Cyclic peptide production using a macrocyclase with enhanced substrate promiscuity and relaxed recognition determinants

Cristina N Alexandru-Crivac; Christian Umeobika; Niina Leikoski; Jouni Jokela; Kirstie A Rickaby; André M Grilo; Peter Sjö; Alleyn T Plowright; Mohannad Idress; Eike Siebs; Ada Nneoyi-Egbe; Matti Wahlsten; Kaarina Sivonen; Marcel Jaspars; Laurent Trembleau; David P Fewer; Wael E Houssen

doi:10.1039/c7cc05913b

Cyclic peptide production using a macrocyclase with enhanced substrate promiscuity and relaxed recognition determinants

Chem Commun (Camb). 2017 Sep 26;53(77):10656-10659. doi: 10.1039/c7cc05913b.

Authors

Cristina N Alexandru-Crivac¹, Christian Umeobika², Niina Leikoski³, Jouni Jokela³, Kirstie A Rickaby², André M Grilo¹, Peter Sjö⁴, Alleyn T Plowright⁵, Mohannad Idress¹, Eike Siebs², Ada Nneoyi-Egbe², Matti Wahlsten³, Kaarina Sivonen³, Marcel Jaspars², Laurent Trembleau², David P Fewer³, Wael E Houssen⁶

Affiliations

¹ Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, UK. l.trembleau@abdn.ac.uk w.houssen@abdn.ac.uk and Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
² Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, UK. l.trembleau@abdn.ac.uk w.houssen@abdn.ac.uk.
³ Microbiology and Biotechnology Division, Department of Food and Environmental Sciences, University of Helsinki, P.O.Box 56, Biocenter 1, Viikinkaari 9, 00014, Finland. david.fewer@helsinki.fi.
⁴ Medicinal Chemistry, Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
⁵ Medicinal Chemistry, Cardiovascular and Metabolic Diseases Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
⁶ Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, UK. l.trembleau@abdn.ac.uk w.houssen@abdn.ac.uk and Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK and Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

PMID: 28905052
DOI: 10.1039/c7cc05913b

Abstract

Macrocyclic peptides have promising therapeutic potential but the scaling up of their chemical synthesis is challenging. The cyanobactin macrocyclase PatG_mac is an efficient tool for production but is limited to substrates containing 6-11 amino acids and at least one thiazoline or proline. Here we report a new cyanobactin macrocyclase that can cyclize longer peptide substrates and those not containing proline/thiazoline and thus allows exploring a wider chemical diversity.

MeSH terms

Bacterial Proteins
Cyclization
Gene Expression Regulation, Bacterial / physiology
Gene Expression Regulation, Enzymologic / physiology
Macrocyclic Compounds / chemical synthesis*
Molecular Dynamics Simulation
Oscillatoria / enzymology*
Oscillatoria / metabolism
Peptide Fragments
Peptides, Cyclic / chemical synthesis*
Substrate Specificity

Substances

Bacterial Proteins
Macrocyclic Compounds
Peptide Fragments
Peptides, Cyclic