Stanford Synchrotron Radiation Lightsource
Date Published: April 30, 2009

Novel Mechanism for DNA Biosynthesis in Organisms with Gene thyX could Lead to Better Antibiotics
summary written by Raven Hanna

Before DNA is made, the subunits composing DNA must be made. The essential process of making one of these subunits, thymidine monophosphate (TMP), was thought to be similar for most living things, but scientists recently discovered that some bacteria and viruses use a different type of enzyme to perform this reaction. The discovery might result in new antibiotics that would be effective against human pathogens, but not affect human cells.

The research group led by Prof. Amnon Kohen of the University of Iowa analyzed the reactions of the enzyme called flavin-dependent thymidylate synthase (FDTS), used by some pathogenic bacteria, to turn dexoyuridine monophosphate (dUMP) into TMP. The mechanism they propose is not only different than the mechanism used by thymidylate synthase in eukaryotes including humans, it also has novel properties that had not previously been seen in biological systems.

The proposed mechanism is based on chemical and structural analysis of the FDTS enzyme. Kohen's group performed crucial chemical analysis of the enzyme and reaction, including labeled isotopic substitution and a form of mass spectrometry. To determine the molecular structure, Kohen's group provided purified material to Irimpan Mathews of SSRL, who crystallized and solved the structures of selected mutant FDTS enzymes. Structural data provided a detailed description of the active site of the enzyme. They collected x-ray diffraction data at SSRL's Beam Line 9-2.

Drugs designed to target the FDTS enzyme could provide treatments for various diseases including anthrax, tuberculosis, botulism, syphilis, pneumonia, and Lyme disease. Multiple drug resistant bacteria are likely to be susceptible to such agents, since the antibiotics currently in use do not target FDTS. This work was published in the April 16 issue of Nature.

To learn more about this research see the full Scientific Highlight

Eric M. Koehn, Todd Fleischmann, John A. Conrad, Bruce A. Palfey, Scott A. Lesley, Irimpan I. Mathews, and Amnon Kohen, "A Novel Chemical Mechanism of Thymidylate Biosynthesis in Human Pathogens Containing the thyX Gene" Nature 458, 919 (2009).

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