Total Mycosynthesis: Rational Bioconstruction and Bioengineering of Fungal Natural Products

Kahlert, Lukas; Schotte, Carsten; Cox, Russell J.

doi:10.1055/a-1401-2716

Cited by 8 publications

(11 citation statements)

References 109 publications

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“…We, [20,21] and others, [22] have shown that reconstruction of cryptic fungal biosynthetic pathways in the host organism Aspergillus oryzae NSAR1 is an effective way to understand complex transformations. Here, we deploy those methods and in vitro studies of isolated enzymes aiming to overcome the hurdles that have previously hampered characterization of pathway intermediates during the biosynthesis of these intriguing metabolites [3] …”

Section: Introductionmentioning

confidence: 99%

Early Oxidative Transformations During the Biosynthesis of Terrein and Related Natural Products

Kahlert

Bernardi

Hauser

et al. 2021

Chemistry A European J

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The mycotoxin terrein is derived from the C10‐precursor 6‐hydroxymellein (6‐HM) via an oxidative ring contraction. Although the corresponding biosynthetic gene cluster (BGC) has been identified, details of the enzymatic oxidative transformations are lacking. Combining heterologous expression and in vitro studies we show that the flavin‐dependent monooxygenase (FMO) TerC catalyzes the initial oxidative decarboxylation of 6‐HM. The reactive intermediate is further hydroxylated by the second FMO TerD to yield a highly oxygenated aromatic species, but further reconstitution of the pathway was hampered. A related BGC was identified in the marine‐derived Roussoella sp. DLM33 and confirmed by heterologous expression. These studies demonstrate that the biosynthetic pathways of terrein and related (polychlorinated) congeners diverge after oxidative decarboxylation of the lactone precursor that is catalyzed by a conserved FMO and further indicate that early dehydration of the side chain is an essential step.

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Section: Introductionmentioning

confidence: 99%

Early Oxidative Transformations During the Biosynthesis of Terrein and Related Natural Products

Kahlert

Bernardi

Hauser

et al. 2021

Chemistry A European J

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“…oryzae is a highly useful host organism for the heterologous expression and engineering of fungal secondary metabolites. In particular, it has been extensively used for the production of fungal metabolites stemming from iterative type I PKS that use predominantly acetyl-CoA and malonyl-CoA for their construction [17]. Bacterial modular PKS, on the other hand, often use propionyl-CoA and methylmalonyl-CoA for the construction of polyketides [23][24][25][26][27].…”

Section: Discussionmentioning

confidence: 99%

“…It has a generally regarded as safe (GRAS) status and is easily cultured in the lab, amenable to genetic modification using a variety of techniques, and is known for its high protein production. Recently, A. oryzae has proven itself to be an extremely capable host for heterologous expression of complete and partial fungal biosynthetic gene clusters (BGC), and for their systematic engineering [10][11][12][13][14][15][16][17]. A. oryzae does not produce significant amounts of its own secondary metabolites, meaning it is a clean host allowing facile detection and purification of heterologously produced compounds.…”

Section: Introductionmentioning

confidence: 99%

Engineering Aspergillus oryzae for the Heterologous Expression of a Bacterial Modular Polyketide Synthase

Feng

Hauser

Cox

et al. 2021

JoF

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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.

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“…Heterologous expression of its coding gene and of the upstream gene for the CYP450 AuAP450 in Aspergillus oryzae allowed the isolation of ve sesterterpene hydrocarbons, including aspergildienes A-D (115,117,119,121) and aspergiltriene (123). In addition, the CYP450 oxidation products aspergilols A-D (116, 118, 120, 122) were obtained.…”

Section: Heterologous Expression Of Sesterterpenoid Pathways In Asper...mentioning

confidence: 99%

Engineering fungal terpene biosynthesis

Yin

Dickschat

2023

Nat. Prod. Rep.

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Total Mycosynthesis: Rational Bioconstruction and Bioengineering of Fungal Natural Products

Abstract: Total biosynthesis in fungi is beginning to compete with traditional chemical total synthesis campaigns. Advantages, disadvantages and future opportunities are discussed within the scope of several recent examples.

Cited by 8 publications

References 109 publications

Early Oxidative Transformations During the Biosynthesis of Terrein and Related Natural Products

Early Oxidative Transformations During the Biosynthesis of Terrein and Related Natural Products

Engineering Aspergillus oryzae for the Heterologous Expression of a Bacterial Modular Polyketide Synthase

Engineering fungal terpene biosynthesis

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