The Department was organized in 1965 and was first headed by Prof. A. B. Silaev, and later by Prof. S. M. Avaeva (1968-1989) and Prof. A. A. Baykov (1989-present). The Department includes three research groups headed by Dr. T.I Nazarova, Dr. G.A. Korshunova and Prof. A.A. Baykov. There are in total seven research fellows and one research assistant in the Department.
The research efforts mainly fall in three principal areas: (a) structure, mechanism and role of the enzymes catalyzing inorganic polyphosphate hydrolysis, (b) interaction of ribosome with antibiotics, (c) chemical synthesis of the target-directed analogs of natural compounds.
(i) Studies on enzymes hydrolizing inorganic polyphosphates (A.A. Baykov)
The group of Prof. Baykov has been studying three enzymes earlier discovered in a joint project with the group of Prof. R. Lahti of the University of Turku (Finland) – regulated CBS domain-containing soluble pyrophosphatase, membrane-bound Na+-transporting bacterial pyrophosphatase, and human exopolyphosphatase. Work is underway to elucidate the molecular mechanism of CBS-pyrophosphatase regulation, which underlies the physiological function of this enzyme. We also focus on the mechanism which couples pyrophosphate hydrolysis with ion transport in the membrane pyrophosphatase and on the evolution of its cation specificity.
(ii) Mechanism of ribosome functioning and design of new ribosome-directed antibiotics (G.A. Korshunova)
The group of Dr. Korshunova is interested in the mechanism of ribosome functioning and establishing the molecular basis for the design of new ribosome-directed antibiotics. The basis idea is to use macrolid antibiotic anchors for an amino acid or peptide that would mimic growing peptide in the ribosome tunnel. We are also pursuing chemical modifications of antibiotics based on computer modeling of the complexes formed by ribosomes and macrolids. Our thrust is to create a new class of protein synthesis inhibitors based on peptidyl nucleic acid derivatives whose action is specifically directed to the P site of the peptidyl transferase center.
(ii) Investigation of bacterial protein complexes (T.I. Nazarova)
The group of Dr. Nazarova has been studying the protein complexes existing in the bacterium Escherichia coli. We previously characterized the complexes formed by inorganic pyrophosphatase and showed that this enzyme interacts with the enzymes fructose-1,6-bisphosphatase, 5-keto-4-desoxyuronate isomerase and glutamate decarboxylase, which take part in the core metabolic pathways. We are currently searching for other pyrophosphatase partners and the partners of their partners in order to define the whole network of the key protein-protein interactions. A further development of this research includes studies of the proteome of the mycoplasm Acholeplasma laidlawii.
Our major achievements include determination of several tens of 3D structures of various derivatives of inorganic pyrophosphatases. Together with the results of detailed functional studies, these data allowed formulation of a most detailed mechanism of enzyme-catalyzed hydrolysis/synthesis of phosphoanhydride bond in pyrophosphate. This reaction mechanism involves two reaction pathways and five reaction intermediates. The key element of the mechanism is metal-assisted generation of a nucleophilic hydroxide ion via coordination of water molecule by two/three magnesium and transition metal ions. These studies also elucidated the role of quaternary structure in pyrophosphatase catalysis.
We also developed a range of analytical procedures to determine phosphate, pyrophosphate and various metal ions and procedures utilizing pyrophosphatase as an analytical reagent.
More recent achievements include design and synthesis of tylosin and erythromycin derivatives forming novel contacts with ribosomal tunnel walls, synthesis of new promising erythromycin analogs to overcome the resistance of microorganisms caused by methylation of the nucleotide residue A2058 in 23S rRNA, discoveries of a new evolutionary independent family (family II) of soluble pyrophosphatases, subfamily of pyrophosphatases containing regulatory CBS domain, Na+-transporting subfamily of membrane-bound bacterial pyrophosphatases, and identification of animal exopolyphosphatase.
