Vol 1, No 3 (2009)


Letter from the Editor

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Acta Naturae. 2009;1(3):1-1
pages 1-1 views

The Pharmaceutical Industry in Russia: Reality and Prospects

Gordeev A.I.


This section “Forum” is about the pharmaceutical industry in Russia. We were encouraged to debate this topic after the unveiling of the Strategy of Development of the Pharmaceutical Industry in the Russian Federation developed by the Ministry of Industry and Trade of the Russian Federation. The majority of our experts, who are authorities in the federal government, business, academia, and industrial science, believe that Russia needs a fully developed pharmaceutical industry. What are the main arguments for an intensive development of a Russian pharmaceutical industry- In our opinion, there are four major reasons.
Acta Naturae. 2009;1(3):6-9
pages 6-9 views

Biopharma: How Can the “Valley of Death” between R&D and Innovation Be Overcome?

Konov A.L., Leonov A.A.


“Today Russian biopharma has two obvious main problems,” believes Alexey Konov, investment director, and Andrey Leonov, investment manager, at Bioprocess Capital Partners Ltd. Russian satirical poet Igor Guberman’s line about a “crowd of researchers staring at life’s enigma” was written more than 25 years ago. If we consider the sad end to that quatrain (about “life that sends all of those researchers far, far away”) as an illustration of the process of putting new knowledge to practice, we must admit that the current situation is even worse. In fact, until the collapse of the USSR (in the end of the 1980s), the pharmaceutical and biopharmaceutical industries provided most of the drugs the nation required. Biopharmacy in the USSR functioned the way modern corporations do. Each branch had specialized Research Institutes in which production-orientated R-D was conducted. There were also communal usage centers that worked on certain scientific tasks of the Soviet biopharmaceuticals industry. Centralized R-D and innovations made the Soviet Union one of the world’s leaders in certain fields.
Acta Naturae. 2009;1(3):10-15
pages 10-15 views

Recipe for Russian Insulin

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The share of locally produced insulin on the Russian market estimated at more than seven billion roubles in 2008 is, in reality, microscopic: national industry covers only 2 % of the market (see Table 1). This is unreasonably small, especially because а) Russian producers have enough capacity to produce insulin for the entire country, with similar or even higher quality as compared with foreign products, b) hundreds of thousands of insulindependent patients in some particular political or economical circumstances could suffer without this life-saving treatment. The World Health Organization recommends that any country with a population of more than 50 millions have its own manufacturing base for insulin. Anatoly Miroshnikov is an assistant director of the M.M. Shemiakin and Y.A. Ovchinnikov’ Institute of Bioorganic Chemistry of the RAS, which produces insulin with the trade name Insuran. He talks to Acta Naturae on why Russia needs its own factories for the production of genetically engineered drugs.
Acta Naturae. 2009;1(3):16-19
pages 16-19 views

Phage Display on the Base of Filamentous Bacteriophages: Application for Recombinant Antibodies Selection

Tikunova N.V., Morozova V.V.


The display of peptides and proteins on the surface of filamentous bacteriophage is a powerful methodology for selection of peptides and protein domains, including antibodies. An advantage of this methodology is the direct physical link between the phenotype and the genotype, as an analyzed polypeptide and its encoding DNA fragment exist in one phage particle. Development of phage display antibody libraries provides repertoires of phage particles exposing antibody fragments of great diversity. The biopanning procedure facilitates selection of antibodies with high affinity and specificity for almost any target. This review is an introduction to phage display methodology. It presents recombinant antibodies display in more details:, construction of phage libraries of antibody fragments and different strategies for the biopanning procedure.
Acta Naturae. 2009;1(3):20-28
pages 20-28 views

Chemical and Functional Aspects of Posttranslational Modification of Proteins

Knorre D.G., Kudryashova N.V., Godovikova T.S.


