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  • 101.
    Pettersson, Mats E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Kurland, Charles G.
    Berg, Otto G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Deletion rate evolution and its effect on genome size and coding density2009In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 26, no 6, p. 1421-1430Article in journal (Refereed)
    Abstract [en]

    Deletion rates are thought to be important factors in determining the genome size of organisms in nature. Although it is indisputable that deletions, and thus deletion rates, affect genome size, it is unclear how, or indeed if, genome size is regulated via the deletion rate. Here, we employ a mathematical model to determine the evolutionary fate of deletion rate mutants. Simulations are employed to explore the interactions between deletions, deletion rate mutants, and genome size. The results show that, in this model, the fate of deletion rate mutants   will depend on the fraction of essential genomic material, on the   frequency of sexual recombination, as well as on the population size of the organism. We find that there is no optimal deletion rate in any state. However, at one critical coding density, all changes in deletion rate are neutral and the rate may drift either up or down. As a consequence, the coding density of the genome is expected to fluctuate around this   critical density. Characteristic differences in the impact of deletion rate mutations on prokaryote and eukaryote genomes are described.

  • 102.
    Pettersson, Mats E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Sun, Song
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berg, Otto G
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Evolution of new gene functions: simulation and analysis of the amplification model.2009In: Genetica, ISSN 0016-6707, E-ISSN 1573-6857, Vol. 135, no 3, p. 309-324Article in journal (Refereed)
    Abstract [en]

    Creation of new genes and functions is a central feature of evolution. Duplication of existing genes has long been assumed to be the source of new genes, but the precise mechanism has remained unclear. One suggestion is that new genes are created via temporary amplifications, which simultaneously increase both the selective advantage of weak, pre-existing secondary functions and the target for optimizing mutations. This paper examines the amplification model by formalizing it into a mathematical framework. This framework is used to perform stochastic (Monte Carlo) simulations. In addition, experimental data from Salmonella typhimurium LT2 are used to support the modelling, by providing estimates for parameter values. The results show that amplification of tandem repeats is likely to contribute to creation of new genes in nature.

  • 103. Philippot, Laurent
    et al.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Battin, Tom J.
    Prosser, James I.
    Schimel, Joshua P.
    Whitman, William B.
    Hallin, Sara
    The ecological coherence of high bacterial taxonomic ranks2010In: Nature Reviews Microbiology, ISSN 1740-1526, E-ISSN 1740-1534, Vol. 8, no 7, p. 523-529Article, review/survey (Refereed)
    Abstract [en]

    The species is a fundamental unit of biological organization, but its relevance for Bacteria and Archaea is still hotly debated. Even more controversial is whether the deeper branches of the ribosomal RNA-derived phylogenetic tree, such as the phyla, have ecological importance. Here, we discuss the ecological coherence of high bacterial taxa in the light of genome analyses and present examples of niche differentiation between deeply diverging groups in terrestrial and aquatic systems. The ecological relevance of high bacterial taxa has implications for bacterial taxonomy, evolution and ecology.

  • 104. Reiner, David S.
    et al.
    Ankarklev, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Troell, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Palm, Daniel
    Bernander, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Gillin, Frances D.
    Andersson, Jan O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Synchronisation of Giardia lamblia: identification of cell cycle stage-specific genes and a differentiation restriction point2008In: International Journal of Parasitology, ISSN 0020-7519, E-ISSN 1879-0135, Vol. 38, no 8-9, p. 935-944Article in journal (Refereed)
    Abstract [en]

    The intestinal parasite Giardia lamblia undergoes cell differentiations that entail entry into and departure from the replicative cell cycle. The pathophysiology of giardiasis depends directly upon the ability of the trophozoite form to replicate in the host upper small intestine. Thus, cell proliferation is tightly linked to disease. However, studies of cell cycle regulation in Giardia have been hampered by the inability to synchronise cultures. Here we report that Giardia isolates of the major human genotypes A and B can be synchronised using aphidicolin, a mycotoxin that reversibly inhibits replicative DNA polymerases in eukaryotic cells. Aphidicolin arrests Giardia trophozoites in the early DNA synthesis (S) phase of the cell cycle. We identified a set of cell cycle orthologues in the Giardia genome using bioinformatic analyses and showed that synchronised parasites express these genes in a cell cycle stage-specific manner. The synchronisation method also showed that during encystation, exit from the ordinary cell cycle occurs preferentially in GZ and defines a restriction point for differentiation. Synchronisation opens up possibilities for further molecular and cell biological studies of chromosome replication, mitosis and segregation of the complex cytoskeleton in Giardia.

  • 105. Repsilber, Dirk
    et al.
    Mira, Alex
    Lindroos, Hillevi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Ziegler, Andreas
    Data rotation improves genomotyping efficiency2005In: Biometrical Journal, ISSN 0323-3847, E-ISSN 1521-4036, Vol. 47, no 4, p. 585-598Article in journal (Refereed)
    Abstract [en]

    Unsequenced bacterial strains can be characterized by comparing their genomic DNA to a sequenced reference genome of the same species. This comparative genomic approach, also called genomotyping, is leading to an increased understanding of bacterial evolution and pathogenesis. It is efficiently accomplished by comparative genomic hybridization on custom-designed cDNA microarrays. The microarray experiment results in fluorescence intensities for reference and sample genome for each gene. The logratio of these intensities is usually compared to a cut-off, classifying each gene of the sample genome as a candidate for an absent or present gene with respect to the reference genome. Reducing the usually high rate of false positives in the list of candidates for absent genes is decisive for both time and costs of the experiment. We propose a novel method to improve efficiency of genomotyping experiments in this sense, by rotating the normalized intensity data before setting up the list of candidate genes. We analyze simulated genomotyping data and also re-analyze an experimental data set for comparison and illustration. We approximately halve the proportion of false positives in the list of candidate absent genes for the example comparative genomic hybridization experiment as well as for the simulation experiments.

