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Nucleotide metabolism - enzymes, pathways and drug discovery

Research project We study the regulation of nucleotide levels in mammalian cells and in pathogens such as Trypanosoma brucei. This parasite causes African sleeping sickness.

Nucleotides have central roles in cellular metabolism by being energy donors and as building blocks in DNA and RNA. It is very important that the cellular amount of nucleotides is regulated and there are many genetic diseases described caused by disbalanced nucleotide levels. We are studying the regulation of some of the enzymes involved in the nucleotide metabolism with a main focus on ribonucleotide reductase and nucleoside kinases. Trypanosoma brucei causes African sleeping sickness, a fatal disease to which there is no good treatment. Current medicines are limited by efficacy and severe toxicity. We try to exploit differences in nucleotide metabolism between the trypanosomes and mammalian cells in order to selectively kill the parasites with minimized side effects.

Head of project

Anders Hofer
Associate professor
E-mail
Email

Project overview

Project period:

2016-07-21 2020-01-01

Funding

SIDA, 2010-2012: SEK 1,800,000
The Swedish Research Council, 2010-2015: SEK 3,600,000
Carl Tryggers stiftelse, 2013: SEK 222,000
Carl Tryggers stiftelse, 2016: SEK 377,000

Participating departments and units at Umeå University

Department of Medical Biochemistry and Biophysics, Faculty of Medicine

Project description

We are studying the regulation of nucleotide metabolism to understand basal cellular processes and to design drugs that exploit specific properties of enzymes/pathways related to nucleotide metabolism in malignant cells and pathogens. We have a particularly strong interest in the pathogen Trypanosoma brucei, which causes African sleeping sickness.

Enzyme regulation/oligomerization - Nucleotides are used as energy donors, cellular regulators and building blocks for DNA and RNA. It is important to have balanced cellular supplies of nucleotides to avoid metabolic diseases and minimize the mutation rate. We investigate the regulatory mechanisms of these enzymes. One of the techniques used is Gas-Phase Electrophoretic Mobility Macromolecule Analysis (GEMMA).

Drug discovery - Substrate analogs of nucleotide metabolizing enzymes can be used against diseases such as cancer and infectious diseases. We are studying the nucleotide metabolism of the parasite Trypanosoma brucei, which causes African sleeping sickness in humans and Nagana in domestic animals. The different properties of T. brucei nucleotide metabolism in comparison to that of the host can be exploited to find drugs that specifically target the parasite.

The following research projects are currently running in our lab:

• Mammalian ribonucleotide reductase is composed of R1 (alpha) and R2 (beta) subunits and is regulated by two allosteric sites located on the R1 subunit. One of these sites, the overall activity site, binds ATP or dATP. We have previously seen that dATP (enzyme inhibitor) and ATP (activator) induce the formation of an alpha-6-beta-2 protein complex in mammalian cells. The type of complex varies between species and we are now trying to delineate the molecular mechanism behind the opposite effect of these two nucleotides on enzyme activity in mammalian cells and other species.

• T. brucei is able to accumulate unusually high levels of dATP when it is cultivated in the presence of deoxyadenosine. This strong salvage capacity can be utilized to activate nucleoside analogs that can be used as drugs against T. brucei. We are characterizing enzymes involved in the metabolism of deoxyadenosine and other nucleosides in T. brucei.