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Applied and environmental microbiology

A Consensus Ochratoxin A Biosynthetic Pathway: Insights from the Genome Sequence of Aspergillus ochraceus and a Comparative Genomic Analysis.


PMID 30054361

Abstract

Ochratoxin A (OTA) is a toxic secondary metabolite produced by Aspergillus and Penicillium species that widely contaminate food and feed. We sequenced and assembled the complete ∼37 Mb genome of A. ochraceus fc-1, a well-known producer of OTA. Key genes of the OTA biosynthetic pathway were identified by comparative genomic analyses with five other sequenced OTA-producing fungi, A. carbonarius, A. niger, A. steynii, A. westerdijkiae, and Penicillium nordicum OTA production was completely inhibited in the deletion mutants (ΔotaA-D and ΔotaR1), and OTA biosynthesis was restored by feeding a post-block substrate to the corresponding mutant. The OTA biosynthetic pathway was unblocked with the addition of heterologously expressed halogenase in the ΔotaD mutant. OTA biosynthesis begins with PKS (OtaA), utilizing acetyl-CoA and malonyl-CoA to synthesize 7-methylmellein, which is oxidized to OTβ by cytochrome P450 monooxygenase (OtaC). OTβ and L-β-phenylalanine are combined by NRPS (OtaB) to form an amide bond to synthesize OTB. Finally, OTB is chlorinated by halogenase (OtaD) to OTA. The otaA-D genes were expressed at low levels in the ΔotaR1 mutant. A second regulator, otaR2, which is adjacent to the biosynthetic gene, could modulate only the expression of otaA, otaB and otaD Thus, we have identified a consensus OTA biosynthetic pathway that can be used to prevent and control OTA synthesis, and to understand variation and production of the intermediate components in the biosynthetic pathway.IMPORTANCE Ochratoxin A (OTA) is a significant mycotoxin that contaminates cereal products, coffee, grapes, wine, cheese and meat. OTA is nephrotoxic, carcinogenic, teratogenic and immunotoxic. OTA contamination is a serious threat to food safety, endangers human health and can cause huge economic losses. At present, more than 20 species of the genera Aspergillus and Penicillium are known to produce OTA. Here, we demonstrate that a consensus OTA biosynthetic pathway exists in all OTA-producing fungi and that is encoded by a gene cluster containing four highly conserved biosynthetic genes and a bZIP transcription factor.

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