  • 106. Rhomberg, Thomas A.
    et al.
    Karlberg, Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Mini, Thierry
    Zimny-Arndt, Ursula
    Wickenberg, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Röttgen, Marlene
    Jungblut, Peter
    Jenö, Paul
    Andersson, Siv
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Dehio, Christoph
    Proteomic analysis of the sarcosine-insoluble outer membrane fraction of the bacterial pathogen Bartonella henselae2004In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 4, no 10, p. 3021-3033Article in journal (Refereed)
    Abstract [en]

    Bartonella henselae is an emerging zoonotic pathogen causing a wide range of disease manifestations in humans. In this study, we report on the analysis of the sarcosine-insoluble outer membrane fraction of B. henselae ATCC 49882 Houston-1 by one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (1-D SDS-PAGE) and two-dimensional nonequilibrium pH gradient polyacrylamide gel electrophoresis (2-D NEPHGE). Protein species were identified by matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) and subsequent database query against the B. henselae genome sequence. Subcellular fractionation, application of the ionic detergent lauryl sarcosine, assessment of trypsin sensitivity, and heat modifiability of surface-exposed proteins represented valuable tools for the analysis of the outer membrane subproteome of B. henselae. 2-D NEPHGE was applied to display and catalogue a substantial number of proteins associated with the B. henselae sarcosine-insoluble outer membrane fraction, resulting in the establishment of a first 2-D reference map of this compartment. Thus, 53 distinct protein species associated with the outer membrane subproteome fraction were identified. This study provides novel insights into the membrane biology and the associated putative virulence factors of this pathogen of increasing medical importance.

  • 107. Riess, Tanja
    et al.
    Andersson, Siv
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Lupas, Andrei
    Schaller, Martin
    Schäfer, Andrea
    Kyme, Pierre
    Martin, Jörg
    Wälzlein, Joo-Hee
    Ehehalt, Urs
    Lindroos, Hillevi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Schirle, Markus
    Nordheim, Alfred
    Autenrieth, Ingo B.
    Kempf, Volkhard A. J.
    Bartonella adhesin A mediates a proangiogenic host cell response2004In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 200, no 10, p. 1267-1278Article in journal (Refereed)
    Abstract [en]

    Bartonella henselae causes vasculoproliferative disorders in humans. We identified a nonfimbrial adhesin of B. henselae designated as Bartonella adhesin A (BadA). BadA is a 340-kD outer membrane protein encoded by the 9.3-kb badA gene. It has a modular structure and contains domains homologous to the Yersinia enterocolitica nonfimbrial adhesin (Yersinia adhesin A). Expression of BadA was restored in a BadA-deficient transposon mutant by complementation in trans. BadA mediates the binding of B. henselae to extracellular matrix proteins and to endothelial cells, possibly via β1 integrins, but prevents phagocytosis. Expression of BadA is crucial for activation of hypoxia-inducible factor 1 in host cells by B. henselae and secretion of proangiogenic cytokines (e.g., vascular endothelial growth factor). BadA is immunodominant in B. henselae–infected patients and rodents, indicating that it is expressed during Bartonella infections. Our results suggest that BadA, the largest characterized bacterial protein thus far, is a major pathogenicity factor of B. henselae with a potential role in the induction of vasculoproliferative disorders.

  • 108. Robinson, Nicholas P.
    et al.
    Dionne, Isabelle
    Lundgren, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Marsh, Victoria L.
    Bernander, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Bell, Stephen D.
    Identification of two origins of replication in the single chromosome of the archaeon Sulfolobus solfataricus2004In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 116, no 1, p. 25-38Article in journal (Refereed)
    Abstract [en]

    Eukaryotic chromosomes possess multiple origins of replication, whereas bacterial chromosomes are replicated from a single origin. The archaeon Pyrococcus abyssi also appears to have a single origin, suggesting a common rule for prokaryotes. However, in the current work, we describe the identification of two active origins of replication in the single chromosome of the hyperthermophilic archaeon Sulfolobus solfataricus. Further, we identify conserved sequence motifs within the origins that are recognized by a family of three Sulfolobus proteins that are homologous to the eukaryotic initiator proteins Orc1 and Cdc6. We demonstrate that the two origins are recognized by distinct subsets of these Orc1/Cdc6 homologs. These data, in conjunction with an analysis of the levels of the three Orc1/Cdc6 proteins in different growth phases and cell cycle stages, lead us to propose a model for the roles for these proteins in modulating origin activity.

