The Role of LaeA and LovE Regulators in Lovastatin Biosynthesis with Exogenous Polyamines in Aspergillus terreus

Abstract

The filamentous fungus Aspergillus terreus is the main industrial producer of a cholesterol-lowering drug, lovastatin, and simvastatin obtained on its basis. The biosynthesis of lovastatin in A. terreus is under the control of two major positive regulators, the LovE pathway-specific regulator and LaeA global regulator of the secondary metabolism of fungi. It is shown that laeA expression can be negatively regulated by LovE, the Zn₂Cys₆ transcription factor of lovastatin biosynthesis. The overexpression of lovE under the control of the gpdA constitutive promoter from Aspergillus nidulans, which results in a 10- to 30-fold increase in lovastatin production is accompanied by a decrease in laeA expression in the fermentation process. The observed negative interrelationship between the LovE and LaeA regulators consists of the downregulation of lov resistance and transport genes in A. terreus with an additional copy of lovE and phenotypically manifests itself as polyamine toxicity for lovastatin production. Polyamine addition into the medium in the course of fermentation of A. terreus OE::lovE leads to a decrease in the lovastatin production by 30–40% and inhibited the expression of the lov and laeA genes.