This paper reviews the chemical and functional aspects of the posttranslational modifications of proteins, which are achieved by the addition of various groups to the side chain of the amino acid residue backbone of proteins. It describes the main prosthetic groups and the interaction of these groups and the apoenzyme in the process of catalysis, using pyridoxal catalysis as an example. Much attention is paid to the role of posttranslational modification of proteins in the regulation of biochemical processes in live organisms, and especially to the role of protein kinases and their respective phosphotases. Methylation and acetylation reactions and their role in the “histone code,” which regulates genome expression on the transcription level, are also reviewed. This paper also describes the modification of proteins by large hydrophobic residues and their role in the function of membrane-associated proteins. Much attention is paid to the glycosylation of proteins, which leads to the formation of glycoproteins. We also describe the main non-enzymatic protein modifications such as glycation, homocysteination, and desamidation of amide residues in dibasic acids.
Acta Naturae. 2009;1(3):29-51
pages 29-51 views

Genetic View on the Phenomenon of Combined Diseases in Man

Puzyrev V.P., Freidin M.B.


In clinical medicine, the phenomenon of polypathy, as a particular object of investigation, was first put forth by French clinicians at the end of the 19th century through the “arthritismus” doctrine. In the first half of the 20th century, German paediatricians singled out “syntropias,” which are combinations of diseases with common pathophysiological mechanisms, and “dystropias,” which are diseases that rarely co-occur in one individual. In the present paper, syntropy/dystropy is defined as a natural generic nonrandom phenomenon with an evolutionary-genetic basis. The genes involved in the development of syntropy are called “syntropic genes,” whereas the genes that co-participate in pathophysiological mechanisms and prevent the co-occurrence of particular phenotypes are called “dystropic genes.” Prospects for studying the genetic basis of this phenomenon are highlighted. The publicly available database Hu-EN et can be used in order to identify syntropic genes, as will be shown as examples in an analysis of cardiovascular diseases.
Acta Naturae. 2009;1(3):52-57
pages 52-57 views

Achievements and Peculiarities in Studies of Ancient DNA and DNA from Complicated Forensic Specimens

Grigorenko A.P., Borinskaya S.A., Yankovsky N.K., Rogaev E.I.


Studies of ancient DNA specimens started 25 years ago. At that time short mitochondrial DNA (mtDNA) fragments were the main targets in ancient DNA studies. The last three years were especially productive in the development of new methods of DNA purification and analysis. Complete mtDNA molecules and relatively large fragments of nuclear DNA are the targets of ancient DNA studies today. Ancient DNA studies allowed us to study organisms that went extinct more than ten thousand years ago, to reconstruct their phenotypic traits and evolution. Ancient DNA analyses can help understand the development of ancient human populations and how they migrated. A new evolutionary hypothesis and reconstruction of the biota history have been re-created from recent ancient DNA data. Some peculiarities and problems specific to the study of ancient DNA were revealed, such as very limited amounts of DNA available for study, the short length of the DNA fragments, breaks and chemical modifications in DNA molecules that result in “postmortem” mutations or complete blockage of DNA replication in vitro. The same specific features of DNA analysis were revealed for specimens from complicated forensic cases that result in the lack of experimental data or interpretation problems.. Here, we list the specific features of ancient DNA methodology and describe some achievements in fundamental and applied research of ancient DNA, including our own work in the field.
Acta Naturae. 2009;1(3):58-69
pages 58-69 views

Genome Paths A Way to Personalized and Predictive Medicine

Baranov V.S.


The review is devoted to the impact of human genome research on progress in modern medicine. Basic achievements in genome research have resulted in the deciphering of the human genome and creation of a molecular landmarks map of the human haploid genome (HapMap Project), which has made a tremendous contribution to our understanding of common genetic and multifactorial (complex) disorders. Current genome studies mainly focus on genetic testing and gene association studies of multifactorial (complex) diseases, with the purpose of their efficient diagnostics and prevention . Identification of candidate (“predisposition”) genes participating in the functional genetic modules underlying each common disorder and the use of this genetic background to elaborate sophisticated measures to efficiently prevent them constitutes a major goal in personalized molecular medicine. The concept of a genetic pass as an individual DNA databank reflecting inherited human predisposition to different complex and monogenic disorders, with special emphasis on its present state, and the numerous difficulties related to the practical implementation of personalized medicine are outlined. The problems related to the uncertainness of the results of genetic testing could be overcome at least partly by means of new technological achievements in genome research methods, such as genome-wide association studies (GWAS), massive parallel DNA sequencing, and genetic and epigenetic profiling. The basic tasks of genomic today could be determined as the need to properly estimate the clinical value of genetic testing and its applicability in clinical practice. Feasible ways towards the gradual implementation of personal genetic data, in line with routine laboratory tests, for the benefit of clinical practice are discussed.
Acta Naturae. 2009;1(3):70-80
pages 70-80 views

