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Interception of the Bycroft-Gowland Intermediate in the Enzymatic Macrocyclization of Thiopeptides.
J Am Chem Soc. 2020 Jul 29; 142(30):13170-13179.JA

Abstract

Thiopeptides are a broad class of macrocyclic, heavily modified peptide natural products that are unified by the presence of a substituted, nitrogen-containing heterocycle core. Early work indicated that this core might be fashioned from two dehydroalanines by an enzyme-catalyzed aza-[4 + 2] cycloaddition to give a cyclic-hemiaminal intermediate. This common intermediate could then follow a reductive path toward a dehydropiperidine, as in the thiopeptide thiostrepton, or an aromatization path to yield the pyridine groups observed in many other thiopeptides. Although several of the enzymes proposed to perform this cycloaddition have been reconstituted, only pyridine products have been isolated and any hemiaminal intermediates have yet to be observed. Here, we identify the conditions and substrates that decouple the cycloaddition from subsequent steps and allow interception and characterization of this long hypothesized intermediate. Transition state modeling indicates that the key amide-iminol tautomerization is the major hurdle in an otherwise energetically favorable cycloaddition. An anionic model suggests that deprotonation and polarization of this amide bond by TbtD removes this barrier and provides a sufficient driving force for facile (stepwise) cycloaddition. This work provides evidence for a mechanistic link between disparate cyclases in thiopeptide biosynthesis.

Authors+Show Affiliations

Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States.Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Ithaca, New York 14853, United States.Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States. Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, North Carolina 28403, United States.Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States.Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32609512

Citation

Bogart, Jonathan W., et al. "Interception of the Bycroft-Gowland Intermediate in the Enzymatic Macrocyclization of Thiopeptides." Journal of the American Chemical Society, vol. 142, no. 30, 2020, pp. 13170-13179.
Bogart JW, Kramer NJ, Turlik A, et al. Interception of the Bycroft-Gowland Intermediate in the Enzymatic Macrocyclization of Thiopeptides. J Am Chem Soc. 2020;142(30):13170-13179.
Bogart, J. W., Kramer, N. J., Turlik, A., Bleich, R. M., Catlin, D. S., Schroeder, F. C., Nair, S. K., Williamson, R. T., Houk, K. N., & Bowers, A. A. (2020). Interception of the Bycroft-Gowland Intermediate in the Enzymatic Macrocyclization of Thiopeptides. Journal of the American Chemical Society, 142(30), 13170-13179. https://doi.org/10.1021/jacs.0c05639
Bogart JW, et al. Interception of the Bycroft-Gowland Intermediate in the Enzymatic Macrocyclization of Thiopeptides. J Am Chem Soc. 2020 Jul 29;142(30):13170-13179. PubMed PMID: 32609512.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interception of the Bycroft-Gowland Intermediate in the Enzymatic Macrocyclization of Thiopeptides. AU - Bogart,Jonathan W, AU - Kramer,Nicholas J, AU - Turlik,Aneta, AU - Bleich,Rachel M, AU - Catlin,Daniel S, AU - Schroeder,Frank C, AU - Nair,Satish K, AU - Williamson,R Thomas, AU - Houk,K N, AU - Bowers,Albert A, Y1 - 2020/07/16/ PY - 2020/7/2/pubmed PY - 2020/7/2/medline PY - 2020/7/2/entrez SP - 13170 EP - 13179 JF - Journal of the American Chemical Society JO - J. Am. Chem. Soc. VL - 142 IS - 30 N2 - Thiopeptides are a broad class of macrocyclic, heavily modified peptide natural products that are unified by the presence of a substituted, nitrogen-containing heterocycle core. Early work indicated that this core might be fashioned from two dehydroalanines by an enzyme-catalyzed aza-[4 + 2] cycloaddition to give a cyclic-hemiaminal intermediate. This common intermediate could then follow a reductive path toward a dehydropiperidine, as in the thiopeptide thiostrepton, or an aromatization path to yield the pyridine groups observed in many other thiopeptides. Although several of the enzymes proposed to perform this cycloaddition have been reconstituted, only pyridine products have been isolated and any hemiaminal intermediates have yet to be observed. Here, we identify the conditions and substrates that decouple the cycloaddition from subsequent steps and allow interception and characterization of this long hypothesized intermediate. Transition state modeling indicates that the key amide-iminol tautomerization is the major hurdle in an otherwise energetically favorable cycloaddition. An anionic model suggests that deprotonation and polarization of this amide bond by TbtD removes this barrier and provides a sufficient driving force for facile (stepwise) cycloaddition. This work provides evidence for a mechanistic link between disparate cyclases in thiopeptide biosynthesis. SN - 1520-5126 UR - https://www.unboundmedicine.com/medline/citation/32609512/Interception_of_the_"Bycroft-Gowland"_intermediate_in_the_enzymatic_macrocyclization_of_thiopeptides L2 - https://doi.org/10.1021/jacs.0c05639 DB - PRIME DP - Unbound Medicine ER -
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