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991.
Palmieri F Agrimi G Blanco E Castegna A Di Noia MA Iacobazzi V Lasorsa FM Marobbio CM Palmieri L Scarcia P Todisco S Vozza A Walker J 《Biochimica et biophysica acta》2006,1757(9-10):1249-1262
The inner membranes of mitochondria contain a family of carrier proteins that are responsible for the transport in and out of the mitochondrial matrix of substrates, products, co-factors and biosynthetic precursors that are essential for the function and activities of the organelle. This family of proteins is characterized by containing three tandem homologous sequence repeats of approximately 100 amino acids, each folded into two transmembrane alpha-helices linked by an extensive polar loop. Each repeat contains a characteristic conserved sequence. These features have been used to determine the extent of the family in genome sequences. The genome of Saccharomyces cerevisiae contains 34 members of the family. The identity of five of them was known before the determination of the genome sequence, but the functions of the remaining family members were not. This review describes how the functions of 15 of these previously unknown transport proteins have been determined by a strategy that consists of expressing the genes in Escherichia coli or Saccharomyces cerevisiae, reconstituting the gene products into liposomes and establishing their functions by transport assay. Genetic and biochemical evidence as well as phylogenetic considerations have guided the choice of substrates that were tested in the transport assays. The physiological roles of these carriers have been verified by genetic experiments. Various pieces of evidence point to the functions of six additional members of the family, but these proposals await confirmation by transport assay. The sequences of many of the newly identified yeast carriers have been used to characterize orthologs in other species, and in man five diseases are presently known to be caused by defects in specific mitochondrial carrier genes. The roles of eight yeast mitochondrial carriers remain to be established. 相似文献
992.
Different classes of topoisomerase (TOP) inhibitors and antitrypanosomatid agents exhibited variable efficacies against Leishmania donovani parasites and human mononuclear cells both at the level of DNA topoisomerase I (TOPI) catalytic activity and in cytotoxicity assays. Bis-benzimidazoles and the diamidine diminazene aceturate exhibited uniformly high efficacies against parasite and host enzymes as well as against parasite and mononuclear cells, but pentamidine showed around 2 orders of magnitude greater specificity for Leishmania TOPI and amastigote cells (P<0.05). The protoberberine coralyne and the flavonoid quercetin were highly potent, but non-selective, inhibitors in vitro, although the latter showed slight selectivity for parasite TOPI. Camptothecin was selective for mononuclear cells at both levels (P<0.05) and sodium stibogluconate was selective only at the enzyme level displaying 30-fold greater potency against parasite TOPI (P<0.05). These data suggest that at least part of pentamidines' leishmanicidal activity may be mediated through TOPI inhibition, and support the feasibility of exploiting differences between Leishmania and human TOPs to develop modified compounds with improved selectivity. 相似文献
993.
Chakrabarti R Walker JM Stewart DT Trdan RJ Vijayaraghavan S Curole JP Hoeh WR 《FEBS letters》2006,580(3):862-866
Analyses of unionoidean bivalve male-transmitted (M) mtDNA genomes revealed an approximately 555 bp 3' coding extension to cox2. An antibody was generated against this predicted C-terminus extension to determine if the unique cox2 protein is expressed. Western blot and immunohistochemistry analyses demonstrated that the protein was predominantly expressed in testes. Weak expression was detected in other male tissues but the protein was not detected in female tissues. This is the first report documenting the expression of a cox2 protein with a long C-terminus in animals. Its universal presence in unionoidean bivalve testes suggests a functional significance for the protein. 相似文献
994.
995.
Wall teichoic acids (WTAs) are anionic polymers that coat the cell walls of Gram-positive bacteria. Because they are essential for survival or virulence in many organisms, the enzymes involved in the biosynthesis of WTAs are attractive antibiotic targets. The first committed step in the WTA biosynthetic pathway in Bacillus subtilis is catalyzed by TagA, which transfers N-acetylmannosamine (ManNAc) to the C4 hydroxyl of a membrane-anchored N-acetylglucosaminyl diphospholipid (GlcNAc-pp-undecaprenyl, lipid I) to make ManNAc-beta-(1,4)-GlcNAc-pp-undecaprenyl (lipid II). We have previously shown that TagA utilizes an alternative substrate containing a saturated C(13)H(27) lipid chain. Here we use unnatural substrates and products to establish the lipid preferences of the enzyme and to characterize the kinetic mechanism. We report that TagA is a metal ion-independent glycosyltransferase that follows a steady-state ordered Bi-Bi mechanism in which UDP-ManNAc binds first and UDP is released last. TagA shares homology with a large family of bacterial glycosyltransferases, and the work described here should facilitate structural analysis of the enzyme in complex with its substrates. 相似文献
996.
This study investigates the evolution of human growth by analyzing differences in body mass growth trajectories among three populations: the Ache of eastern Paraguay, the US (NHANES, 1999-2000), and captive chimpanzees. The relative growth statistic "A" from the mammalian growth law is allowed to vary with age and proves useful for comparing growth across different ages, populations, and species. We demonstrate ontogenetic separation between chimpanzees and humans, and show that interspecific differences are robust to variable environmental conditions. The human pattern of slow growth during the lengthened period from weaning to the beginning of the adolescent growth spurt is found among the Ache (low energy availability and high disease load) and also in the US (high energy availability and low disease load). The human growth pattern contrasts with that of the chimpanzee, where absolute growth rates and relative "A" values are faster and less prolonged. We suggest that selection has acted to decrease human growth rates to allow more time for increased cognitive development with lower body-maintenance costs. 相似文献
997.
