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Insight into the molecular basis of aromatic polyketide cyclization: crystal structure and in vitro characterization of WhiE-ORFVI.

Lee MY, Ames BD, Tsai SC
Biochemistry 51 3079-91 (2012)
Related entries: 3tvq, 3tvr

Cited: 17 times
EuropePMC logo PMID: 22432862

Abstract

Aromatic polyketides are biologically active natural products. Many important pharmaceuticals are derived from aromatic polyketides. Especially important in aromatic polyketide biosynthesis is the regiospecific cyclization of a linear, preassembled polyketide chain catalyzed by aromatase/cyclase (ARO/CYC), which serves as a key control point in aromatic ring formation. How different ARO/CYCs promote different cyclization patterns is not well understood. The whiE locus of Streptomyces coelicolor A3(2) is responsible for the biosynthesis of an aromatic polyketide precursor to the gray spore pigment. The WhiE ARO/CYC catalyzes the regiospecific C9-C14 and C7-C16 cyclization and aromatization of a 24-carbon polyketide chain. WhiE ARO/CYC shares a high degree of similarity to another nonreducing PKS ARO/CYC, TcmN ARO/CYC. This paper presents the apo crystal structure of WhiE ARO/CYC, and cocrystal structures of WhiE and TcmN ARO/CYCs bound with polycyclic aromatic compounds that mimic the respective ARO/CYC products. Site-directed mutagenesis coupled with in vitro PKS reconstitution assays was used to characterize the interior pocket residues of WhiE ARO/CYC. The results confirmed that the interior pocket of ARO/CYCs is a critical determinant of polyketide cyclization specificity. A unified ARO/CYC-mediated cyclization mechanism is proposed on the basis of these structural and functional results.

Reviews - 3tl1 mentioned but not cited (1)

  1. Diversity and function of arthropod endosymbiont toxins. Massey JH, Newton ILG. Trends Microbiol 30 185-198 (2022)

Articles - 3tl1 mentioned but not cited (1)

  1. Insight into the molecular basis of aromatic polyketide cyclization: crystal structure and in vitro characterization of WhiE-ORFVI. Lee MY, Ames BD, Tsai SC. Biochemistry 51 3079-3091 (2012)


Reviews citing this publication (3)

  1. Disruption of aromatase homeostasis as the cause of a multiplicity of ailments: A comprehensive review. Patel S. J Steroid Biochem Mol Biol 168 19-25 (2017)
  2. The Structural Enzymology of Iterative Aromatic Polyketide Synthases: A Critical Comparison with Fatty Acid Synthases. Tsai SC. Annu Rev Biochem 87 503-531 (2018)
  3. Recent Advances in the Biosynthesis of Carbazoles Produced by Actinomycetes. Kobayashi M, Kuzuyama T. Biomolecules 10 E1147 (2020)

Articles citing this publication (12)

  1. Rational reprogramming of fungal polyketide first-ring cyclization. Xu Y, Zhou T, Zhou Z, Su S, Roberts SA, Montfort WR, Zeng J, Chen M, Zhang W, Lin M, Zhan J, Molnár I. Proc Natl Acad Sci U S A 110 5398-5403 (2013)
  2. Transcriptomic analysis of liquid non-sporulating Streptomyces coelicolor cultures demonstrates the existence of a complex differentiation comparable to that occurring in solid sporulating cultures. Yagüe P, Rodríguez-García A, López-García MT, Rioseras B, Martín JF, Sánchez J, Manteca A. PLoS One 9 e86296 (2014)
  3. Structural and functional analysis of two di-domain aromatase/cyclases from type II polyketide synthases. Caldara-Festin G, Jackson DR, Barajas JF, Valentic TR, Patel AB, Aguilar S, Nguyen M, Vo M, Khanna A, Sasaki E, Liu HW, Tsai SC. Proc Natl Acad Sci U S A 112 E6844-51 (2015)
  4. Enzymology of Anthraquinone-γ-Pyrone Ring Formation in Complex Aromatic Polyketide Biosynthesis. Hou XF, Song YJ, Zhang M, Lan W, Meng S, Wang C, Pan HX, Cao C, Tang GL. Angew Chem Int Ed Engl 57 13475-13479 (2018)
  5. Letter Structural and genetic analysis of START superfamily protein MSMEG_0129 from Mycobacterium smegmatis. Zheng S, Zhou Y, Fleming J, Zhou Y, Zhang M, Li S, Li H, Sun B, Liu W, Bi L. FEBS Lett 592 1445-1457 (2018)
  6. A thermoacidophile-specific protein family, DUF3211, functions as a fatty acid carrier with novel binding mode. Miyakawa T, Sawano Y, Miyazono K, Miyauchi Y, Hatano K, Tanokura M. J Bacteriol 195 4005-4012 (2013)
  7. An unusual intramolecular trans-amidation. Rivera H, Dhar S, La Clair JJ, Tsai SC, Burkart MD. Tetrahedron 72 3605-3608 (2016)
  8. Domain swapping of the C-terminal helix promotes the dimerization of a novel ribonuclease protein from Mycobacterium tuberculosis. Kim DH, Na Y, Chang H, Boo JH, Kang SM, Jin C, Kang SJ, Lee SY, Lee BJ. Protein Sci 32 e4644 (2023)
  9. Solution NMR structure of CGL2373, a polyketide cyclase-like protein from Corynebacterium glutamicum. Cai C, Nie Y, Gong Y, Li S, Ramelot TA, Kennedy MA, Yue X, Zhu J, Liu M, Yang Y. Proteins 88 237-241 (2020)
  10. The putative polyketide cyclase MSMEG_0129 from Mycobacterium smegmatis: purification, crystallization and X-ray crystallographic analysis. Zheng S, Zhou Y, Fleming J, Zhou Y, Liu W, Bi L. Acta Crystallogr F Struct Biol Commun 73 437-442 (2017)
  11. Investigation of the Biosynthetic Mechanism of Bipentaromycin Featuring an Unprecedented Cyclic Head-to-Tail Dimeric Scaffold. Huang C, Cui H, Ren H, Zhao H. JACS Au 3 195-203 (2023)
  12. Structural characterization of DynU16, a START/Bet v1-like protein involved in dynemicin biosynthesis. Alvarado SK, Miller MD, Bhardwaj M, Thorson JS, Van Lanen SG, Phillips GN. Acta Crystallogr F Struct Biol Commun 77 328-333 (2021)


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