Биологические науки/ 9. Биохимия и биофизика

MD Rasulov M.M., DCh Storozhenko P.A., student Susova M.I.,

BioD Snisarenko T.A., post-graduate Rasulov R.M.,

State Research Institute for Chemistry and Technology of Organoelement

Compounds, Moscow

AMINOACYL TRNA SYNTHETASES PARTICIPATION

IN PHYSIOLOGICAL PROCESSES CONTROL

Aminoacyl tRNA synthetases (aaRS) are enzymes of nonribosomal stage of protein synthesis. They perform one of the central functions in the cell ensuring genetic code embodiment accuracy by means of specific amino acid addition to homological tRNA. It means that even on the early stages of cellular forms of life aaRSes were one of the first enzymes that “filled in” the necessary link in the process of genetic information embodiment. As an example: tyrosyl- tRNA - synthetas - TyrRS, tryptophanyl - tRNA - synthetas – TrpRS, Seryl-tRNA synthetase (SerRS). Demand for precise control over metabolic reactions simultaneously occurring in a cell promoted multienzyme complexes development. In its turn, aminoacylation efficiency resulted from targeted transport of amino acids and regulator factors pool set up.

The pathologies which are associated with aaRSes include: Charcot-Marie-Tooth neuropathy; erroneous acylation and tentorium dysfunction; leukoencephalopathy which includes brainstem lesion and spinal injury, higher lactate (LBSL) level, Parkinson's disease, oncological diseases (disorder in synthesis of a specific set of proteins and enzymes of a protein-synthesizing apparatus, abnormal activation of Methionyl-tRNA synthetase, conjugation with other proteins of cysteinyl-tRNA synthetase, mutations in the promoter region and overexpression of isoleucyl-tRNA synthetase, overexpression of alpha - subunit of phenylalanyl-tRNA synthetase, overexpression of glycyl - and lysyl- tRNA synthetase at various cancer kinds) and finally, autoimmune diseases and diabetes. Considered series of studies led us to the initial problems of catalytic center structure, as such, as well as support structures of protein macromolecules defined as “pockets” and structural determinants for ligand binding – amino acids, ATP and tRNA. Furthermore, a great variety of proteins and enzymes in the process of evolution was provided by mean of so called “alternative splicing” representing all-pervading principle of molecular protein diversity without sharp increase of genetic material (for example, TrpRS) for eukaryotes and other higher organisms. We have determined TrpRS responsibility in cellular metabolism of higher organisms. TrpRS secretion, alternative splicing, TrpRS mRNA synthesis promotion under the effect of gamma-interferon were found, as well as the presence of non-angiogenic (which means antioncogene and antiatherogenic) activity TrpRS clipped form. We believe that these kinds of activity depend on zinc cation as part of TrpRS and its participation along with other enzyme systems in synthesis of dinucleotide polyphosphates (ApnA), Ар3А in particular. We were the first to discover zinc ions in TrpRS. It is common knowledge that zinc is an enzyme activator, but stoichiometric relationship and lability of zinc bond with the enzyme remained unclear. This situation gave us a reason to carry out experiments with zinc removal from the enzyme. The enzyme activity was found to reduce which confirms the hypothesis.

We also found additional TrpRS activity, in particular its ability to Ар3А synthesis. Data concerning the importance of Ap3A and Ap4A relationship in a cell are of special interest. Ap3A excess on Ap4A leads to cell proliferation and differentiation but when the ratio is reverse a cell is subject to an adjustable death in the process of apoptosis. Moreover aaRS is evidently synthesized as an apoenzyme, and its activity is determined by zinc availability in the cell.

Possibility of some metals hypervalent compounds synthesis underlay the development of bioactive silicon compounds. This discovery of M.G. Voronkov allowed to create a new branch of silicon chemistry – bioorganosilicon chemistry. It was found that silatranes promote enzymes and nucleic acids synthesis, intensify proliferative and reparative function of connective tissue, accelerate the healing of wounds and burns, have anti-stress and adaptogenic effect [1, 2].

In recent years hypervalent zinc compounds - zincatranes - RZn(CH₂CH₂)n have been synthesized, their biological activity is being studied [3]. Zincatrane was found to have antidotal action at ethanol intoxication, at the same time it promotes triptophanyl synthetase activity [4]. This allows us to declare a new trend in pharmacology - "Molecular Pharmacology of organometallic compounds".

References

1. Rasulov M.M., Voronkov M.G. Organoelement compounds for medications: yesterday, today and tomorrow // Vestnik RAEN, 2008, v.8., No 1, p.82-86.

2. Rasulov M.M., Nurbekov M.K., Susova M.I. Aminoacyl tRNA synthetases participation in physiological processes monitoring in health and disease // In: Phytotherapy and Folk Medicine of Avicenna Period. Dushanbe, 2010, p.314-316

3. Voronkov M.G., Adamovich S.N., Mirskov R.G., Mirskova A.N. Synthesis of new bioactive О-hydrometalloatranes // Zhurnal Obshchei Khimii, 2009, v.79, №1, p.162-163.

4. Voronkov M. G., Nurbekov M. K. Rasulov M.M., Zvereva M. V., Mirskova A. N., R. G. Mirskov Adamovich S. N. The Complex of Zinc bis-(2- Methylphenoxyacetate) with Tris -2 (hydroxyl-ethyl) Amine as an Activator of Synthesis of Total Tryptophanyl -tRNA Synthetase. // Doklady Biochemistry and Biophysics, 2012, Vol. 444, pp. 147–148.