  • 109. Smits, Paulien
    et al.
    Smeitink, Jan A. M.
    van den Heuvel, Lambert P.
    Huynen, Martijn A.
    Ettema, Thijs J. G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Reconstructing the evolution of the mitochondrial ribosomal proteome2007In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 35, no 14, p. 4686-4703Article in journal (Refereed)
    Abstract [en]

    For production of proteins that are encoded by the mitochondrial genome, mitochondria rely on their own mitochondrial translation system, with the mitoribosome as its central component. Using extensive homology searches, we have reconstructed the evolutionary history of the mitoribosomal proteome that is encoded by a diverse subset of eukaryotic genomes, revealing an ancestral ribosome of alpha-proteobacterial descent that more than doubled its protein content in most eukaryotic lineages. We observe large variations in the protein content of mitoribosomes between different eukaryotes, with mammalian mitoribosomes sharing only 74 and 43% of its proteins with yeast and Leishmania mitoribosomes, respectively. We detected many previously unidentified mitochondrial ribosomal proteins (MRPs) and found that several have increased in size compared to their bacterial ancestral counterparts by addition of functional domains. Several new MRPs have originated via duplication of existing MRPs as well as by recruitment from outside of the mitoribosomal proteome. Using sensitive profile-profile homology searches, we found hitherto undetected homology between bacterial and eukaryotic ribosomal proteins, as well as between fungal and mammalian ribosomal proteins, detecting two novel human MRPs. These newly detected MRPs constitute, along with evolutionary conserved MRPs, excellent new screening targets for human patients with unresolved mitochondrial oxidative phosphorylation disorders.

  • 110.
    Sun, Song
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berg, Otto G
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Roth, John R
    Contribution of gene amplification to evolution of increased antibiotic resistance in Salmonella typhimurium2009In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 182, no 4, p. 1183-1195Article in journal (Refereed)
    Abstract [en]

    The use of beta-lactam antibiotics has led to the evolution and global spread of a variety of resistance mechanisms, including beta-lactamases, a group of enzymes that degrade the beta-lactam ring. The evolution of increased beta-lactam resistance was studied by exposing independent lineages of Salmonella typhimurium to progressive increases in cephalosporin concentration. Each lineage carried a beta-lactamase gene (bla(TEM-1)) that provided very low resistance. In most lineages, the initial response to selection was an amplification of the bla(TEM-1) gene copy number. Amplification was followed in some lineages by mutations (envZ, cpxA, or nmpC) that reduced expression of the uptake functions, the OmpC, OmpD, and OmpF porins. The initial resistance provided by bla(TEM-1) amplification allowed the population to expand sufficiently to realize rare secondary point mutations. Mathematical modeling showed that amplification often is likely to be the initial response because events that duplicate or further amplify a gene are much more frequent than point mutations. These models show the importance of the population size to appearance of later point mutations. Transient gene amplification is likely to be a common initial mechanism and an intermediate in stable adaptive improvement. If later point mutations (allowed by amplification) provide sufficient adaptive improvement, the amplification may be lost.

  • 111.
    Szabó-Taylor, Katalin É.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Limnology.
    Kiss, Keve T.
    Logares, Ramiro
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Limnology.
    Eiler, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Acs, Eva
    Toth, Bence
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Limnology.
    Composition and dynamics of microeukaryote communities in the River Danube2010In: Fottea, ISSN 1802-5439, Vol. 10, no 1, p. 99-113Article in journal (Refereed)
    Abstract [en]

    The diversity of microeukaryote communities inhabiting rivers is still poorly known. Here, we have analyzed the periphytic and planktonic microeukaryote communities present in one section of the River Danube by two different methods: 18S rRNA-based terminal restriction fragment length polymorphism with fragment sequencing and microscopical analysis of the phytoplankton and periphyton. Both data sets were then related to environmental variables. Molecular fingerprinting revealed diverse communities with fluctuating composition, with the majority of sequences affiliated to the groups Bacillariophyta, Synurophyceae and Chlorophyceae. This was in accordance with microscopical data. The total number of detected T-RFs during the study period was 145, with more than half of the T-RFs being restricted to either plankton or periphyton. This suggests that the likely different natural selection regimes experienced by microeukaryotes in these two environments may promote the presence of different lineages in each of them. Significant correlations were found between phytoplankton chlorophyll a content, phosphorus content, temperature, and the T RFLP pattern of the planktonic microeukaryotic community, suggesting that the former environmental factors are especially important in structuring the planktonic microeukaryote communities in the River Danube. These data, together with earlier studies suggest that molecular methods are an invaluable addition in pursuit of the better understanding of the diversity and fluctuation of freshwater microeukaryotic communities.

  • 112.
    Sällström, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Genome reduction in the alpha-Proteobacteria2005In: Current Opinion in Microbiology, ISSN 1369-5274, E-ISSN 1879-0364, Vol. 8, no 5, p. 579-585Article in journal (Refereed)
    Abstract [en]

    More than 20 α-proteobacterial genomes are currently available. These range in size from 1–9 Mb and represent excellent model systems for evolutionary studies of the organizational features of bacterial genomes. Computational inferences have shown that genome reductions have occurred independently in lineages such as Rickettsia and Bartonella that are associated with intracellular lifestyles. Analyses of these reduced genomes have provided insights into the evolution of vector-borne transmission pathways. Further research into the population biology of bacteria, arthropods and vertebrate hosts will help to refine the biology of host–pathogen interactions and will facilitate the design of vaccines and vector-control programs.

