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An unprecedented mechanism of nucleotide methylation in organisms containing thyX

Science  29 Jan 2016:
Vol. 351, Issue 6272, pp. 507-510
DOI: 10.1126/science.aad0300

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A special way to make T

The genomes of all cell-based life consist of DNA. Blocking DNA synthesis is thus lethal, and if targeted selectively, its inhibition can provide cancer and antibiotic treatments. For example, the drug methotrexate interferes with the synthesis of thymidine, the base T in DNA. Mishanina et al. found that the enzyme that carries out the last step of thymidine synthesis in several human pathogens, which cause tuberculosis, anthrax, and typhus, uses a previously undescribed mechanism. Knowing the mechanism may allow the development of specific inhibitors for this enzyme.

Science, this issue p. 507

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.

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