The slow Wallerian degeneration protein, WldS, binds directly to VCP/p97 and partially redistributes it within the nucleus
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Laser H Conforti L Morreale G Mack TG Heyer M Haley JE Wishart TM Beirowski B Walker SA Haase G Celik A Adalbert R Wagner D Grumme D Ribchester RR Plomann M Coleman MP 《Molecular biology of the cell》2006,17(3):1075-1084
Slow Wallerian degeneration (Wld(S)) mutant mice express a chimeric nuclear protein that protects sick or injured axons from degeneration. The C-terminal region, derived from NAD(+) synthesizing enzyme Nmnat1, is reported to confer neuroprotection in vitro. However, an additional role for the N-terminal 70 amino acids (N70), derived from multiubiquitination factor Ube4b, has not been excluded. In wild-type Ube4b, N70 is part of a sequence essential for ubiquitination activity but its role is not understood. We report direct binding of N70 to valosin-containing protein (VCP; p97/Cdc48), a protein with diverse cellular roles including a pivotal role in the ubiquitin proteasome system. Interaction with Wld(S) targets VCP to discrete intranuclear foci where ubiquitin epitopes can also accumulate. Wld(S) lacking its N-terminal 16 amino acids (N16) neither binds nor redistributes VCP, but continues to accumulate in intranuclear foci, targeting its intrinsic NAD(+) synthesis activity to these same foci. Wild-type Ube4b also requires N16 to bind VCP, despite a more C-terminal binding site in invertebrate orthologues. We conclude that N-terminal sequences of Wld(S) protein influence the intranuclear location of both ubiquitin proteasome and NAD(+) synthesis machinery and that an evolutionary recent sequence mediates binding of mammalian Ube4b to VCP. 相似文献
998.
Lorino AJ Lloyd LK Crixell SH Walker JL 《Journal of strength and conditioning research / National Strength & Conditioning Association》2006,20(4):851-854
Caffeine has been shown to improve sprint time, anaerobic power, and reaction time, all integral aspects of agility. The purpose of this study was to determine whether an acute caffeine dose would enhance agility and anaerobic power. Sixteen subjects participated in a randomized, double-blind experiment and performed the proagility run and the 30-second Wingate test 60 minutes after ingestion of caffeine (6 mg.kg(-1)) or placebo. No significant change was observed in the proagility run after caffeine ingestion compared with placebo. Also, no significant change was observed in peak power, mean power, or percent power decrease. Agility is an integral component of athletic skill and any reasonable method for enhancing agility would benefit active individuals. However, results from this study indicate that a 6 mg.kg(-1) dose of caffeine does not impact agility as measured by the proagility run test or power output as measured by the 30-second Wingate test in recreationally active young adult males who are not habituated to caffeine. 相似文献
999.
An understanding of large-scale eukaryotic evolution is beginning to crystallise, as molecular and morphological data demonstrate that eukaryotes fall into six major groups. However, there are several taxa of which the affinities are yet to be resolved, and for which there are only either molecular or morphological data. One of these is the amoeboid flagellate Mastigamoeba invertens. This organism was originally misidentified and studied as a pelobiont using molecular data. We present its first light microscopical and ultrastructural characterisation. We demonstrate that it does not show affinities to the amoebozoan pelobionts, because unlike the pelobionts, it has a double basal body and two flagellar roots, a classical Golgi stack, and a large branching double membrane-bound organelle. Phylogenetic analyses of small subunit ribosomal RNA suggest an affinity with the apusomonads, when a covariotide correction for rate heterogeneity is used. We suggest that previous molecular results have been subject to artefacts from an insufficient correction for rate heterogeneity. We propose a new name for the taxon, Breviata anathema; and the unranked, apomorphy-based name "Breviates" for Breviata and its close relatives. 相似文献
1000.
Rossi AG Sawatzky DA Walker A Ward C Sheldrake TA Riley NA Caldicott A Martinez-Losa M Walker TR Duffin R Gray M Crescenzi E Martin MC Brady HJ Savill JS Dransfield I Haslett C 《Nature medicine》2006,12(9):1056-1064
Apoptosis is essential for clearance of potentially injurious inflammatory cells and subsequent efficient resolution of inflammation. Here we report that human neutrophils contain functionally active cyclin-dependent kinases (CDKs), and that structurally diverse CDK inhibitors induce caspase-dependent apoptosis and override powerful anti-apoptosis signals from survival factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We show that the CDK inhibitor R-roscovitine (Seliciclib or CYC202) markedly enhances resolution of established neutrophil-dependent inflammation in carrageenan-elicited acute pleurisy, bleomycin-induced lung injury, and passively induced arthritis in mice. In the pleurisy model, the caspase inhibitor zVAD-fmk prevents R-roscovitine-enhanced resolution of inflammation, indicating that this CDK inhibitor augments inflammatory cell apoptosis. We also provide evidence that R-roscovitine promotes apoptosis by reducing concentrations of the anti-apoptotic protein Mcl-1. Thus, CDK inhibitors enhance the resolution of established inflammation by promoting apoptosis of inflammatory cells, thereby demonstrating a hitherto unrecognized potential for the treatment of inflammatory disorders. 相似文献