D-Arabinose Methabolism: Characterization of Bifunctional Arabinokinase/ Pyrophosphorylase of Leishmania major

Novozhilova N.M., Bovin N.V.


In this work we describe an unusual enzyme from Leishmania major (Arabinokinase/Pyrophosphorylase) that catalyzes the synthesis of GDP-Darabinopyranose (GDP-D-Ara p) via a D-arabinose-1-phosphate intermediate in the presence of ATP and GTP. Our data indicate GDP-D-Ara p transport in vivo by the LPG2 multispecific nucleotide sugar transporter into the Leishmania Golgi apparatus, in which it can be used by glycosyltransferases as a donor substrate for glycosylation.
Acta Naturae. 2009;1(3):81-83
pages 81-83 views

Protein Tyrosine Kinase Panel As a Tool for Anticancer Drug Design

Rakitina T.V., Yudkina O.V., Smirnova E.V., Lipkin A.V.


The discovery of the pharmaceutical potential of small molecule inhibitors of oncogenic protein tyrosine kinases is one of the directions in target therapy in oncology. Presently, investigations aiming at developing new therapeutically important inhibitors have to be based on a combination of computational and experimental approaches including biochemical, cell-based or in silico screening and the study of the three-dimensional structure of the kinase active center, in complex with an inhibitor, using crystallography and X-ray analysis or molecular modeling. This work is an example of a combination of inhibitor experimental search with the computational analysis of the potential mechanism of the inhibitors’ action, which allowed to propose the 2-hydroxyphenol group as a scaffold for the design of new tyrosine kinase inhibitors.
Acta Naturae. 2009;1(3):84-88
pages 84-88 views

Atomic Resolution Crystal Structure of NAD +Dependent Formate Dehydrogenase from Bacterium Moraxella sp. C-1

Shabalin I.G., Polyakov K.M., Tishkov V.I., Popov V.O.


The crystal structure of the ternary complex of NAD--dependent formate dehydrogenase from the methylotrophic bacterium Moraxella sp. С -1 with the cofactor (NAD-) and the inhibitor (azide ion) was established at 1.1 A resolution. The complex mimics the structure of the transition state of the enzymatic reaction. The structure was refined with anisotropic displacements parameters for non-hydrogen atoms to a R factor of 13.4%. Most of the nitrogen, oxygen, and carbon atoms were distinguished based on the analysis of the temperature factors and electron density peaks, with the result that side-chain rotamers of histidine residues and most of asparagine and glutamine residues were unambiguously determined. A comparative analysis of the structure of the ternary complex determined at the atomic resolution and the structure of this complex at 1.95 A resolution was performed. In the atomic resolution structure, the covalent bonds in the nicotinamide group are somewhat changed in agreement with the results of quantum mechanical calculations, providing evidence that the cofactor acquires a bipolar form in the transition state of the enzymatic reaction.
Acta Naturae. 2009;1(3):89-93
pages 89-93 views

Mutation of Residue βF71 of Escherichia coli Penicillin Acylase Results in Enhanced Enantioselectivity and Improved Catalytic Properties

Shapovalova I.V., Alkema W.B., Jamskova O.V., de Vries E., Guranda D.T., Janssen D.B., Švedas V.K.


