Document Detail


Insights into bacterial 6-methylsalicylic acid synthase and its engineering to orsellinic acid synthase for spirotetronate generation.
MedLine Citation:
PMID:  20534347     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The enzymes 6-methylsalicylic acid (6-MSA) synthases (6-MSASs) are involved in the building of an aryl moiety in many bioactive secondary metabolites produced by fungi and bacteria. Using the bacterial 6-MSAS ChlB1 in the biosynthesis of spirotetronate antibiotic chlorothricin (CHL) as a model, functional analysis of its dehydratase (DH) and ketoreductase (KR) domains by site-specific mutagenesis revealed that selective ketoreduction is not essential for polyketide chain extension. Promiscuity of the ketoacylsynthase domain in beta functionality recognition allows for engineering ChlB1 to an orsellinic acid (OSA) synthase (OSAS) by inactivating KR at the active site. The engineered ChlB1 is compatible with the enzymes for late-stage tailoring in CHL biosynthesis, featuring specific protein recognitions that facilitate variable aryl group incorporation. The resulting spirotetronates, which bear an OSA-derived aryl group, exhibited antibacterial activities comparable to those of the parent products.
Authors:
Wei Ding; Chun Lei; Qingli He; Qinglin Zhang; Yurong Bi; Wen Liu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemistry & biology     Volume:  17     ISSN:  1879-1301     ISO Abbreviation:  Chem. Biol.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-06-10     Completed Date:  2010-09-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9500160     Medline TA:  Chem Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  495-503     Citation Subset:  IM    
Copyright Information:
2010 Elsevier Ltd. All rights reserved.
Affiliation:
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
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MeSH Terms
Descriptor/Qualifier:
Acyltransferases / chemistry,  genetics,  metabolism*
Aminoglycosides / biosynthesis*,  chemistry
Anti-Bacterial Agents / biosynthesis*,  chemistry
Bacterial Proteins / chemistry,  genetics,  metabolism*
Ligases / chemistry,  genetics,  metabolism*
Multienzyme Complexes / chemistry,  genetics,  metabolism*
Oxidation-Reduction
Oxidoreductases / chemistry,  genetics,  metabolism*
Protein Engineering*
Protein Structure, Tertiary
Resorcinols / metabolism
Salicylic Acids / metabolism
Streptomyces / enzymology
Chemical
Reg. No./Substance:
0/Aminoglycosides; 0/Anti-Bacterial Agents; 0/Bacterial Proteins; 0/Multienzyme Complexes; 0/Resorcinols; 0/Salicylic Acids; 0/orsellinic acid; 34707-92-1/chlorothricin; 567-61-3/6-methylsalicylic acid; EC 1.-/Oxidoreductases; EC 2.3.-/Acyltransferases; EC 6.-/6-methylsalicylic acid synthetase; EC 6.-/Ligases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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