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Tailoring Enzyme Stringency Masks the Multispecificity of a Lyngbyatoxin (Indolactam Alkaloid) Nonribosomal Peptide Synthetase.
Soeriyadi, Angela H; Ongley, Sarah E; Kehr, Jan-Christoph; Pickford, Russel; Dittmann, Elke; Neilan, Brett A.
Afiliación
  • Soeriyadi AH; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, 2052, Australia.
  • Ongley SE; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, 2052, Australia.
  • Kehr JC; School of Environmental and Life Sciences, University of Newcastle, Callaghan, 2308, Australia.
  • Pickford R; Department of Microbiology, Institute for Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany.
  • Dittmann E; Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, 2052, Australia.
  • Neilan BA; Department of Microbiology, Institute for Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany.
Chembiochem ; 23(3): e202100574, 2022 02 04.
Article en En | MEDLINE | ID: mdl-34850512
Indolactam alkaloids are activators of protein kinase C (PKC) and are of pharmacological interest for the treatment of pathologies involving PKC dysregulation. The marine cyanobacterial nonribosomal peptide synthetase (NRPS) pathway for lyngbyatoxin biosynthesis, which we previously expressed in E. coli, was studied for its amenability towards the biosynthesis of indolactam variants. Modification of culture conditions for our E. coli heterologous expression host and analysis of pathway products suggested the native lyngbyatoxin pathway NRPS does possess a degree of relaxed specificity. Site-directed mutagenesis of two positions within the adenylation domain (A-domain) substrate-binding pocket was performed, resulting in an alteration of substrate preference between valine, isoleucine, and leucine. We observed relative congruence of in vitro substrate activation by the LtxA NRPS to in vivo product formation. While there was a preference for isoleucine over leucine, the substitution of alternative tailoring domains may unveil the true in vivo effects of the mutations introduced herein.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptido Sintasas / Toxinas de Lyngbya Idioma: En Revista: Chembiochem Asunto de la revista: BIOQUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptido Sintasas / Toxinas de Lyngbya Idioma: En Revista: Chembiochem Asunto de la revista: BIOQUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Alemania