Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists discover new chemical reaction for DNA production in bacteria and viruses

20.04.2009
Findings could help lead to development of new antibacterial and antiviral drugs

A team of researchers has discovered a new chemical reaction for producing one of the four nucleotides, or building blocks, needed to build DNA. The reaction includes an unusual first step, or mechanism, and unlike other known reactions that produce the DNA building block, uses an enzyme that speeds up, or catalyzes, the reaction without bonding to any of the compounds, or substrates, in the reaction.

The chemical reaction discovered by the researchers uses an enzyme called flavin-dependent thymidylate synthase, or FDTS. The enzyme is coded by the thyX gene and has been found primarily in bacteria and viruses, including several human pathogens and biological warfare agents. In the future, scientists may use this knowledge for the development of new antibacterial and antiviral drugs.

Supported with partial funding from the National Science Foundation (NSF) and led by Amnon Kohen, an associate professor in the departments of chemistry and molecular and cellular biology at the University of Iowa, the team reports their findings in the April 16, 2009, issue of Nature, Letters section.

Prior to the team's discovery, it was thought that thymidylate synthase, or TS, was the primary enzyme catalyzing a reaction that produced one of the four DNA building blocks called deoxy-thymidine monophosphate.

The TS enzyme is coded by the thyA and TYMS genes and is present in most multi-cellular forms of life, including humans.

Both the new and classical enzymatic reactions complete a key step in producing the DNA building block by adding a methyl group--one carbon atom attached to three hydrogen atoms--to the building block's precursor molecule called deoxy-uridine monophosphate, or dUMP.

Even though both reactions accomplish this key step, the reaction mechanisms, or steps, catalyzed by the FDTS and TS enzymes are structurally different.

Kohen and his team identified these differences using a traditional chemical method labeled isotopic substitution and a contemporary form of mass spectrometry using electron spray ionization. In particular, the team identified that the first step of the FTDS-catalyzed reaction involves the transfer of a proton and two electrons, known as a hydride, from a flavin co-factor molecule to dUMP whereas the first step of the TS-catalyzed reaction involves an amino acid from the enzyme's active site forming a bond with dUMP.

"This work nicely illustrates how chemists using traditional techniques and contemporary instrumentation methods can make substantial contributions to important and interesting problems in biology," said Charles Pibel, a program director in NSF's Division of Chemistry.

Since the two chemical reaction mechanisms used for the production of the DNA building block, and therefore DNA, are structurally different in humans and bacteria and viruses, and the enzymes used to catalyze the chemical reactions are different, the researchers' findings may assist with the development of structure-based antibiotics and antiviral drugs that selectively inhibit the activity of FDTS enzymes with little effect on TS enzymes--thereby combating pathogens causing anthrax, tuberculosis, botulism, syphilis, pneumonia, Lyme disease and other human diseases without interfering with human DNA synthesis.

"The proposed new catalytic path of the FDTS enzyme appears to be so very different from that of the classical TS enzyme that we hope that specific inhibitors against it will have little effect on DNA production in humans and thus may lead to development of new drugs with low toxicity. Also, some aspects of the proposed chemistry are not common in enzymology or biological chemistry in general, making the future testing of this mechanism very interesting and of potential broader impact," said Kohen.

Co-authors of the Nature Letter include: Eric M. Koehn and Todd Fleischmann, University of Iowa; John A. Conrad and Bruce A. Palfey, University of Michigan Medical School; Scott A. Lesley, The Joint Center for Structural Genomics at the Genomics Institute of Novartis Research Foundation; and Irimpan I. Mathews, Stanford Synchrotron Radiation Laboratory.

The research was supported by NSF's Divisions of Chemistry and Molecular and Cellular Biosciences award number 0715448 and National Institutes of Health (NIH) award number R01 GM065368 to Amnon Kohen; the Iowa Center for Biocatalysis and Bioprocessing to Eric M. Koehn; NIH award number R01 GM61087 to Bruce A. Palfey; NIH training grant GM08270 to John A. Conrad; and The Joint Center for Structural Genomics grant U54GM074898 to Scott A. Lesley.

Portions of the research, including using an x-ray source to help reveal enzyme structure and function, were carried out at the Stanford Synchrotron Radiation Laboratory (SSRL), a national user facility operated by Stanford University on behalf of the Department of Energy, OBER. The SSRL Structural Molecular Biology Program is supported by DOE, OBER and by NIH, NCRR, Biomedical Technology Program and National Institute of General Medical Sciences.

Jennifer A. Grasswick | EurekAlert!
Further information:
http://www.nsf.gov

More articles from Life Sciences:

nachricht Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>