scholarly journals Ketosynthase Domain Constrains the Design of Polyketide Synthases

2020 ◽  
Vol 15 (9) ◽  
pp. 2422-2432 ◽  
Author(s):  
Maja Klaus ◽  
Lynn Buyachuihan ◽  
Martin Grininger
Keyword(s):  
Polyketide Synthases ◽  
Ketosynthase Domain

scholarly journals The Ketosynthase Domain Constrains the Design of Polyketide Synthases

2020 ◽  
Author(s):  
Maja Klaus ◽  
Lynn Buyachuihan ◽  
Martin Grininger
Keyword(s):  
Substrate Specificity ◽  
Polyketide Synthases ◽  
Biologically Active ◽  
Success Rates ◽  
Turnover Rates ◽  
Ketosynthase Domain ◽  
Polyketide Chain ◽  
Multistep Reactions ◽  
Low Efficiency ◽  
Do So

AbstractModular polyketide synthases (PKSs) produce complex, bioactive secondary metabolites in assembly line-like multistep reactions. Longstanding efforts to produce novel, biologically active compounds by recombining intact modules to new modular PKSs have mostly resulted in poorly active chimeras and decreased product yields. Recent findings demonstrate that the low efficiencies of modular chimeric PKSs also result from rate limitations in the transfer of the growing polyketide chain across the non-cognate module:module interface and further processing of the non-native polyketide substrate by the ketosynthase (KS) domain. In this study, we aim at disclosing and understanding the low efficiency of chimeric modular PKSs and at establishing guidelines for modular PKSs engineering. To do so, we work with a bimodular PKS testbed and systematically vary substrate specificity, substrate identity, and domain:domain interfaces of the KS involved reactions. We observe that KS domains employed in our chimeric bimodular PKSs are bottlenecks with regards to both substrate specificity as well as interaction with the ACP. Overall, our systematic study can explain in quantitative terms why early oversimplified engineering strategies based on the plain shuffling of modules mostly failed and why more recent approaches show improved success rates. We moreover identify two mutations of the KS domain that significantly increased turnover rates in chimeric systems and interpret this finding in mechanistic detail.

Active-site residue, domain and module swaps in modular polyketide synthases

2003 ◽  
Vol 30 (8) ◽  
pp. 489-494 ◽  
Author(s):  
Francesca Del Vecchio ◽  
Hrvoje Petkovic ◽  
Steven G. Kendrew ◽  
Lindsey Low ◽  
Barrie Wilkinson ◽  
...  
Keyword(s):  
Active Site ◽  
Polyketide Synthases ◽  
Active Site Residue
Sign in / Sign up

Export Citation Format

Share Document