The structures of Escherichia coli inorganic pyrophosphatase complexed with Ca(2+) or CaPP(i) at atomic resolution and their mechanistic implications

Two structures of Escherichia coli soluble inorganic pyrophosphatase (EPPase) complexed with calcium pyrophosphate (CaPP(i)-EPPase) and with Ca(2+) (Ca(2+)-EPPase) have been solved at 1.2 and 1.1 A resolution, respectively. In the presence of Mg(2+), this enzyme cleaves pyrophosphate (PP(i)) into two molecules of orthophosphate (P(i)). This work has enabled us to locate PP(i) in the active site of the inorganic pyrophosphatases family in the presence of Ca(2+), which is an inhibitor of EPPase.Upon PP(i) binding, two Ca(2+) at M1 and M2 subsites move closer together and one of the liganded water molecules becomes bridging. The mutual location of PP(i) and the bridging water molecule in the presence of inhibitor cation is catalytically incompetent. To make a favourable PP(i) attack by this water molecule, modelling of a possible hydrolysable conformation of PP(i) in the CaPP(i)-EPPase active site has been performed. The reasons for Ca(2+) being the strong PPase inhibitor and the role in catalysis of each of four metal ions are the mechanistic aspects discussed on the basis of the structures described.     

Cold-induced paralysis and recovery of lung respiration and heart contractions in newborn rats (inversion of Arrhenius law for physiological functions)

Arrest of respiration and heart activity in new-born rats aged 3-4 days and 10-11 days was shown to occur at a body temperature 6-7 degrees C and 2-3 degrees C lower than in adult rats, resp. At room temperature the body temperature of profoundly cooled rat's litter gradually increases and the functions are restored. In 3-4-day old rats, at the body temperature rising from profound cooling to 15-18 degrees C, the respiration and heart rates are 2-4-fold more than at the same temperature attained from the normal body temperature. These differences in the respiration and heart rates at the same body temperature suggest an inversion of the Arrhenius law (the Q10 coefficient) for physiological functions in early ontogenesis. This effect completely disappears in 10-11-day old rats.     

Genetic data concerning the problem of differentiation of Northern Mongoloids, American Indians and Caucasoids in the northern territory of Eurasia

Basing on the frequencies of 28 alleles of 12 polymorphic loci of blood groups, serum proteins and red cell enzymes the matrix of genetic distances between 11 populations of Europe, Asia and America was calculated. This matrix and the dendrogram based on it permitted to suggest that the region of South Siberia and the neighbouring regions of Central Asia was the place, where the paleolithic populations were divided into the ancestors of the Northern Mongoloids, Caucasoids and American Indians. The published data concerning the human mtDNA polymorphisms support the hypothesis of the author.     

The diagnostic of membranes' state after exposure of gamma-radiation of small doses

There are the results of experimental research of the change of membranes' conditions under the action of gamma-radiation using the method of following membranes' electroporation of the accurate impulse of the electrical field for the analysis of defects after the action of gamma-radiation. As of the research material the suspension of erythrocytes was used. It was shown that the velocity of decreasing of the erythrocytes in the case of combined action of gamma-radiation and the impulse of the electrical field is more than the sum of such velocities in the case of the action of the factors separately. The method of the electroporation of the accurate impulse of the electircal field is obvious for the practicaland the analytical research of membranes' defects.     

Calcidiol and prostate cancer

Epidemiological studies suggest that serum calcidiol (25(OH)-Vitamin D3) seems to be associated with several cancers including prostate cancer. We have made several experimental studies in order to clarify the mechanism(s) involved in the association. Calcidiol has been regarded as an inactive prohormone for calcitriol, which possesses the highest biological activity of the Vitamin D metabolites, when it is evaluated on the basis of bioactivity/nmol. However, we found recently that at the physiological concentration calcidiol (100-200 nM) is an active hormone, whereas calcitriol (1alpha,25(OH)2-Vitamin D3) (100 pM) is inactive in human primary prostate stromal cells. Calcidiol is able to inhibit cell growth and to induce or inhibit several genes including 1alpha-hydroxylase and 24-hydroxylase genes. This suggests that calcidiol might be an independent endocrine system involved in the control of cell differentiation and proliferation, whereas calcitriol might be mainly involved in the regulation of calcium and phosphorous balance. Several mechanisms may mediate the action of Vitamin D in the prostate. This is a review of some recent studies on the role of (1) Vitamin D metabolism, (2) growth factors and (3) fatty acid metabolism.     

New developments in developmental biology

A report on the 15th International Society of Developmental Biologists Congress, Sydney, Australia, 3-7 September 2005.     

Effect of substituents on photochemical and biological properties of 13,15-N-cycloimide derivatives of chlorin p6

The effect of electron-accepting substituents in position 3 of the chlorine p6 macrocycle in neutral and carboxyl-containing negatively charged cycloimide derivatives of chlorin p6 (CIC) on the photochemical and biological properties of these photosensitizers was studied. A relationship between the structure and properties of CICs was analyzed on the basis of information on their photoinduced cytotoxicity, efficiency of the generation of reactive oxygen species, photostability, intracellular localization, quantitative parameters of accumulation in cells, and cellular pharmacokinetics. It was shown that these compounds can be used for the development of photosensitizers with intense light absorption at 740 nm, controlled intracellular localization, and a high photodynamic activity toward tumor cells.