Residue phenylalanine 71 of the β-chain of penicillin acylase from E. coli is involved in substrate binding and chiral discrimination of its enantiomers. Different amino acid residues have been introduced at position βF71, and the mutants were studied with respect to their enantioselectivity and substrate specificity. Some mutants demonstrated remarkably improved catalytic activity. Moreover, mutation of βF71 residue allowed to enhance penicillin acylase enantioselectivity. The catalytic activity to the specific substrates was improved up to 36 times, most notably for K, R, and L mutants. Increased activity to a D-phenylglycine derivative – a valuable specificity improvement for biocatalytic synthesis of new penicillins and cephalosporins – was shown for βF71R and βF71L mutants. The synthetic capacity of penicillin acylase with 6-aminopenicillanic acid as an external nucleophile was especially sensitive to mutation of the β71 residue in contrast to the synthesis with 7-aminodeacetoxycephalosporanic acid.
Acta Naturae. 2009;1(3):94-98
pages 94-98 views

Genotoxic Effects of Silver Nanoparticles on Mice in Vivo

Ordzhonikidze C.G., Ramaiyya L.K., Egorova E.M., Rubanovich A.V.


The toxic and genotoxic effects of silver nanoparticles were studied on injected mice (BALB/c line) in vivo. A water solution of silver nanoparticles (SNP) with particle sizes of 9±6 nm was obtained by means of the original method of biochemical synthesis. The effect of the SNP solution was compared to those of AOT (anionic surfactant used as SNP stabilizer) and silver nitrate (i.e. Ag- ions) introduced as water solutions. In studies of the toxic effects, the death of mice was registered 12-24 hours after injection only at two maximum dozes of SNP (equivalent to 0.54 and 0.36 gAg/l). It is shown that the toxic effect decreases in the sequence SNP>AOT>>AgNO3. The LE50/30 values for SNP and AOT are equal to 0.30±0.07 gAg/l and 13.3±2.1 gAg/l, respectively. Genotoxic effects were assessed by the abnormal sperm heads test and neutral Comet assay. The frequencies of abnormal sperm heads (ASHs) did not differ after treatment by SNP and AOT, but both were significantly higher than those found with AgNO3 and in control mice. Comet assay showed an increase of the DNA percentage in the comet tail in spleen cells after the injection of SNP and AOT in concentrations of ½ LE50/30. Tail DNA % was 32.8±1.3 and 26.3±1.7%, respectively, vs 16.2±0.7% for the untreated control. To sum up, these tests showed that the genotoxic effects of the SNP solution are associated with the presence of AOT rather than SNP.
Acta Naturae. 2009;1(3):99-101
pages 99-101 views

Combining Two Technologies for Full Genome Sequencing of Human

Skryabin K.G., Prokhortchouk E.B., Mazur A.M., Boulygina E.S., Tsygankova S.V., Nedoluzhko A.V., Rastorguev S.M., Matveev V.B., Chekanov N.N., Goranskaya D.A., Teslyuk A.B., Gruzdeva N.M., Velikhov V.E., Zaridze D.G., Kovalchuk M.V.


At present, the new technologies of DNA sequencing are rapidly developing allowing quick and efficient characterisation of organisms at the level of the genome structure. In this study, the whole genome sequencing of a human (Russian man) was performed using two technologies currently present on the market - Sequencing by Oligonucleotide Ligation and Detection (SOLiDTM) (Applied Biosystems) and sequencing technologies of molecular clusters using fluorescently labeled precursors (Illumina). The total number of generated data resulted in 108.3 billion base pairs (60.2 billion from Illumina technology and 48.1 billion from SOLiD technology). Statistics performed on reads generated by GAII and SOLiD showed that they covered 75% and 96% of the genome respectively. Short polymorphic regions were detected with comparable accuracy however, the absolute amount of them revealed by SOLiD was several times less than by GAII. Optimal algorithm for using the latest methods of sequencing was established for the analysis of individual human genomes. The study is the first Russian effort towards whole human genome sequencing.
Acta Naturae. 2009;1(3):102-107
pages 102-107 views

Cell Regulation of Proliferation and Differentiation ex vivo for Cells Containing Ph Chromosome in Chronic Myeloid Leukemia

Grineva N.I., Akhlynina T.V., Gerasimova L.P., Manakova T.E., Sarycheva N.G., Schmarov D.A., Tumofeev A.M., Nydenova N.M., Kolosova L.Y., Kolosheynova T.I., Kovaleva L.G., Kuznetsov S.V., Vorontsova A.V., Turkina A.G.


