Journal article
An unprecedented mechanism of nucleotide methylation in organisms containing thyX
Science (American Association for the Advancement of Science), Vol.351(6272), pp.507-510
01/29/2016
DOI: 10.1126/science.aad0300
PMCID: PMC4744818
PMID: 26823429
Abstract
In several human pathogens, thyX-encoded flavin-dependent thymidylate synthase (FDTS) catalyzes the last step in the biosynthesis of thymidylate, one of the four DNA nucleotides. ThyX is absent in humans, rendering FDTS an attractive antibiotic target; however, the lack of mechanistic understanding prohibits mechanism-based drug design. Here, we report trapping and characterization of two consecutive intermediates, which together with previous crystal structures indicate that the enzyme's reduced flavin relays a methylene from the folate carrier to the nucleotide acceptor. Furthermore, these results corroborate an unprecedented activation of the nucleotide that involves no covalent modification but only electrostatic polarization by the enzyme's active site. These findings indicate a mechanism that is very different from thymidylate biosynthesis in humans, underscoring the promise of FDTS as an antibiotic target.
Details
- Title: Subtitle
- An unprecedented mechanism of nucleotide methylation in organisms containing thyX
- Creators
- Tatiana V. Mishanina - University of IowaLiping Yu - University of IowaKalani Karunaratne - University of IowaDibyendu Mondal - University of IowaJohn M. Corcoran - University of IowaMichael A. Choi - University of IowaAmnon Kohen - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Science (American Association for the Advancement of Science), Vol.351(6272), pp.507-510
- DOI
- 10.1126/science.aad0300
- PMID
- 26823429
- PMCID
- PMC4744818
- NLM abbreviation
- Science
- ISSN
- 0036-8075
- eISSN
- 1095-9203
- Publisher
- Amer Assoc Advancement Science
- Number of pages
- 4
- Grant note
- R01GM110775 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01 GM110775 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32 GM008365 / Iowa Center of Biocatalysis and Bioprocessing (NIH)
- Language
- English
- Date published
- 01/29/2016
- Academic Unit
- Biochemistry and Molecular Biology; Chemistry; Medicine Administration
- Record Identifier
- 9984627252502771
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