The Department has been collaborating with the Institute of Crystallography and the Institute of Protein Research of the Russian Academy of Sciences, the Institute of Physico-Chemical Medicine of FMBA of the Russian Federation, the Institute for New Antibiotics, the University of Turku (Finland), the University of Illinois (U.S.A.) and the European Molecular Biology Laboratory (EMBL, Germany). Also involved in our work are researchers from the Chair of the Natural Compounds of the Department of Chemistry of the Moscow State University.
Grants and projects
The research was supported by grants from the Russian Foundation for Basic Research, the Federal Program “Leading Scientific Schools”, NIH Fogarty Program, Volkswagen Foundation. There are currently 3 grants from the Russian Foundation for Basic Research. The group of Dr. Korshunova is additionally supported in the framework of the “MegaProject for the practical use of the Skulachev ions” established by Mitotech Ltd.
The scientific achievements of the Department were recognized by The State Prize of the USSR (S. M. Avaeva), VDNH medals (A. A. Baykov, C. M. Avaeva, V. N. Kasho) and All-Union Biochemical Society Prize (S. M. Avaeva). Department members has obtained 15 patents, including 5 international ones.
The Department is actively involved in the educational activity of the Chair of Natural Compounds and the Department of Bioengineering and Bioinformatics of the Moscow State University. During the last 5 years, members of the Department staff supervised 23 annual student projects, 10 Master and 5 PhD thesis works.
Baykov A.A., Tuominen H.K., Lahti R. (2011) The CBS Domain: A Protein Module with an Emerging Prominent Role in Regulation. ACS Chemical Biology, 6 (11): 1156-1163.
Lyamzaev K.G., Pustovidko A.V., Simonyan R.A., Rokitskaya T.I., Domnina L.V., Ivanova O.Y., Severina I.I., Sumbatyan N.V., Korshunova G.A., Tashlitsky V.N., Roginsky V.A., Antonenko Y.N., Skulachev M.V., Chernyak B.V., Skulachev V.P. (2011) Novel Mitochondria-Targeted Antioxidants: Plastoquinone Conjugated with Cationic Plant Alkaloids Berberine and Palmatine. Pharmaceutical Research, 28 (11): 2883-2895.
Luoto H.H., Belogurov G.A., Baykov A.A., Lahti R., Malinen A.M. (2011) Na(+)-translocating Membrane Pyrophosphatases Are Widespread in the Microbial World and Evolutionarily Precede H(+)-translocating Pyrophosphatases. Journal of Biological Chemistry, 286 (24): 21633-21642.
Bogdanov A.A., Sumbatyan N.V., Shishkina A.V., Karpenko V.V., Korshunova G.A. (2010) Ribosomal tunnel and translation regulation. Biochemistry-Moscow, 75 (13): 1501-1516.
Starosta A.L., Karpenko V.V., Shishkina A.V., Mikolajka A., Sumbatyan N.V., Schluenzen F., Korshunova G.A., Bogdanov A.A., Wilson D.N. (2010) Interplay between the Ribosomal Tunnel, Nascent Chain, and Macrolides Influences Drug Inhibition. Biology, 17 (5): 504-514.
Severin F.F., Severina I.I., Antonenko Y.N., Rokitskaya T.I., Cherepanov D.A., Mokhova E.N., Vyssokikh M.Y., Pustovidko A.V., Markova O.V., Yaguzhinsky L.S., Korshunova G.A., Sumbatyan N.V., Skulachev M.V., Skulachev V.P. (2010) Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore. Proceedings of the National Academy of Sciences of the United States of America, 107 (2): 663-668.
Skulachev V.P., Anisimov V.N., Antonenko Y.N., Bakeeva L.E., Chernyak B.V., Erichev V.P., Filenko O.F., Kalinina N.I., Kapelko V.I., Kolosova N.G., Kopnin B.P., Korshunova G.A., Lichinitser M.R., Obukhova L.A., Pasyukova E.G., Pisarenko O.I., Roginsky V.A., Ruuge E.K., Senin I.I., Severina I.I., Skulachev M.V., Spivak I.M., Tashlitsky V.N., Tkachuk V.A., Vyssokikh M.Y., Yaguzhinsky L.S., Zorov D.B. (2009) An attempt to prevent senescence: A mitochondrial approach. Biochimica et Biophysica Acta-Bioenergetics, 1787 (5): 437-461.