  • 113.
    Sällström, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv G.E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Genome reduction in the alpha-Proteobacteria2005In: Current Opinion in Microbiology, ISSN 1369-5274, E-ISSN 1879-0364, Vol. 8, no 5, p. 579-585Article in journal (Refereed)
    Abstract [en]

    More than 20 alpha-proteobacterial genomes are currently available. These range in size from 1–9 Mb and represent excellent model systems for evolutionary studies of the organizational features of bacterial genomes. Computational inferences have shown that genome reductions have occurred independently in lineages such as Rickettsia and Bartonella that are associated with intracellular lifestyles. Analyses of these reduced genomes have provided insights into the evolution of vector-borne transmission pathways. Further research into the population biology of bacteria, arthropods and vertebrate hosts will help to refine the biology of host–pathogen interactions and will facilitate the design of vaccines and vector-control programs.

  • 114.
    Sällström, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Arnaout, Ramy A.
    Davids, Wagied
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Bjelkmar, Pär
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Protein evolutionary rates correlate with expression independently of synonymous substitutions in Helicobacter pylori2006In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 62, no 5, p. 600-614Article in journal (Refereed)
    Abstract [en]

    In free-living microorganisms, such as Escherichia coli and Saccharomyces cerevisiae, both synonymous and nonsynonymous substitution frequencies correlate with expression levels. Here, we have tested the hypothesis that the correlation between amino acid substitution rates and expression is a by-product of selection for codon bias and translational efficiency in highly expressed genes. To this end, we have examined the correlation between protein evolutionary rates and expression in the human gastric pathogen Helicobacter pylori, where the absence of selection on synonymous sites enables the two types of substitutions to be uncoupled. The results revealed a statistically significant negative correlation between expression levels and nonsynonymous substitutions in both H. pylori and E. coli. We also found that neighboring genes located on the same, but not on opposite strands, evolve at significantly more similar rates than random gene pairs, as expected by co-expression of genes located in the same operon. However, the two species differ in that synonymous substitutions show a strand-specific pattern in E. coli, whereas the weak similarity in synonymous substitutions for neighbors in H. pylori is independent of gene orientation. These results suggest a direct influence of expression levels on nonsynonymous substitution frequencies independent of codon bias and selective constraints on synonymous sites.

  • 115.
    Sällström, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Arnaout, Ramy A.
    Davids, Wagied
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Bjelkmar, Pär
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Protein Evolutionary Rates Correlate with Expression Independently of Synonymous Substitutions in Helicobacter pylori2006In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 62, no 5, p. 600-614Article in journal (Refereed)
    Abstract [en]

    In free-living microorganisms, such as Escherichia coli and Saccharomyces cerevisiae, both synonymous and nonsynonymous substitution frequencies correlate with expression levels. Here, we have tested the hypothesis that the correlation between amino acid substitution rates and expression is a by-product of selection for codon bias and translational efficiency in highly expressed genes. To this end, we have examined the correlation between protein evolutionary rates and expression in the human gastric pathogen Helicobacter pylori, where the absence of selection on synonymous sites enables the two types of substitutions to be uncoupled. The results revealed a statistically significant negative correlation between expression levels and nonsynonymous substitutions in both H. pylori and E. coli. We also found that neighboring genes located on the same, but not on opposite strands, evolve at significantly more similar rates than random gene pairs, as expected by co-expression of genes located in the same operon. However, the two species differ in that synonymous substitutions show a strand-specific pattern in E. coli, whereas the weak similarity in synonymous substitutions for neighbors in H. pylori is independent of gene orientation. These results suggest a direct influence of expression levels on nonsynonymous substitution frequencies independent of codon bias and selective constraints on synonymous sites.

  • 116.
    Söderberg, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Berg, Otto
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Mutational interference and the progression of Muller's ratchet when mutations have a broad range of deleterious effects2007In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 177, no 2, p. 971-986Article in journal (Refereed)
    Abstract [en]

    Deleterious mutations can accumulate in asexual haploid genomes through the process known as Muller's ratchet. This process has been described in the literature mostly for the case where all mutations are assumed to have the same effect on fitness. In the more realistic situation, deleterious mutations will affect fitness with a wide range of effects, from almost neutral to lethal. To elucidate the behavior of the ratchet in this more realistic case, simulations were carried out in a number of models, one where all mutations have the same effect on selection [one-dimensional (1D) model], one where the deleterious mutations can be divided into two groups with different selective effects [two-dimensional (2D) model], and finally one where the deleterious effects are distributed. The behavior of these models suggests that deleterious mutations can be classified into three different categories, such that the behavior of each can be described in a straightforward way. This makes it possible to predict the ratchet rate for an arbitrary distribution of fitness effects using the results for the well-studied 1D model with a single selection coefficient. The description was tested and shown to work well in simulations where selection coefficients are derived from an exponential distribution.

