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 What happens in the cell nucleus after fertilization
06.12.2016 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Simple processing technique could cut cost of organic PV and wearable electronics

06.12.2016 | Materials Sciences

3-D printed kidney phantoms aid nuclear medicine dosing calibration

06.12.2016 | Medical Engineering

Robot on demand: Mobile machining of aircraft components with high precision

06.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>