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Thymidyl biosynthesis enzymes as antibiotic targets
Anatoly Chernyshev1, Todd Fleischmann, Amnon Kohen
1Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA.
Applied Microbiology and Biotechnology
|January 12, 2007
Summary
Two newly discovered alternative enzymes for uridyl-5-methylation, flavin-dependent thymidylate synthase and folate-dependent ribothymidyl synthase, are crucial for pathogen survival. These enzymes represent promising new targets for antibiotic development.
Area of Science:
- Biochemistry
- Microbiology
- Drug Discovery
Background:
- Classical enzymes for uridyl-5-methylation include thymidylate synthase and ribothymidyl synthase.
- Two novel alternative enzymes, flavin-dependent thymidylate synthase and folate-dependent ribothymidyl synthase, have been identified.
- These alternative enzymes utilize distinct biochemical pathways compared to their classical counterparts.
Purpose of the Study:
- To characterize the newly discovered alternative uridyl-5-methylation enzymes.
- To investigate the role of these enzymes in human pathogens.
- To explore the potential of these enzymes as targets for novel antibiotic development.
Main Methods:
- Enzyme assays to determine catalytic activity and substrate specificity.
- Genetic analysis to identify and characterize the genes encoding the alternative enzymes.
- Comparative biochemical pathway analysis.
Main Results:
- The alternative enzymes, flavin-dependent thymidylate synthase and folate-dependent ribothymidyl synthase, were characterized.
- Both enzymes utilize flavin cofactors and methylenetetrahydrofolate for thymidylate synthesis.
- Several human pathogens rely on these alternative enzymes for replication.
- Distinct chemical pathways differentiate these enzymes from classical counterparts.
Conclusions:
- The alternative enzymes represent a distinct class of uridyl-5-methylation enzymes.
- Their essentiality for pathogen survival highlights their potential as antimicrobial targets.
- Targeting these alternative enzymes offers a promising strategy for developing new antibiotics against resistant pathogens.
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