Tammenkoski M., Koivula K., Cusanelli E., Zollo M., Steegborn C., Baykov A.A., Lahti R. (2008) Human metastasis regulator protein H-prune is a short-chain exopolyphosphatase. Biochemistry, 47 (36): 9707-9713.
Jamsen J., Tuominen H., Salminen A., Belogurov G.A., Magretova N.N., Baykov A.A., Lahti R. (2007) A CBS domain-containing pyrophosphatase of Moorella thermoacetica is regulated by adenine nucleotides. Biochemical Journal, 408: 327-333.
Samygina V.R., Moiseev V.M., Rodina E.V., Vorobyeva N.N., Porov A.N., Kurilova S.A., Nazarova T.I., Avaeva S.M., Bartunik H.D. (2007) Reversible inhibition of Escherichia coli inorganic pyrophosphatase by fluoride: Trapped catalytic intermediates in cryo-crystallographic studies. Journal of Molecular Biology, 366 (4): 1305-1317.
Malinen A.M., Belogurov G.A., Baykov A.A., Lahti R. (2007) Na+-pyrophosphatase: a novel primary sodium pump. Biochemistry, 46 (30): 8872–8878. >>
Samygina V.R., Popov A.N., Rodina E.V., Vorobyeva N.N., Lamzin V.S., Polyakov K.M., Kurilova S.A., Nazarova T.I., Avaeva S.M. (2001) The structures of Escherichia coli inorganic pyrophosphatase complexed with Ca2+ or CaPPi at atomic resolution and their mechanistic implications. Journal of Molecular Biology, 314 (3): 633-645.
Merckel M.C., Fabrichniy I.P., Salminen A., Kalkkinen N., Baykov A.A., Lahti R., Goldman A. (2001) Crystal structure of Streptococcus mutans pyrophosphatase: A new fold for an old mechanism. Structure, 9 (4): 289-297.
Korshunova G.A., Sumbatyan N.V., Topin A.N., Mtchedlidze M.T. (2000) Photoactivatable reagents based on aryl(trifluoromethyl) diazirines: Synthesis and application for studying nucleic acid-protein interactions. Molecular Biology, 34 (6): 823-839.
Sivula T., Salminen A., Parfenyev A.N., Pohjanjoki P., Goldman A., Cooperman B.S., Baykov A.A., Lahti R. (1999) Evolutionary aspects of inorganic pyrophosphatase. FEBS Letters, 454 (1): 75-80.
Baykov A.A., Cooperman B.S., Goldman A., Lahti R. (1999) Cytoplasmic inorganic pyrophosphatase. Progress in Molecular and Subcellular Biology, 23: 127-150.
Shintani T., Uchiumi T., Yonezawa T., Salminen A., Baykov A.A., Lahti R., Hachimori A. (1998) Cloning and expression of a unique inorganic pyrophosphatase from Bacillus subtilis: evidence for a new family of enzymes. FEBS Letters, 439 (3): 263-266.
Avaeva S.M., Rodina E.V., Vorobyeva N.N., Kurilova S.A., Nazarova T.I., Sklyankina V.A., Oganessyan V.Y., Samygina V.R., Harutyunyan E.H. (1998) Three-dimensional structures of mutant forms of E-coli inorganic pyrophosphatase with Asp -> Asn single substitution in positions 42, 65, 70, and 97. Biochemistry-Moscow, 63 (6): 671-684.
Harutyunyan E.H., Oganessyan V.Y., Oganessyan N.N., Avaeva S.M., Nazarova T.I., Vorobyeva N.N., Kurilova S.A., Huber R., Mather T. (1997) Crystal structure of hole inorganic pyrophosphatase from Escherichia coli at 1.9 angstrom resolution. Mechanism of hydrolysis. Biochemistry, 36 (25): 7754-7760.
Cooperman B.S., Baykov A.A., Lahti R. (1992) Evolutionary Conservation of the Active-Site of Soluble Inorganic Pyrophosphatase. Trends in Biochemical Sciences, 17 (7): 262-266.