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When the oxygen kills

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An international team of scientists including the Lomonosov Moscow State University researcher showed under which conditions a body produces more superoxide — a dangerous form of oxygen, able to destruct DNA. The article was published in Free Radical Biology and Medicine.

Human mutations in a gene encoding the DHTKD1 protein result in a range of neurological disturbances. On a molecular level the mutations cause accumulation of the reactive oxygen species (ROS) and degradation products of lysine and tryptophan. The structure of the DHTKD1 protein is similar to an enzyme, 2-oxoglutarate dehydrogenase, which is able to produce superoxide — a dangerous form of oxygen, able to destruct cellular components including DNA. An international scientific team including Victoria Bunik, the leading researcher of the A.N. Belozersky Research Institute of Physico-Chemical Biology, the Lomonosov Moscow State University, associate professor of the Faculty of Bioengineering and Bioinformatics, PhD in chemistry, showed under what conditions production of the superoxide increases because of the DHTKD1 protein. According to the researcher, further study of DHTKD1 will allow to elaborate methods for curing mutations in a gene, encoding this protein.

A cellular Nuclear Power plant

Mitochondria are often compared to an NPP inside a cell. Its fuel are fatty acids and pyruvate, that finally produce ATP — 'a battery substance', an all-purpose source of energy for all in-cell processes. Just as our nuclear power plants, a mitochondrion is complex in operation, interacts with dangerous substances and produces wastes — free radicals (chemical compounds, containing one or several unpaired electron in the outer shell, which makes them negatively charged and highly active. Here belongs the superoxide — a toxic type of oxygen, which may harm cellular components including DNA, thus impairing cellular homeostasis, i.e. a coordinated ensemble of the life-supporting chemical reactions. A cell combats the 'poisonous' forms of oxygen with a help of antioxidants (substances preventing oxidation), and antioxidant defense system proteins (for example, superoxide dismutase).

The adipate twins

Disturbed metabolism of amino acids may reduce synthesis of enzymes (proteins, catalysing particular chemical reactions in a body). So, a shortage of amino acids (the bricks for building proteins) lysine and tryptophan may cause physical, neurologic and mental malfunctions, and even lead to death. Those amino acids belong to irreplaceable and can not be produced from other substances in human body, so they should come from food.

2-aminoadipate and 2-oxoadipate are the degradation products of lysine, tryptophan and hydroxylysine.

Recently, scientists found the connection between aciduria (increased acidity of urine, showing serious malfunction in metabolism) in patients with increased content of 2-aminoadipate and 2-oxoadipate and gene mutations in the DHTKD1 protein. That confirms an earlier hypothesis of the MSU researchers (Bunik & Degtyarev, 2008) that an enzyme, encoded by DHTKD1, oxidizes 2-oxoadipate.

The DHTKD1 protein does not belong to central metabolism, produced in higher quantities in liver and kidney cells, where lysine and tryptophan are more actively degraded, and in human organisms also — in skeletal muscles. Both the down- and up-regulation of the DHTKD1 expression increased the level of reactive, dangerous forms of oxygen.

A way decades long

the Lomonosov Moscow State University scientist, Doctor of chemical sciences Victoria Bunik was invited to participate in the research as an international expert in the multienzyme complexes of 2-oxo acid dehydrogenases (which also include the above mentioned 2-oxoglutarate dehydrogenase, similar to the DHTKD1 protein) and their side-reactions of ROS formation. In 2003 Victoria Bunik published a review of her own studies on the mechanism of such side-reactions, and in 2008 — a work predicting the DHTKD1-dependent expression of the 2-oxoadipate dehydrogenase previously unknown in mammals.

The current publication on DHTKD1 enzyme together with the US colleagues from the Buck Institute for Research on Aging, California, was dedicated to experimental research on a generation of active oxygen forms, catalyzed by the 2-oxoadipate dehydrogenase complex.

In this research, biochemical methods were used to register the amount of hydrogen peroxide produced by mitochondria. A specific fluorescent compound was created for that purpose. It was spotted that the production of the superoxide increases under high concentrations of 2-oxoadipate, and also detected, that it is exactly the 2-oxoadipate oxidization what causes the formation of the superoxide.

'Apart from characterization of a new potential source generating ROS, the scientific significance of the study extends to a demonstration of a high level of understanding of living systems, attained in fundamental research. The level allowed us not only to decipher the genome-coded information in terms of the DHTKD1 function, but also to predict the behavior of a biological system (i.e. mitochondria) under variety of conditions' comments Victoria Bunik.

'Our current work on characterizing this new mammalian complex in the Lomonosov Moscow State University includes the cooperation with Medico-genetic scientific centre in Moscow, where a new human mutation of DHTKD1 was identified. The research promotes developing therapies to cure such patients' the scientist concludes.

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Vladimir Koryagin
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http://www.msu.ru

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