  • 117.
    Tamas, Ivica
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Wernegreen, Jennifer J
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Kauppinen, Seth N
    Darby, Alistair C
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Gomez-Valero, Laura
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Lundin, Daniel
    Poole, Anthony M
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Endosymbiont gene functions impaired and rescued by polymerase infidelity at poly(A) tracts2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 39, p. 14934-14939Article in journal (Refereed)
    Abstract [en]

    Among host-dependent bacteria that have evolved by extreme reductive genome evolution, long-term bacterial endosymbionts of insects have the smallest (160-790 kb) and most A + T-rich (>70%) bacterial genomes known to date. These genomes are riddled with poly(A) tracts, and 5-50% of genes contain tracts of 10 As or more. Here, we demonstrate transcriptional slippage at poly(A) tracts within genes of Buchnera aphidicola associated with aphids and Blochmannia pennsylvanicus associated with ants. Several tracts contain single frameshift deletions; these apparent pseudogenes showed patterns of constraint consistent with purifying selection on the encoded proteins. Transcriptional slippage yielded a heterogeneous population of transcripts with variable numbers of As in the tract. Across several frameshifted genes, including B. aphidicola cell wall biosynthesis genes and a B. pennsylvanicus histidine biosynthesis gene, 12-50% of transcripts contained corrected reading frames that could potentially yield full-length proteins. In situ immunostaining confirmed the production of the cell wall biosynthetic enzyme UDP-N-acetylmuramyl pentapeptide synthase encoded by the frameshifted murF gene. Simulation studies indicated an overrepresentation of poly(A) tracts in endosymbiont genomes relative to other A + T-rich bacterial genomes. Polymerase infidelity at poly(A) tracts rescues the functionality of genes with frameshift mutations and, conversely, reduces the efficiency of expression for in-frame genes carrying poly(A) regions. These features of homopolymeric tracts could be exploited to manipulate gene expression in small synthetic genomes.

  • 118.
    Thollesson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    LDDist: a Perl module for calculating LogDet pair-wise distances for protein and nucleotide sequences2004In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 20, no 3, p. 416-418Article in journal (Refereed)
    Abstract [en]

    Summary: LDDist is a Perl module implemented in C++ that allows the user to calculate LogDet pair-wise genetic distances for amino acid as well as nucleotide sequence data. It can handle site-to-site rate variation by treating a proportion of the sites as invariant and/or by assigning sites to different, presumably homogenous, rate categories. The rate-class assignments and invariant proportion can be set explicitly, or estimated by the program; the latter using either of two different capture–recapture methods. The assignment to rate categories in lieu of a phylogeny can be done using Shannon–Wiener index as a crude token for relative rate.

  • 119.
    Täpp, Jenny
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Thollesson, Mikael
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Herrmann, Björn
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Phylogenetic relationships and genotyping of the genus Streptococcus by sequence determination of the RNase P RNA gene, rnpB2003In: Int J of Systematic and Evolutionary Microbiology, Vol. 53, p. 1861-1871Article in journal (Refereed)
  • 120. van der Oost, John
    et al.
    Walther, Jasper
    Brouns, Stan
    van de Werken, Harmen
    Snijders, Ambrosius
    Wright, Philip
    Andersson, Anders
    Bernander, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    de Vos, Willem
    Functional genomics of the thermo-acidophilic archaeon Sulfolobus solfataricus2006In: Extremophiles / [ed] Fred A. Rainey, Elsevier , 2006, p. 201-231Chapter in book (Other academic)
  • 121.
    Vinnere, Olga
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Approaches to Species Delineation in Anamorphic (mitosporic) Fungi: A Study on Two Extreme Cases2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Since the beginning of mycology, studies of species concept in fungi have been mainly based on morphology, partially due to the history of mycology as part of botany. Current advances in biochemical and molecular research have provided mycologists with powerful tools that can be used for delineation of fungal taxa. Recently, an integrated approach to fungal taxonomy involving both morphological and molecular traits has found a wide application for identification of species, especially in anamorphic (mitosporic) fungi.

    In this thesis, I have tried to use this approach for identification of species units in two rather unrelated groups of organisms. One of the case studies concerned Colletotrichum acutatum – a worldwide economically important plant pathogenic anamorphic fungus, which is exhibiting a high level of variation in both morphological and molecular features. This fungus has been intensively studied during the past decades, and several attempts have been made to find reliable markers to separate it from other closely related species of Colletotrichum. The second case studied in this thesis was Mycelia Sterilia – an artificial group of fungi, which are deficient in production of spores of any kind, therefore lacking the main morphological feature used for assigning them to any certain fungal taxon below class level. Due to this peculiarity, Mycelia Sterilia have usually been neglected, and currently there is no working species concept applicable to these fungi.

    In this work, I have tried to clarify the relationships among C. acutatum and several other anamorphic (C. gloeosporioides and C. fructigenum) and teleomorphic (Glomerella acutata, G. cingulata and G. miyabeana) taxa that are closely related to each other. For this purpose, examination of morphological traits was employed in combination with comparison of DNA sequencing data from three loci and subsequent phylogenetic analysis. As a result, re-description of C. acutatum and separation of (at least) two new species was proposed.

    For studies of Mycelia Sterilia, a large collection of sterile strains was screened in search for biologically interesting organisms. One novel pathogen has been found, and two plant growth promoting strains with antifungal properties were selected. Attempt for tentative identification of those fungi was made based on their morphological, physiological and molecular features. Sequencing of several genes and spacers of the ribosomal DNA array revealed that the plant pathogenic strain is closely related to the teleomorphic basidiomycete genus Campanella, and plant growth-promoting isolates were identified as belonging to the anamorphic ascomycete genus Phoma. However, assigning the sterile strains to any existing species was not possible.

    The main conclusion of the thesis is that species in anamorphic fungi should be defined based on a combination of morphological and molecular methods, both equally important, involving as many aspects of fungal biology as is possible at our current state of knowledge.

