TY - JOUR

T1 - Engineering aspergillus oryzae for the heterologous expression of a bacterial modular polyketide synthase

AU - Feng, Jin

AU - Hauser, Maurice

AU - Cox, Russell J.

AU - Skellam, Elizabeth

N1 - Funding Information: J.F. thanks the China Scholarship council for funding (201709110130). We thank DFG for the funding of LCMS (INST 187/626-1) and 600 MHz NMR instruments (INST 187/686-1). The publication of this article was funded by the Open Access Fund of the Leibniz Universität Hannover.

PY - 2021/12/17

Y1 - 2021/12/17

N2 - Microbial natural products have had phenomenal success in drug discovery and development yet form distinct classes based on the origin of their native producer. Methods that enable metabolic engineers to combine the most useful features of the different classes of natural products may lead to molecules with enhanced biological activities. In this study, we modified the metabolism of the fungus Aspergillus oryzae to enable the synthesis of triketide lactone (TKL), the product of the modular polyketide synthase DEBS1-TE engineered from bacteria. We established (2S)-methylmalonyl-CoA biosynthesis via introducing a propionyl-CoA carboxylase complex (PCC); reassembled the 11.2 kb DEBS1-TE coding region from synthetic codon-optimized gene fragments using yeast recombination; introduced bacterial phosphopantetheinyltransferase SePptII; investigated propionyl-CoA synthesis and degradation pathways; and developed improved delivery of exogenous propionate. Depending on the conditions used titers of TKL ranged from <0.01–7.4 mg/L. In conclusion, we have demonstrated that A. oryzae can be used as an alternative host for the synthesis of polyketides from bacteria, even those that require toxic or non-native substrates. Our metabolically engineered A. oryzae may offer advantages over current heterologous platforms for producing valuable and complex natural products.

AB - Microbial natural products have had phenomenal success in drug discovery and development yet form distinct classes based on the origin of their native producer. Methods that enable metabolic engineers to combine the most useful features of the different classes of natural products may lead to molecules with enhanced biological activities. In this study, we modified the metabolism of the fungus Aspergillus oryzae to enable the synthesis of triketide lactone (TKL), the product of the modular polyketide synthase DEBS1-TE engineered from bacteria. We established (2S)-methylmalonyl-CoA biosynthesis via introducing a propionyl-CoA carboxylase complex (PCC); reassembled the 11.2 kb DEBS1-TE coding region from synthetic codon-optimized gene fragments using yeast recombination; introduced bacterial phosphopantetheinyltransferase SePptII; investigated propionyl-CoA synthesis and degradation pathways; and developed improved delivery of exogenous propionate. Depending on the conditions used titers of TKL ranged from <0.01–7.4 mg/L. In conclusion, we have demonstrated that A. oryzae can be used as an alternative host for the synthesis of polyketides from bacteria, even those that require toxic or non-native substrates. Our metabolically engineered A. oryzae may offer advantages over current heterologous platforms for producing valuable and complex natural products.

KW - Heterologous expression

KW - Modular polyketide synthase

KW - Propionyl-CoA carboxylase

KW - Propionyl-CoA metabolism

UR - http://www.scopus.com/inward/record.url?scp=85121472528&partnerID=8YFLogxK

U2 - 10.3390/jof7121085

DO - 10.3390/jof7121085

M3 - Article

AN - SCOPUS:85121472528

VL - 7

JO - Journal of Fungi

JF - Journal of Fungi

IS - 12

M1 - 1085

ER -