conference

    ConferenceYeast Genetics Meeting
    CountryUnited States
    CitySeattle, Washington
    Period29/07/201403/08/2014

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