    List of papers
    1. The causal agent of anthracnose of Rhododendron in Sweden and Latvia
    Open this publication in new window or tab >>The causal agent of anthracnose of Rhododendron in Sweden and Latvia
    In: Mycological Research, ISSN 0953-7562Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91184 (URN)
    Available from: 2003-12-19 Created: 2003-12-19Bibliographically approved
    2. Presence of Colletotrichum acutatum causing leaf spot on Azalea japonica in Italy
    Open this publication in new window or tab >>Presence of Colletotrichum acutatum causing leaf spot on Azalea japonica in Italy
    2004 (English)In: Plant Disease, ISSN 0191-2917, E-ISSN 1943-7692, Vol. 88, no 5, p. 572-Article in journal (Refereed) Published
    Abstract [en]

    Rhododendron cultivation has a long history in northern Italy where a wide selection of varieties and hybrids are grown. In the fall of 2002, a previously unknown disease was observed on Azalea japonica cv. Palestrina in several commercial farms in the Province of Verbania. Leaves showed irregular necrotic areas that were 1 mm in diameter. Lesions were dark brown to black and were surrounded by a chlorotic halo. Eventually, lesions coalesced, forming large irregular spots. Heavily infected leaves fell prematurely, resulting in severe defoliation. On the infected leaves, acervuli were present from which cylindrical tapered conidia measuring 4.8 to 7.2 × 11.0 to 22.8 μm at one end were released. Fifty conidia per isolate were measured. Fungus identified as Colletotrichum acutatum was consistently recovered from infected leaves, disinfested in 1% NaOCl for 1 min, and plated on potato dextrose agar amended with 100 mg/l of streptomycin sulfate. Pathogenicity of three fungal isolates was confirmed by inoculating healthy A. japonica (cvs. Palestrina and Snow) plants grown in plastic pots (18-cm diameter, 3 liters). Plants (five per treatment) were sprayed with a conidial suspension (1 × 106 conidia per ml) of the three isolates of C. acutatum. Noninoculated plants served as a control. Inoculated and control plants were covered with plastic bags to maintain high relative humidity conditions. All plants were maintained in growth chambers at 20 ± 1°C (12 h per day of fluorescent light). Six days after the artificial inoculation, plants developed typical symptoms on the leaves. C. acutatum was consistently reisolated from infected plants. The pathogenicity test was carried out twice. Sequencing of the internal transcribed spacer region of the rDNA and a portion of the β-tubulin gene were performed, and the obtained sequences were compared with those available in GenBank. Identification of the fungus as C. acutatum, therefore was confirmed. To our knowledge, this is the first report of the presence of C. acutatum on A. japonica in Italy. Although observed presently only in a few nurseries, the disease has the potential to spread, becoming more relevant in an area where rhododendron cultivation is economically important. Anthracnose on rhododendron has already been described in several countries (1,2).

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-91185 (URN)10.1094/PDIS.2004.88.5.572A (DOI)
    Available from: 2003-12-19 Created: 2003-12-19 Last updated: 2017-12-14Bibliographically approved
    3. A study of the type material of Colletotrichum fructigenum
    Open this publication in new window or tab >>A study of the type material of Colletotrichum fructigenum
    In: Mycotaxon, ISSN 0093-4666Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-91186 (URN)
    Available from: 2003-12-19 Created: 2003-12-19Bibliographically approved
    4. What is Glomerella miyabeana?
    Open this publication in new window or tab >>What is Glomerella miyabeana?
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91187 (URN)
    Available from: 2003-12-19 Created: 2003-12-19 Last updated: 2010-01-13Bibliographically approved
    5. A new plant pathogenic Sterile White Basidiomycete from Australia
    Open this publication in new window or tab >>A new plant pathogenic Sterile White Basidiomycete from Australia
    In: European Journal of Plant Pathology, ISSN 0929-1873Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-91188 (URN)
    Available from: 2003-12-19 Created: 2003-12-19Bibliographically approved
    6. Molecular characterization of two plant pathogenic Sterile White Basidiomycetes
    Open this publication in new window or tab >>Molecular characterization of two plant pathogenic Sterile White Basidiomycetes
    In: European Journal of Plant Pathology, ISSN 0929-1873Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-91189 (URN)
    Available from: 2003-12-19 Created: 2003-12-19Bibliographically approved
  • 122. Visser, Sandra A. G.
    et al.
    Sällström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Forsberg, Tomas
    Peletier, Lambertus A.
    Gabrielsson, Johan
    Modeling drug- and system-related changes in body temperature: application to clomethiazole-induced hypothermia, long-lasting tolerance development, and circadian rhythm in rats2006In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 317, no 1, p. 209-219Article in journal (Refereed)
    Abstract [en]

