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We have developed an approach to search for molecules that can be used as lead compounds in designing an inhibitor for a given proteolytic enzyme when the 3D structure of a homologous protein is known. This approach is based on taking the cast of the binding pocket of the protease and comparing its dimensions with that of the dimensions of small molecules. Herein the 3D structure of papain is used to model cathepsin L using the comparative modeling technique. The cast of the binding pocket is computed using the crystal structure of papain because the structures of papain and the model of cathepsin L are found to be similar at the binding site. The dimensions of the cast of the binding site of papain are used to screen for molecules from the Cambridge Structural Database (CSD) of small molecules. Twenty molecules out of the 80,000 small molecules in the CSD are found to have dimensions that are accommodated by the papain binding pocket. Visual comparison of the shapes of the cast and the 20 screened molecules resulted in identifying brevotoxin b, a toxin isolated from the 'red tide' dinoflagellate Ptycho brevis (previously classified as Gymonodium breve), as the structure that best fits the binding pocket of papain. We tested the proteolytic activity of papain and cathepsin L in the presence of brevotoxin b and found inhibition of papain and cathepsin L with Kis of 25 microM and 0.6 microM, respectively. We also compare our method with a more elaborate method in the literature, by presenting our results on the computer search for inhibitors of the HIV-1 protease.
J Comput Aided Mol Des 1992 Jun
PMID:An approach to computer-aided inhibitor design: application to cathepsin L. 151 75

Several forms of maximum likelihood models are applied to aligned amino acid sequence data coded for in the mitochondrial DNA of six species (chicken, frog, human, bovine, mouse, and rat). These models range in form from relatively simple models of the type currently used for inferring phylogenetic tree structure to models more complex than those that have been used previously. No major discrepancies between the optimal trees inferred by any of these methods are found, but there are huge differences in adequacy of fit. A very significant finding is that the fit of any of these models is vastly improved by allowing a certain proportion of the amino acid sites to be invariant. An even more important, although disquieting, finding is that none of these models fits well, as judged by standard statistical criteria. The primary reason for this is that amino acid sites undergo substitution according to a process that is very heterogeneous. Because most phylogenetic inference is accomplished by choosing the optimal tree under the assumption that a homogeneous process is acting on the sites, the potential invalidity of some such conclusions is raised by this article's results. The seriousness of this problem depends upon the robustness of the phylogenetic inferential procedure to departures from the underlying model.
J Mol Evol 1992 Jul
PMID:Heterogeneity in the substitution process of amino acid sites of proteins coded for by mitochondrial DNA. 151 82

Our knowledge concerning the pathology of fetal cases of human Minamata disease (methylmercury poisoning) is relatively limited. We report here a case with description of the distribution of mercury in the systemic organs, and the ultrastructural changes of the nervous system after a survival of 29 yr. The patient was a female born in 1957, with a body wt of 3000 g, who died in 1987. She carried a diagnosis of cerebral palsy, and had a convulsion at age 3 yr. Mercury levels in her mother's hair were 101 micrograms/g at the time of examination in 1959. At autopsy, the body measured 43 cm and weighed 23 kg. The brain weighed 920 g and showed marked cerebral atrophy, mild neuronal loss in the calcarine, postcentral and precentral cortices, cerebellar atrophy, and segmental demyelination of peripheral nerves. Mercury granules were present in the brain, kidney, and liver. Ultrastructural examination of the calcarine, post- and precentral cortices, and cerebellar cortices, showed severe atrophy of nerve cells, with a decrease in rough ER and an increase in nuclear chromatin and preservation of mitochondria. Autophagosomes were increased in number. In addition, high electron density, globular and dense bodies, measuring 0.3-1.8 microns in diameter, were found, surrounded by limited membrane, within both cerebral and cerebellar neurons. In the cellebellum, synapses were well-preserved.
Mol Chem Neuropathol
PMID:A fetal type of Minamata disease. An autopsy case report with special reference to the nervous system. 152 Apr 2