Cell regulation of Ph +cell proliferation and differentiation has been studied ex vivo in various chronic myeloid leukemia (CML) patients. The regulation is provided by alternation of effective stages of proliferation and maturation with inhibition of Ph+ cell proliferation by accumulating neutrophils under apoptosis blockage. The alternation of stages consists of switching stage 1 (effective proliferation) to stage 2 (effective maturation) and proceeds according to the 1/2 -1/2/1 or 2/1-2/1/2/1 schemes. The kinetic plots of alternations pass through control points of crossing plots, where the parameters of proliferation and maturation are equal. The indices of P/D efficiency (ratio of proliferation and maturation rates) are 1.06±0.23 and don’t depend on time, alternation order, or sources of Ph+ cells – CML patients. During stages alternation, conversely, the parameters of Ph + cell proliferation and maturation vary. The proliferation stages are characterized by increased proliferating cells content, a decreased number of neutrophils, and apoptosis induction. At the maturation stages, conversely, apoptosis is inhibited, the number of mature neutrophils increases, while immature Ph + cells decrease. High content neutrophils inhibit the proliferation of Ph + cells and impair their own maturation by inversion of maturation order, probably through a feedback mechanism. The regulation differences ex vivo reveal three types of Ph + cells from various individual CML patients, distinguished by the number and duration of alternating stages of proliferation and maturation. Ph + cells types 1 and 2 have one prolonged stage of effective proliferation or effective maturation with efficiency indices P/D 1 = 1-20 or P/D 2 ≤ 1. At the same time period, the proliferation and differentiation of the Ph + cells type 3 proceeds with repeated alternations of stages with P/D 1 = 1-4 or P/D 2 ≤ 1. Type 1 Ph + cells (~20%) were isolated from patients in advanced stages of CML, while Ph + cells types 2 and 3 (30 and 50% correspondingly) were isolated from CML chronic phase patients sensitive to chemotherapy.
Acta Naturae. 2009;1(3):108-120
pages 108-120 views

Deamination of 5-Methylcytosine Residues in Mammalian Cells

Gromenko E.V., Spirin P.V., Kubareva E.A., Romanova E.A., Prassolov V.S., Shpanchenko O.V., Dontsova O.A.


DNA demethylation in mammalia occurs after fertilization and during embryogenesis and accompanies cell aging and cancer transformation. With the help of the primer extension reaction, MALDI MS and DNA cleavage by thymine DNA glycosylase deamination of 5-methylcytosine residues has been shown to take place when the model methylated DNA duplexes are treated with nuclear extracts from the cell lines СНO, HeLa, and Skov3. The hypothesis that deamination of 5-methylcytosine is the first stage of demethylation in mammalia has been postulated.
Acta Naturae. 2009;1(3):121-124
pages 121-124 views

Study of Molecular Mechanisms Involved in the Pathogenesis of Immune-Mediated Inflammatory Diseases, using Psoriasis As a Model

Piruzian E.S., Sobolev V.V., Abdeev R.M., Zolotarenko A.D., Nikolaev A.A., Sarkisova M.K., Sautin M.E., Ishkin A.A., Piruzyan A.L., Ilyina S.A., Korsunskaya I.M., Rahimova O.Y., Bruskin S.A.


Psoriasis was used as a model to analyze the pathogenetic pathways of immune-mediated inflammatory diseases, and the results of bioinformatic, molecular-genetic and proteomic studies are provided. Cell mechanisms, common for the pathogenesis of psoriasis, as well as Crohn’s disease, are identified. New approaches for immune-mediated diseases are discussed.
Acta Naturae. 2009;1(3):125-135
pages 125-135 views

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Acta Naturae. 2009;1(3):126-126
pages 126-126 views

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