    The aim of the present investigation was to develop a pharmacokinetic-pharmacodynamic model for the characterization of clomethiazole (CMZ)-induced hypothermia and the rapid development of long-lasting tolerance in rats while taking into account circadian rhythm in baseline and the influence of handling. CMZ-induced hypothermia and tolerance was measured using body temperature telemetry in male Sprague-Dawley rats, which were given s.c. bolus injections of 0, 15, 150, 300, and 600 micromol kg(-1) and 24-h s.c. continuous infusions of 0, 20, and 40 micromol kg(-1) h(-1) using osmotic pumps. The duration of tolerance was studied by repeated injections of 300 micromol kg(-1) at 3- to 32-day intervals. Plasma exposure to CMZ was obtained in satellite groups of catheterized rats. Fitted population concentration-time profiles served as input for the pharmacodynamic analysis. The asymmetric circadian rhythm in baseline body temperature was successfully described by a novel negative feedback model incorporating external light-dark conditions. An empirical function characterized the transient increase in temperature upon handling of the animal. A feedback model for temperature regulation and tolerance development allowed estimation of CMZ potency at 30 +/- 1 microM. The delay in onset of tolerance was estimated via a series of four transit compartments at 7.6 +/- 2 h. The long-lasting tolerance was assumed to be caused by inactivation of a mediator with an estimated turnover time of 46 +/- 3 days. This multicomponent turnover model was able to quantify the CMZ-induced hypothermia, circadian rhythm in baseline, and rapid onset of a long-lasting tolerance to CMZ in rats.

  • 123.
    Wallberg, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Systematic Zoology.
    Thollesson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Farris, James S.
    Jondelius, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Systematic Zoology.
    The phylogenetic position of the comb jellies (Ctenophora) and the importance of taxonomic sampling2004In: Cladistics, ISSN 0748-3007, E-ISSN 1096-0031, Vol. 20, no 6, p. 558-578Article in journal (Refereed)
    Abstract [en]

    The transition to a vermiform body shape is one of the most important events in animal evolution, having led to the impressive radiation of Bilateria. However, the sister group of Bilateria has remained obscure. Cladistic analyses of morphology indicate that Ctenophora is the sister group of Bilateria. Previous analyses of SSU rRNA sequences have yielded conflicting results; in many studies Ctenophora forms the sister group of Cnidaria + Bilateria, but in others the ctenophores group with poriferans. Here we re-examine the SSU sequence by analyzing a dataset with 528 metazoan + outgroup sequences, including almost 120 poriferan and diploblast sequences. We use parsimony ratchet and jackknife methods, as well as Bayesian methods, to analyze the data. The results indicate strong phylogenetic signals for a cnidarian + bilaterian group and for the comb jellies to have branched off early within a group uniting all epithelial animals [(Ct,(Cn,Bi))]. We demonstrate the importance of inclusive taxonomic coverage of ribosomal sequences for resolving this problematic part of the metazoan tree: topological stability increases dramatically with the addition of taxa, and the jackknife frequencies of the internal nodes uniting the lineages [(Cn,Bi) and ((Ct,(Cn,Bi))] also increase. We consider the reconstructed topology to represent the current best hypothesis of the interrelationships of these old lineages. Some morphological features supporting alternative hypotheses are discussed in the light of this result.

  • 124. Yu, Bao-Zhu
    et al.
    Apitz-Castro, Rafael J.
    Jain, Mahendra K.
    Berg, Otto G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Role of 57-72 loop in the allosteric action of bile salts on pancreatic IB phospholipase A(2): Regulation of fat and cholesterol homeostasis2007In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1768, no 10, p. 2478-2490Article in journal (Refereed)
    Abstract [en]

    Mono- and biphasic kinetic effects of bile salts on the pancreatic IB phospholipase A2 (PLA2) catalyzed interfacial hydrolysis are characterized. This novel phenomenon is modeled as allosteric action of bile salts with PLA2 at the interface. The results and controls also show that these kinetic effects are not due to surface dilution or solubilization or disruption of the bilayer interface where in the mixed-micelles substrate replenishment becomes the rate-limiting step. The PLA2-catalyzed rate of hydrolysis of zwitterionic dimyristoylphosphatidylcholine (DMPC) vesicles depends on the concentration and structure of the bile salt. The sigmoidal rate increase with cholate saturates at 0.06 mole fraction and changes little at the higher mole fractions. Also, with the rate-lowering bile salts (B), such as taurochenodeoxycholate (TCDOC), the initial sigmoidal rate increase at lower mole fraction is followed by nearly complete reversal to the rate at the pre-activation level at higher mole fractions. The rate-lowering effect of TCDOC is not observed with the (62–66)-loop deleted ΔPLA2, or with the Naja venom PLA2 that is evolutionarily devoid of the loop. The rate increase is modeled with the assumption that the binding of PLA2 to DMPC interface is cooperatively promoted by bile salt followed by allosteric kcat-activation of the bound enzyme by the anionic interface. The rate-lowering effect of bile salts is attributed to the formation of a specific catalytically inert EB complex in the interface, which is noticeably different than the 1:1 EB complex in the aqueous phase. The cholate-activated rate of hydrolysis is lowered by hypolidemic ezetimibe and guggul extract which are not interfacial competitive inhibitors of PLA2. We propose that the biphasic modulation of the pancreatic PLA2 activity by bile salts regulates gastrointestinal fat metabolism and cholesterol homeostasis.