A new therapy for the progesterone receptor positive mammary carcinoma may be the treatment with progesterone antagonists. This new class of antihormones causes a strong inhibition of tumor growth comparable to the potency of ovariectomy in a panel of experimental mammary carcinomas. The mechanisms of the strong tumor-inhibiting action of progesterone antagonists on experimental mammary carcinomas mainly depends on a progesterone receptor mediated process leading to induction of terminal differentiation and a blockade of the cell cycle. To further characterize the antitumor mechanism of progesterone antagonists we analyzed the effects of Onapristone and ZK 112.993 on DMBA- and MNU-mammary tumors of the rat and MXT-tumors of the mouse after different therapy intervals. These hormone-dependent mammary tumors normally display intraductal growth in papillary, cribiform or solid formation, whereas after treatment periods of 2-6 weeks with progesterone antagonists they displayed dysplastic ductal and acinous formations, usually filled with secretory material. Whereas tumor size, mitotic index, and the grade of tumor malignancy decreased distinctly, the volume fraction of glandular structures in the tumors as well as the appearance of apoptosis increased 3-fold compared to the controls. In addition, the mammary glands of progesterone antagonist treated animals showed the morphological features of differentiation with the appearance of secretory activity. Interestingly, the staining pattern of some of the lectins used, especially UEA 1 binding pattern, fits to the concept of differentiation since recent studies revealed a higher degree of fucosylation only in benign lesions of human breast cancers. Therefore, these data underline the concept of a differentiation potential of progesterone antagonists on progesterone receptor positive mammary carcinomas.
J Steroid Biochem Mol Biol 1992 Sep
PMID:The antitumor potency of progesterone antagonists is due to their differentiation potential. 152 61

The effect of temperature on the velocity of rhodamine phalloidin-labelled F-actin moving in vitro on rabbit skeletal myosin has been studied. Translating actin filaments were visualized by epi-fluorescence in an inverted microscope, equipped with temperature control (+/- 0.2 K) of the stage and objective. Images were recorded in real time at magnifications of 400x or 160x by an intensified CCD camera on video tape. Motion of individual filaments was tracked by hand and velocities determined using frame times recorded simultaneously on the video tape. Velocity changed from 12 microns per second at 42 degrees C to 11 nm per second at 3 degrees C. The Arrhenius plot is non-linear, with the data following a cubic regression curve with no evident breaks or jumps. Data taken over the temperature range from single preparations followed the same curve for both heating and cooling; this indicates reversibility and absence of hysteresis. A hyperbolic model that smoothly translates with temperature between two asymptotic activation energies fits the data above 7 degrees C: these energies are 50(+/- 5) kJ per mole (Q10 = 1.9) at high temperatures and 289(+/- 29) kJ per mole (Q10 = 76.5) at low temperature with a transition temperature of 15.4(+/- 0.6) degrees C. These values are compared with other measurements made in vitro, in solution studies and on muscle fibres. An Arrhenius activation energy of 50 kJ per mole and a transition temperature of 15 degrees C are consistent with previous determinations but 289 kJ per mole is significantly greater than has been seen at low temperatures in other systems. This may indicate a different rate-limiting step in the kinetics of skeletal myosin driving actin filaments in vitro below 15 degrees C. Current determinations of the myosin "step-size" assume that the actin velocity is determined by the rate of ATP hydrolysis; the data confirm similar activation energies above 20 degrees C but they show that the temperature dependencies and activation energies are different at lower temperatures, implying uncoupling of the two processes.
J Mol Biol 1992 Apr 20
PMID:Temperature dependence and Arrhenius activation energy of F-actin velocity generated in vitro by skeletal myosin. 153 50

