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Abstract
Itaconic acid is an important biomass-derived chemical building block but has also recently been identified as a metabolite produced in mammals, which has antimicrobial activity. The biosynthetic pathway of itaconic acid has been elucidated in the ascomycetous fungus Aspergillus terreus and in human macrophages. In both organisms itaconic acid is generated by decarboxylation of the tricarboxylic acid (TCA) cycle intermediate cis-aconitate. Here, we show that the basidiomycetous fungus Ustilago maydis uses an alternative pathway and produces itaconic acid via trans-aconitate, the thermodynamically favoured isomer of cis-aconitate. We have identified a gene cluster that contains all genes involved in itaconic acid formation. Trans-aconitate is generated from cis-aconitate by a cytosolic aconitate-Δ-isomerase (Adi1) that belongs to the PrpF family of proteins involved in bacterial propionate degradation. Decarboxylation of trans-aconitate is catalyzed by a novel enzyme, trans-aconitate decarboxylase (Tad1). Tad1 displays significant sequence similarity with bacterial 3-carboxy-cis,cis-muconate lactonizing enzymes (CMLE). This suggests that U. maydis has evolved an alternative biosynthetic pathway for itaconate production using the toxic intermediate trans-aconitate. Overexpression of a pathway-specific transcription factor (Ria1) or a mitochondrial tricarboxylic acid transporter (Mtt1) resulted in a twofold increase in itaconate yield. Therefore, our findings offer new strategies for biotechnological production of this valuable biomass-derived chemical.
Highlights
The unsaturated dicarboxylic acid itaconate (Fig. 1A) is commercially used in the production of pharmaceuticals, adhesives and as a copolymer for synthetic resins
Microbial itaconate production was first described for the ascomycetous fungus Aspergillus itaconicus (Kinoshita, 1932) and the related species Aspergillus terreus is still used for industrial production of itaconate via fermentation (Willke and Vorlop, 2001; Okabe et al, 2009; Klement and Büchs, 2013)
Genome analysis revealed that U. maydis contains no orthologue of the A. terreus cis-aconitate decarboxylase CadA, which belongs to the PrpD family of proteins
Summary
The unsaturated dicarboxylic acid itaconate (Fig. 1A) is commercially used in the production of pharmaceuticals, adhesives and as a copolymer for synthetic resins. Production of organic acids enables the liberation of micronutrients, such as phosphate and metals through chelating properties of the acids and a decrease of pH (Whitelaw, 1999; Landeweert et al, 2001). This pH decrease, combined with a high tolerance to low pH of the producing organism, provides a competitive advantage in carbon-rich environments (Cray et al, 2013), complemented by the specific action of itaconate as inhibitor of isocitrate lyase (McFadden and Purohit, 1977)
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