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. 2020 Aug 21;22(16):6637-6641.
doi: 10.1021/acs.orglett.0c02426. Epub 2020 Aug 10.

Engineered Biosynthesis of Fungal 4-Quinolone Natural Products

Mengting Liu  1   2 , Masao Ohashi  1 , Yi Tang  1
Affiliations

Engineered Biosynthesis of Fungal 4-Quinolone Natural Products

Mengting Liu et al. Org Lett. .

Abstract

Quinolone-containing natural products are widely found in bacteria, fungi, and plants. The fungal quinolactacins, which are N-methyl-4-quinolones, display a wide spectrum of biological activities. Here we uncovered a concise nonribosomal peptide synthetase pathway involved in quinolactacin A biosynthesis from Penicillium by using heterologous reconstitution and in vitro enzymatic synthesis. The N-desmethyl analog of quinolactacin A was accessed through the construction of a hybrid bacterial and fungi pathway in the heterologous host.

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Figures

Figure 1.
Figure 1.
Representative 4-quinoline containing natural products, which includes quinolactacin A (1).
Figure 2.
Figure 2.
Biosynthesis of quinolactacin A 1. (A) The qlt BGC identified from P. citrinum DSM1997. Abbreviations: C0, truncated condensation; C, condensation; A, adenylation; T, thiolation; R*, Dieckmann cyclization; N-MT, N-methyltransferase; IDO, indoleamine-2,3-dioxygenase; FMO, flavin-dependent monooxygenase. (B) Proposed biosynthetic pathway of 1. GmdS is an amidase from the heterologous host A. nidulans A1145. (C) LCMS analysis of in vitro biocatalytic synthesis of 1 using purified enzymes in the presence of SAM, FMN, ATP, MgCl2, and l-isoleucine. The authentic standard of 1 was purified from P. citrinum.
Figure 3.
Figure 3.
Combinatorial biosynthesis of N-desmethyl quinolactacin 11. (A) LCMS analysis of the in vitro assays of purified PqsA, PqsD, PqsE, QltA, and QltB in the presence of anthranilic acid, CoA, malonyl-CoA, ATP, MgCl2, and L-isoleucine. (B) HPLC analysis of metabolites produced by the heterologous host A. nidulans. (C) Combinatorial biosynthetic pathway to produce 11. PqsA, D and E biosynthesize 9 from anthranilic acid.
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References

    1. Vitaku E; Smith DT; Njardarson JT J. Med. Chem 2014, 57, 10257–10274. - PubMed
    1. Joule JA Chapter Four - Natural Products Containing Nitrogen Heterocy cles—Some Highlights 1990–2015. In Advances in Heterocyclic Chemistry; Scriven, Ramsden EFV, C. A., Eds.; Heterocyclic Chemistry in the 21st Century; Academic Press, 2016; Vol. 119, pp 81–106.
    1. Chen M; Liu C-T; Tang YJ Am. Chem. Soc 2020, 142, 10506–10515. - PMC - PubMed
    2. Ohashi M; Liu F; Hai Y; Chen M; Tang M; Yang Z; Sato M; Watanabe K; Houk KN; Tang Y Nature 2017, 549, 502–506. - PMC - PubMed
    3. Ames BD; Walsh CT Biochemistry 2010, 49, 3351–3365. - PMC - PubMed
    4. Waldman AJ; Ng TL; Wang P; Balskus EP Chem. Rev 2017, 117, 5784–5863. - PMC - PubMed
    5. Xu W; Gavia DJ; Tang Y Nat. Prod. Rep 2014, 31, 1474–1487. - PMC - PubMed
    6. Dan Q; Newmister SA; Klas KR; Fraley AE; McAfoos TJ; Somoza AD; Sunderhaus JD; Ye Y; Shende VV; Yu F; Sanders JN; Brown WC; Zhao L; Paton RS; Houk KN; Smith JL; Sherman DH; Williams RM Nat. Chem 2019, 11, 972–980. - PMC - PubMed
    7. >Du Y-L; He H-Y; Higgins MA; Ryan KS Nat. Chem. Biol 2017, 13, 836–838. - PubMed
    1. Scherlach K; Hertweck C Org. Biomol. Chem 2006, 4, 3517–3520. - PubMed
    2. Kishimoto S; Hara K; Hashimoto H; Hirayama Y; Champagne PA; Houk KN; Tang Y; Watanabe K Nat. Commun 2018, 9, 2826. - PMC - PubMed
    3. Zou Y; Garcia-Borràs M; Tang MC; Hirayama Y; Li DH; Li L; Watanabe K; Houk KN; Tang Y Nat. Chem. Biol 2017, 13, 325–332. - PMC - PubMed
    1. At submission of this manuscript, a study by Gao and coworkers on the same pathway appeared as reference 6.

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