  • 125. Yu, Bao-Zhu
    et al.
    Bai, Shi
    Berg, Otto G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Jain, Mahendra K.
    Allosteric Effect of Amphiphile Binding to Phospholipase A22009In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 48, no 14, p. 3219-3229Article in journal (Refereed)
    Abstract [en]

    In the preceding paper, we showed that the formation of the second premicellar complex of pig pancreatic IB phospholipase A2 (PLA2) can be considered a proxy for interface-activated substrate binding. Here we show that this conclusion is supported by results from premicellar;E-i(#) (i = 1, 2, or 3) complexes with a wide range of mutants of PLA2. Results also show a structural bass-for the correlated functional changes during the formation of E-2(#), and this is interpreted as an allosteric T (inactive) to R (active) transition. For example, the dissociation constant K-2(#) for decylsulfate bound to E-2(#) is lower at lower pH, at higher calcium concentrations, or with an inhibitor bound to the active site. Also, the lower limits of the K-2(#) values are comparable under these conditions. The pH-dependent increase in K-2(#) with a pK(a) of 6.5 is attributed to E71 which participates in the binding of the second calcium which in turn influences the enzyme binding to phosphatidylcholine interface. Most mutants exhibited kinetic and spectroscopic behavior that is comparable to that of native PLA2 and Delta PLA2 with a deleted 62-66 loop. However, the Delta Y52L substitution mutant cannot undergo the calcium-, pH-, or interface-dependent changes. We suggest that the Y52L substitution impairs the R to T transition and also hinders the approach of the Michaelis complex to the transition state. This allosteric change may be mediated by the structural motifs that connect the D48-D99 catalytic diad, the substrate-binding slot, and the residues of the i-face. Our interpretation is that the 57-72 loop and the H48DNCY52 segment of PLA2 are involved in transmitting the effect of the cooperative amphiphile binding to the i-face as a structural change in the active site.

  • 126. Yu, Bao-Zhu
    et al.
    Kaimal, Rajani
    Bai, Shi
    El Sayed, Khalid A.
    Tatulian, Suren A.
    Apitz, Rafael J.
    Jain, Mahendra K.
    Deng, Ruitang
    Berg, Otto G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Effect of Guggulsterone and Cembranoids of Commiphora mukul on Pancreatic Phospholipase A(2): Role in Hypocholesterolemia2009In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 72, no 1, p. 24-28Article in journal (Refereed)
    Abstract [en]

    Guggulsterone (7) and cembranoids (8-12) from Commiphora mukul stem bark resin guggul were shown to be specific modulators of two independent sites that are also modulated by bile salts (1-6) to control cholesterol absorption and catabolism. Guggulsterone (7) antagonized the chenodeoxycholic acid (3)-activated nuclear farnesoid X receptor (FXR), which regulates cholesterol metabolism in the liver. The cembranoids did not show a noticeable effect on FXR, but lowered the cholate (I)-activated rate of human pancreatic 113 phospholipase A2 (hPLA2), which controls gastrointestinal absorption of fat and cholesterol. Analysis of the data using a kinetic model has suggested an allosteric mechanism for the rate increase of hPLA2 by cholate and also for the rate-lowering effect by certain bile salts or cembranoids on the cholate-activated hPLA2 hydrolysis of phosphatidylcholine vesicles. The allosteric inhibition of PLA2 by certain bile salts and cembranoids showed some structural specificity. Biophysical studies also showed specific interaction of the bile salts with the interface-bound cholate-activated PLA2. Since cholesterol homeostasis in mammals is regulated by FXR in the liver for metabolism and by PLA2 in the intestine for absorption, modulation of PLA2 and FXR by bile acids and selected guggul components suggests novel possibilities for hypolipidemic and hypocholesterolemic therapies.

  • 127. Yu, Bao-Zhu
    et al.
    Polenova, Tatyana
    Jain, Mahendra Kumar
    Berg, Otto
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Premicellar complexes of sphingomyelinase mediate enzyme exchange for the stationary phase turnover2005In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1712, no 2, p. 137-151Article in journal (Refereed)
    Abstract [en]

    During the steady state reaction progress in the scooting mode with highly processive turnover, Bacillus cereus sphingomyelinase (SMase) remains tightly bound to sphingomyelin (SM) vesicles (Yu et al., Biochim. Biophys. Acta 1583, 121–131, 2002). In this paper, we analyze the kinetics of SMase-catalyzed hydrolysis of SM dispersed in diheptanoylphosphatidyl-choline (DC7PC) micelles. Results show that the resulting decrease in the turnover processivity induces the stationary phase in the reaction progress. The exchange of the bound enzyme (E*) between the vesicle during such reaction progress is mediated via the premicellar complexes (Ei#) of SMase with DC7PC. Biophysical studies indicate that in Ei# monodisperse DC7PC is bound to the interface binding surface (i-face) of SMase that is also involved in its binding to micelles or vesicles. In the presence of magnesium, required for the catalytic turnover, three different complexes of SMase with monodisperse DC7PC (Ei# with i = 1, 2, 3) are sequentially formed with Hill coefficients of 3, 4 and 8, respectively. As a result, during the stationary phase reaction progress, the initial rate is linear for an extended period and all the substrate in the reaction mixture is hydrolyzed at the end of the reaction progress. At low mole fraction (X) of total added SM, exchange is rapid and the processive turnover is limited by the steps of the interfacial turnover cycle without becoming microscopically limited by local substrate depletion or enzyme exchange. At high X, less DC7PC will be monodisperse, Ei# does not form and the turnover becomes limited by slow enzyme exchange. Transferred NOESY enhancement results show that monomeric DC7PC in solution is in a rapid exchange with that bound to Ei# at a rate comparable to that in micelles. Significance of the exchange and equilibrium properties of the Ei# complexes for the interpretation of the stationary phase reaction progress is discussed.

123 101 - 127 of 127
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