The biochemical alterations eliciting the growth and spread of afterdischarge and accompanying the evolution of behavioral seizure stages in electrical kindling are not known. In situ hybridization for c-fos mRNA was used to map potential brain structures recruited during the evolution of major seizures from electrical kindling of the amygdala in rats. Two different patterns of c-fos induction were observed in the earliest stages of kindling (stages 1 and 2). A unilateral cortical distribution included the insular, temporal, perirhinal and parietal cortices and the amygdala. No changes in the hippocampus were noted in this group. The second distribution pattern was limited to the hippocampus (either unilateral or bilateral) and amygdala (unilateral) with no changes in the cortical areas. The afterdischarge durations were significantly (2 fold) longer in the 'hippocampal' group as compared to the 'cortical' group. In the later stages of kindling (stages 4 and 5) the distribution of c-fos mRNA was uniformly bilateral and involved a combination of the hippocampal and cortical distributions observed in the earlier stages and including the amygdala bilaterally as well. The induction of c-fos mRNA appears to provide a map of two different routes in the sequential pathways involved in the evolution of kindled seizures; it may also ultimately prove to be an important component of the kindling process itself. Additionally, c-fos mRNA was elevated bilaterally in the inferior colliculus of animals exhibiting running fits with their seizures. The inferior colliculus was previously shown by others to be involved in running fits accompanying convulsions.
Brain Res Mol Brain Res 1991 Aug
PMID:Regional expression of c-fos mRNA in rat brain during the evolution of amygdala kindled seizures. 166 46

Thymidine kinase (TK), which is induced by Herpes Simplex Virus 1 (HSV1), plays a key role in the antiviral activity of guanine derivatives such as aciclovir (ACV). In contrast, ACV shows only low affinity to the corresponding host cell enzyme. In order to define the differences in substrate binding of the two enzymes on molecular level, models for the three-dimensional (3-D) structures of the active sites of HSV1-TK and human TK were developed. The reconstruction of the active sites of HSV1-TK and human TK were developed. The reconstruction of the active sites started from primary and secondary structure analysis of various kinases. The results were validated to homologous enzymes with known 3-D structures. The models predict that both enzymes consist of a central core beta-sheet structure, connected by loops and alpha-helices very similar to the overall structure of other nucleotide binding enzymes. The phosphate binding site is made up of a highly conserved glycine-rich loop at the N-terminus of the proteins and a conserved region at the C-terminus. The thymidine recognition site was found about 100 amino acids downstream from the phosphate binding loop. The differing substrate specificity of human and HSV1-TK can be explained by amino-acid substitutions in the homologous regions. To achieve a better understanding of the structure of the active site and how the thymidine kinase proteins interact with their substrates, the corresponding complexes of thymidine and dihydroxypropoxyguanine (DHPG) with HSV1 and human TK were built. For the docking of the guanine derivative, the X-ray structure of Elongation Factor Tu (EF-Tu), co-crystallized with guanosine diphosphate, was taken as reference. Fitting of thymidine into the active sites was done with respect to similar interactions found in thymidylate kinase. To complement the analysis of the 3-D structures of the two kinases and the substrate enzyme interactions, site-directed mutagenesis of the thymidine recognition site of HSV1-TK has been undertaken, changing Asp162 in the thymidine recognition site into Asn. First investigations reveal that the enzymatic activity of the mutant protein is destroyed.
J Comput Aided Mol Des 1991 Oct
PMID:Computer-aided active-site-directed modeling of the herpes simplex virus 1 and human thymidine kinase. 166 55

The Cavender-Felsenstein edge-length invariants for binary characters on 4-trees provide the starting point for the development of "customized" invariants for evaluating and comparing phylogenetic hypotheses. The binary character invariants may be generalized to k-valued characters without losing the quadratic nature of the invariants as functions of the theoretical frequencies f(UVXY) of observable character configurations (U at organism 1, V at 2, etc.). The key to the approach is that certain sets of these configurations constitute events which are probabilistically independent from other such sets, under the symmetric Markov change models studied. By introducing more complex sets of configurations, we find the quadratic invariants for 5-trees in the binary model and for individual edges in 6-trees or, indeed, in any size tree. The same technique allows us to formulate invariants for entire trees, but these are cubic functions for 6-trees and are higher-degree polynomials for larger trees. With k-valued characters and, especially, with large trees, the types of configuration sets (events) used in the simpler examples are too rare (i.e., their predicted frequencies are too low) to be useful, and the construction of meaningful pairs of independent events becomes an important and nontrivial task in designing invariants suited to testing specific hypotheses. In a very natural way, this approach fits in with well-known statistical methodology for contingency tables. We explore use of events such as "only transitions occur for character i (i.e., position i in a nucleic acid sequence) in subtree a" in analyzing a set of data on ribosomal RNA in the context of the controversy over the origins of archaebacteria, eubacteria, and eukaryotes.
Mol Biol Evol 1990 May
PMID:Designer invariants for large phylogenies. 169 57

