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  • 1.
    Abdulkarim, Farhad
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för molekylärbiologi.
    Tuohy, TMF
    Buckingham, RH
    Hughes, Diarmaid
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för molekylärbiologi.
    Missense substitutions lethal to essential functions of EF-Tu1991Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 73, nr 12, s. 1457-1464Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have used a simple selection and screening method to isolate function defective mutants of EF-Tu. From 28 mutants tested, 12 different missense substitutions, individually lethal to some essential function of EF-Tu, were identified by sequencing. In addition we found a new non-lethal missense mutation. The frequency of isolation of unique mutations suggests that this method can be used to easily isolate many more. The lethal mutations occur in all three structural domains of EF-Tu, but most are in domain II. We aim to use these mutants to define functional domains on EF-Tu.

  • 2.
    Banerjee, Debapriya
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Vovusha, Hakkim
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Pang, Yanhong
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Oumata, Nassima
    Sanyal, Biplab
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Materialteori.
    Sanyal, Suparna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Spectroscopic and DFT studies on 6-Aminophenanthridine and its derivatives provide insights in their activity towards ribosomal RNA2014Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 97, s. 194-199Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    6-Aminophenanthridine (6AP), a plant alkaloid possessing antiprion activity, inhibits ribosomal RNA dependent protein folding activity of the ribosome (referred as PFAR). We have compared 6AP and its three derivatives 6AP8Cl, 6AP8CF3 and 6APi for their activity in inhibition of PFAR. Since PFAR inhibition requires 6AP and its derivatives to bind to the ribosomal RNA (rRNA), we have measured the binding affinity of these molecules to domain V of 23S rRNA using fluorescence spectroscopy. Our results show that similar to the antiprion activity, both the inhibition of PFAR and the affinity towards rRNA follow the order 6AP8CF3 > 6AP8Cl > 6AP, while 6APi is totally inactive. To have a molecular insight for the difference in activity despite similarities in structure, we have calculated the nucleus independent chemical shift using first principles density functional theory. The result suggests that the deviation of planarity in 6APi and steric hindrance from its bulky side chain are the probable reasons which prevent it from interacting with rRNA. Finally, we suggest a probable mode of action of 6AP, 6AP8CF3 and 6AP8Cl towards rRNA.

  • 3.
    Bilgin, Neş'e
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för molekylärbiologi.
    Kirsebom, Leif A
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för molekylärbiologi.
    Ehrenberg, Måns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för molekylärbiologi.
    Kurland, Charles G
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för molekylärbiologi.
    Mutations in ribosomal proteins L7/L12 perturb EF-G and EF-Tu functons1988Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 70, nr 5, s. 611-618Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In vitro cycling rates of E. coli ribosomes and of elongation factors EF-Tu and EF-G have been obtained and these are compatible with translation rates in vivo. We show that the rate of translocation is faster than 50 s-1 and therefore that the EF-G function is not a rate limiting step in protein synthesis. The in vivo phenotype of some L7/L12 mutants could be accounted for by perturbed EF-Tu as well as EF-G functions. The S12 mutants that we studied were, in contrast, only perturbed in their EF-Tu function, while their EF-G interaction was not impaired in relation to wild type ribosomes.

  • 4.
    Dos Reis, Suzana
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Pang, Yanhong
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Vishnu, Neelanjan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Voisset, Cécile
    Galons, Hervé
    Blondel, Marc
    Sanyal, Suparna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Mode of action of the antiprion drugs 6AP and GA on ribosome assisted protein folding2011Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 93, nr 6, s. 1047-1054Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ribosome, the protein synthesis machinery of the cell, has also been implicated in protein folding. This activity resides within the domain V of the main RNA component of the large subunit of the ribosome. It has been shown that two antiprion drugs 6-aminophenanthridine (GAP) and Guanabenz (GA) bind to the ribosomal RNA and inhibit specifically the protein folding activity of the ribosome. Here, we have characterized with biochemical experiments, the mode of inhibition of these two drugs using ribosomes or ribosomal components active in protein folding (referred to as 'ribosomal folding modulators' or RFMs) from both bacteria Escherichia con and yeast Saccharomyces cerevisiae, and human carbonic anhydrase (HCA) as a sample protein. Our results indicate that 6AP and GA inhibit the protein folding activity of the ribosome by competition with the unfolded protein for binding to the ribosome. As a result, the yield of the refolded protein decreases, but the rate of its refolding remains unaffected. Further, 6AP- and GA mediated inhibition of RFM mediated refolding can be reversed by the addition of RFMs in excess. We also demonstrate with delayed addition of the ribosome and the antiprion drugs that there is a short time-span in the range of seconds within which the ribosome interacts with the unfolded protein. Thus we conclude that the protein folding activity of the ribosome is conserved from bacteria to eukaryotes and most likely the substrate for RFMs is an early refolding state of the target protein.

