An iterative, bimodular nonribosomal peptide synthetase that converts anthranilate and tryptophan into tetracyclic asperlicins

  1. Gao, X. 2
  2. Jiang, W. 1
  3. Jiménez-Osés, G. 2
  4. Choi, M.S. 2
  5. Houk, K.N. 2
  6. Tang, Y. 2
  7. Walsh, C.T. 1
  1. 1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, United States
  2. 2 University of California Los Angeles
    info

    University of California Los Angeles

    Los Ángeles, Estados Unidos

    ROR https://ror.org/046rm7j60

Revista:
Chemistry and Biology

ISSN: 1074-5521

Año de publicación: 2013

Volumen: 20

Número: 7

Páginas: 870-878

Tipo: Artículo

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DOI: 10.1016/J.CHEMBIOL.2013.04.019 PMID: 23890005 SCOPUS: 2-s2.0-84880873148 WoS: WOS:000322687600004 GOOGLE SCHOLAR

Otras publicaciones en: Chemistry and Biology

Resumen

The bimodular 276 kDa nonribosomal peptide synthetase AspA from Aspergillus alliaceus, heterologously expressed in Saccharomyces cerevisiae, converts tryptophan and two molecules of the aromatic β-amino acid anthranilate (Ant) into a pair of tetracyclic peptidyl alkaloids asperlicin C and D in a ratio of 10:1. The first module of AspA activates and processes two molecules of Ant iteratively to generate a tethered Ant-Ant-Trp-S-enzyme intermediate on module two. Release is postulated to involve tandem cyclizations, in which the first step is the macrocyclization of the linear tripeptidyl-S-enzyme, by the terminal condensation (CT) domain to generate the regioisomeric tetracyclic asperlicin scaffolds. Computational analysis of the transannular cyclization of the 11-membered macrocyclic intermediate shows that asperlicin C is the kinetically favored product due to the high stability of a conformation resembling the transition state for cyclization, while asperlicin D is thermodynamically more stable. © 2013 Elsevier Ltd.