Schistosomiasis is a trematode infection of some 200 million people. The hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) of the major etiologic agent, Schistosoma mansoni, has been proposed as a potential target for antischistosomal chemotherapy [Dovey, H. F., McKerrow, J. H., & Wang, C. C. (1984) Mol. Biochem. Parasitol, 11, 157-167]. The steady-state kinetic mechanism for the schistosomal HGPRTase has been determined by including both hypoxanthine and guanine in the forward and reverse reactions under identical conditions. Double-reciprocal plots of initial velocity versus the concentration of one substrate, at a series of fixed concentrations of the other, give groups of intersecting straight lines indicating a sequential mechanism for the schistosomal HGPRTase-catalyzed reactions. In product inhibition studies, the results show that magnesium pyrophosphate (MgPPi) is a noncompetitive inhibitor with respect to dimagnesium phosphoribose pyrophosphate (Mg2PRPP), hypoxanthine, and guanine. Also, magnesium inosine monophosphate (MgIMP) and magnesium guanosine monophosphate (MgGMP) are noncompetitive inhibitors with respect to hypoxanthine or guanine, respectively, but are competitive inhibitors to Mg2PRPP. Furthermore, Mg2PRPP is a competitive inhibitor with respect to MgIMP and MgGMP but is a non-competitive inhibitor to MgPPi. The minimum kinetic model which fits the experimental data is an ordered bi-bi mechanism, where the substrates bind to the enzyme in a defined order (first Mg2PRPP followed by the purine bases), while products are released in sequence (first MgPPi followed by MgIMP or MgGMP).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Steady-state kinetics of the schistosomal hypoxanthine-guanine phosphoribosyltransferase. 173 38

The effects of systemic kainic acid (KA) administration on hippocampal levels of prodynorphin and proenkephalin mRNA, as well as opioid peptides derived from these precursors, were evaluated. A single subcutaneous injection of KA induced a range of seizure states, from mild wet dog shakes to generalized motor seizures. Northern blot analysis of hippocampal mRNA revealed an increase in both prodynorphin and proenkephalin mRNA levels which corresponded to the intensity of the convulsions. Conversely, hippocampal levels of immunoreactive dynorphin A (1-8) and [Met]5-enkephalin were decreased as a function of seizure frequency and intensity. The time course of KA-induced alterations in prodynorphin and proenkephalin mRNA and peptide levels was also investigated. Hippocampal prodynorphin mRNA levels rose at a dramatic rate. At 3 h following KA administration, mRNA levels were maximally elevated approximately 13-fold. The levels decreased over a 48 h period, eventually reaching control values. In contrast, proenkephalin mRNA levels increased more slowly. At 24 h, a maximal 24-fold increase was observed. At 72 h after injection, proenkephalin mRNA levels were still slightly elevated. In the same experiment, immunoreactive enkephalin peptide levels, although somewhat decreased at 3-12 h, began to increase between 12 and 24 h after injection, and were still rising at 72 h. In marked contrast, immunoreactive dynorphin peptide levels ranged from 40% to 80% of control values at all times tested.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1991 Jan
PMID:Systemic administration of kainic acid differentially regulates the levels of prodynorphin and proenkephalin mRNA and peptides in the rat hippocampus. 185 80


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