  • 5.
    Ehrenberg, Måns
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Bremer, Hans
    Dennis, Patrick P.
    Medium-dependent control of the bacterial growth rate2013Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 95, nr 4, s. 643-658Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    By combining results from previous studies of nutritional up-shifts we here re-investigate how bacteria adapt to different nutritional environments by adjusting their macromolecular composition for optimal growth. We demonstrate that, in contrast to a commonly held view the macromolecular composition of bacteria does not depend on the growth rate as an independent variable, but on three factors: (i) the genetic background (i.e. the strain used), (ii) the physiological history of the bacteria used for inoculation of a given growth medium, and (iii) the kind of nutrients in the growth medium. These factors determine the ribosome concentration and the average rate of protein synthesis per ribosome, and thus the growth rate. Immediately after a nutritional up-shift, the average number of ribosomes in the bacterial population increases exponentially with time at a rate which eventually is attained as the final post-shift growth rate of all cell components. After a nutritional up-shift from one minimal medium to another minimal medium of higher nutritional quality, ribosome and RNA polymerase syntheses are co-regulated and immediately increase by the same factor equal to the increase in the final growth rate. However, after an up-shift from a minimal medium to a medium containing all 20 amino acids, RNA polymerase and ribosome syntheses are no longer coregulated; a smaller rate of synthesis of RNA polymerase is compensated by a gradual increase in the fraction of free RNA polymerase, possibly due to a gradual saturation of mRNA promoters. We have also analyzed data from a recent publication, in which it was concluded that the macromolecular composition in terms of RNA/protein and RNA/DNA ratios is solely determined by the effector molecule ppGpp. Our analysis indicates that this is true only in special cases and that, in general, medium adaptation also depends on factors other than ppGpp.

  • 6.
    Ehrenberg, Måns
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Dennis, P P
    Bremer, H
    Maximum rrn promoter activity in Escherichia coli at saturating concentrations of free RNA polymerase2010Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 92, nr 1, s. 12-20Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During fast growth, the rrn P1 promoters of Escherichia coli operate at their maximum strength, but below their maximum activity (V-max), since they are not saturated with RNA polymerase. Since higher concentrations of free RNA polymerase are expected to be found in strains carrying rrn deletions, we have analyzed reported electron micrographs of rrn operons from rrn deletion strains growing at maximal rates (at 37 degrees C) in LB medium [1]. We conclude that, in a strain with four of the seven rrn operons inactivated by partial deletions, transcripts are initiated at rrn P1 promoters 1.6-fold more rapidly than in the wild-type strain and the entirety of the rrn operon is transcribed at a 1.5-fold higher average elongation rate due to shortened pauses in the 16S and 23S regions. Under this condition, traffic congestion occurs in front of a pause site in the 5' leader region of the rrn operon near the beginning of the 16S gene; the congestion extends all the way back to the promoter, impedes promoter clearance and limits the promoter activity to one initiation per 0.56 s. This corresponds to a promoter activity of 107 transcripts/min and is assumed to be close to the V-max of rrn P1 promoters.

  • 7.
    Fange, David
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Lovmar, Martin
    Pavlov, Michael Y.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Ehrenberg, Måns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Identification of enzyme inhibitory mechanisms from steady-state kinetics2011Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 93, nr 9, s. 1623-1629Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Enzyme inhibitors are used in many areas of the life sciences, ranging from basic research to the combat of disease in the clinic. Inhibitors are traditionally characterized by how they affect the steady-state kinetics of enzymes, commonly analyzed on the assumption that enzyme-bound and free substrate molecules are in equilibrium. This assumption, implying that an enzyme-bound substrate molecule has near zero probability to form a product rather than dissociate, is valid only for very inefficient enzymes. When it is relaxed, more complex but also more information-rich steady-state kinetics emerges. Although solutions to the general steady-state kinetics problem exist, they are opaque and have been of limited help to experimentalists. Here we reformulate the steady-state kinetics of enzyme inhibition in terms of new parameters. These allow for assessment of ambiguities of interpretation due to kinetic scheme degeneracy and provide an intuitively simple way to analyze experimental data. We illustrate the method by concrete examples of how to assess scheme degeneracy and obtain experimental estimates of all available rate and equilibrium constants. We suggest simple, complementary experiments that can remove ambiguities and greatly enhance the accuracy of parameter estimation.

