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Heterologous Pathway Assembly Reveals Molecular Steps of Fungal Terreic Acid Biosynthesis

Heterologous Pathway Assembly Reveals Molecular Steps of Fungal Terreic Acid Biosynthesis

Chuixing Kong, Hezhou Huang, Ying Xue, Yiqi Liu, Qiangqiang Peng, Qi Liu, Qin Xu, Qiaoyun Zhu, Ying Yin, Xiangshan Zhou, Yuanxing Zhang, Menghao Cai

Sci Rep. 2018 Feb 1;8(1):2116.

PMID: 29391515

Abstract:

Terreic acid is a potential anticancer drug as it inhibits Bruton's tyrosine kinase; however, its biosynthetic molecular steps remain unclear. In this work, the individual reactions of terreic acid biosynthesis were determined by stepwise pathway assembly in a heterologous host, Pichia pastoris, on the basis of previous knockout studies in a native host, Aspergillus terreus. Polyketide synthase AtX was found to catalyze the formation of partially reduced polyketide 6-methylsalicylic acid, followed by 3-methylcatechol synthesis by salicylate 1-monooxygenase AtA-mediated decarboxylative hydroxylation of 6-methylsalicylic acid. Our results show that cytochrome P450 monooxygenase AtE hydroxylates 3-methylcatechol, thus producing the next product, 3-methyl-1,2,4-benzenetriol. A smaller putative cytochrome P450 monooxygenase, AtG, assists with this step. Then, AtD causes epoxidation and hydroxyl oxidation of 3-methyl-1,2,4-benzenetriol and produces a compound terremutin, via which the previously unknown function of AtD was identified as cyclooxygenation. The final step involves an oxidation reaction of a hydroxyl group by a glucose-methanol-choline oxidoreductase, AtC, which leads to the final product: terreic acid. Functions of AtD and AtG were determined for the first time. All the genes were reanalyzed and all intermediates and final products were isolated and identified. Our model fully defines the molecular steps and corrects previous results from the literature.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP121404-B	Terreic Acid		121-40-4	Price

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