Where do radicals come from?
Scientists have found out in what conditions the amount of oxygen dangerous for DNA increases in the body
MSU Press Service
An international group of scientists with the participation of a researcher from Lomonosov Moscow State University showed under what conditions the body releases more superoxide, a dangerous form of oxygen capable of destroying DNA.
Article by Goncalves et al. Production of superoxide/hydrogen peroxide by the mitochondrial 2-oxoadipate dehydrogenase complex was published in the journal Free Radical Biology and Medicine.
In humans, mutations in the gene encoding the DHTKD1 protein accompany many neurological diseases, and at the molecular level, the accumulation of degradation products of the amino acids lysine and tryptophan and free radicals. The structure of the DHTKD1 protein is similar to that of the enzyme 2-oxoglutarate dehydrogenase, which can produce superoxide, a dangerous form of oxygen capable of destroying DNA.
An international group of scientists with the participation of a leading researcher of the A.N. Belozersky Research Institute of the Lomonosov Moscow State University, associate professor of the Faculty of Bioengineering and Bioinformatics of the Lomonosov Moscow State University, Doctor of Chemical Sciences Victoria Bunik showed under what conditions the production of superoxide increases due to the DHTKD1 protein. According to the researcher, further study of the DHTKD1 protein will allow the development of methods for treating patients with mutations of the gene encoding this protein.
Cellular Nuclear Power Plant
Mitochondria are often compared to power plants inside a cell. Their fuel is fatty acids and pyruvate (pyruvic acid residue), thanks to which ATP is obtained at the output – a "battery substance", a universal source of energy for all intracellular processes. Like our nuclear power plants, the mitochondria is difficult to operate, interacts with substances dangerous to the body and forms waste – free radicals (chemical compounds containing an electron or several electrons without a pair on the outer shell, and therefore have a negative charge and are very active). These include superoxide, a toxic form of oxygen, which, when accumulated in large quantities, can damage DNA, causing mutations, and disrupt the coordinated work of an ensemble of other chemical reactions, "breaking the conductor's sticks" of the enzymes controlling them. The cell fights "poisonous" forms of oxygen with the help of antioxidants (substances that prevent oxidation) and proteins of the antioxidant defense system (for example, superoxide dismutase).
Two Adipate brothers
Lack of amino acids can reduce the synthesis of enzymes (proteins that accelerate specific chemical reactions in the body). Thus, the lack of amino acids (building blocks for building proteins) lysine and tryptophan can cause physical, neurological and mental disorders and even lead to death. These amino acids are irreplaceable and cannot be synthesized in the human body from other substances, therefore they must come with food.
2-aminoadipate and 2-oxoadipate are substances formed during the cleavage of lysine, tryptophan and hydroxylysine (more precisely, their L–forms, twisted to the left - in this form, almost all amino acids that make up proteins exist).
Recently, scientists have found a link between aciduria (increased acidity of urine indicating severe metabolic disorders) in patients with elevated levels of 2-aminoadipate and 2-oxoadipate in urine with mutations in the DHTKD1 protein. This confirms the hypothesis previously substantiated by researchers from MSU (Bunik & Degtyarev, 2008) that the protein-enzyme encoded in DHTKD1 oxidizes 2-oxoadipate. In some patients, high levels of 2-aminoadipate and 2-oxoadipate are difficult to diagnose, and the disorders proceed without symptoms. Therefore, it is not possible to associate specific mutations with diseases.
The DHTKD1 protein is produced in large quantities in liver and kidney cells, where lysine and tryptophan are actively cleaved, and in humans – in skeletal muscles. Both suppression and enhancement of the activity of the gene responsible for the production of this protein increases the level of reactive, dangerous forms of oxygen.
The path is decades long
A scientist from Moscow State University, Doctor of Chemical Sciences Victoria Bunik was involved in this work as a well-known international expert on poly-enzyme complexes of 2-oxoacid dehydrogenases (which include the already mentioned 2-oxoglutarate dehydrogenase, which is similar to the DHTKD1 protein) and the side reactions of generation of reactive oxygen species catalyzed by them. In 2003, Victoria Bunik published a review of her own work on the mechanism of such adverse reactions, and in 2008 – a work predicting the existence in mammals of one of these complexes, not previously known.
The experimental study of the generation of reactive oxygen species catalyzed by this new complex was devoted to the work published together with American colleagues from the Institute for Aging Research of the Lhc (California, USA).
In the course of the work, biochemical methods were used to study mitochondria, a method for recording the production of hydrogen peroxide by mitochondria by creating a fluorescent (luminous) compound. It was found that the production of superoxide increases at high concentrations of 2-oxoadipate, and it was also found that superoxide is formed precisely during the oxidation of 2-oxoadipate.
"In addition to solving specific tasks to characterize the sources of generation of harmful by-products of vital activity, the scientific value of the work consists in demonstrating the existing level of understanding of living systems achieved in fundamental research. In this case, such a level allowed not only to interpret the information contained in the genome from the point of view of biochemical functions, but also to correctly predict the behavior of the biochemical system (mitochondria) under certain experimental conditions," comments Victoria Bunik on the results of the work.
"Currently, work on the characterization of this new complex at MSU continues in connection with the mutations found in humans. In particular, together with the Medical and Genetic Research Center in Moscow, we are investigating the function of this protein in mutations of its gene in order to develop currently unknown methods of treating such patients," the scientist concludes.
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05.04.2016