  • 8.
    Freyhult, Eva
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.
    Cui, Yuanyuan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.
    Nilsson, Olle
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.
    Ardell, David H.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.
    New computational methods reveal tRNA identity element divergence between Proteobacteria and Cyanobacteria2007Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 89, nr 10, s. 1276-1288Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There are at least 21 subfunctional classes of tRNAs in most cells that, despite a very highly conserved and compact common structure, must interact specifically with different cliques of proteins or cause grave organismal consequences. Protein recognition of specific tRNA substrates is achieved in part through class-restricted tRNA features called tRNA identity determinants. In earlier work we used TFAM, a statistical classifier of tRNA function, to show evidence of unexpectedly large diversity among bacteria in tRNA identity determinants. We also created a data reduction technique called function logos to visualize identity determinants for a given taxon. Here we show evidence that determinants for lysylated isoleucine tRNAs are not the same in Proteobacteria as in other bacterial groups including the Cyanobacteria. Consistent with this, the lysylating biosynthetic enzyme TilS lacks a C-terminal domain in Cyanobacteria that is present in Proteobacteria. We present here, using function logos, a map estimating all potential identity determinants generally operational in Cyanobacteria and Proteobacteria. To further isolate the differences in potential tRNA identity determinants between Proteobacteria and Cyanobacteria, we created two new data reduction visualizations to contrast sequence and function logos between two taxa. One, called Information Difference logos (ID logos), shows the evolutionary gain or retention of functional information associated to features in one lineage. The other, Kullback–Leibler divergence Difference logos (KLD logos), shows recruitments or shifts in the functional associations of features, especially those informative in both lineages. We used these new logos to specifically isolate and visualize the differences in potential tRNA identity determinants between Proteobacteria and Cyanobacteria. Our graphical results point to numerous differences in potential tRNA identity determinants between these groups. Although more differences in general are explained by shifts in functional association rather than gains or losses, the apparent identity differences in lysylated isoleucine tRNAs appear to have evolved through both mechanisms.

  • 9. Hammann, Philippe
    et al.
    Parmentier, Delphine
    Cerciat, Marie
    Reimegård, Johan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    Helfer, Anne-Catherine
    Boisset, Sandrine
    Guillier, Maude
    Vandenesch, Francois
    Wagner, Gerhart H.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Romby, Pascale
    Fechter, Pierre
    A method to map changes in bacterial surface composition induced by regulatory RNAs in Escherichia coli and Staphylococcus aureus2014Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 106C, s. 175-179Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have adapted a method to map cell surface proteins and to monitor the effect of specific regulatory RNAs on the surface composition of the bacteria. This method involves direct labeling of surface proteins of living bacteria using fluorescent dyes and a subsequent separation of the crude extract by 2D gel electrophoresis. The strategy yields a substantial enrichment in surface proteins over cytoplasmic proteins. We validated this method by monitoring the effect of the regulatory RNA MicA in Escherichia colt, which regulates the synthesis of several outer membrane proteins, and highlighted the role of Staphylococcus aureus RNAIII for the maintenance of cell wall integrity.

    Fulltekst (pdf)
    fulltext
  • 10.
    Harish, Ajith
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Strukturbiologi.
    Kurland, Charles
    Lund Univ, Dept Biol, Lund, Sweden.
    Reply to Caetano-Anolles et al. comment on "Empirical genome evolution models root the tree of life"2018Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 149, s. 137-138Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    We recently analyzed the robustness of competing evolution models developed to identify the root of the Tree of Life: 1) An empirical Sankoff parsimony (ESP) model (Harish and Kurland, 2017), which is a nonstationary and directional evolution model; and 2) An a priori ancestor (APA) model (Kim and Caetano-Anolles, 2011) that is a stationary and reversible evolution model. Both Bayesian model selection tests as well as maximum parsimony analyses demonstrate that the ESP model is, overwhelmingly, the better model. Moreover, we showed that the APA model is not only sensitive to artifacts, but also that the underlying assumptions are neither empirically grounded nor biologically realistic.

  • 11.
    Harish, Ajith
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Kurland, Charles G.
    Lund Univ, Microbial Ecol Program, Dept Biol, Lund, Sweden..
    Akaryotes and Eukaryotes are independent descendants of a universal common ancestor2017Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 138, s. 168-183Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We reconstructed a global tree of life (ToL) with non-reversible and non-stationary models of genome evolution that root trees intrinsically. We implemented Bayesian model selection tests and compared the statistical support for four conflicting ToL hypotheses. We show that reconstructions obtained with a Bayesian implementation (Klopfstein et al., 2015) are consistent with reconstructions obtained with an empirical Sankoff parsimony (ESP) implementation (Harish et al., 2013). Both are based on the genome contents of coding sequences for protein domains (superfamilies) from hundreds of genomes. Thus, we conclude that the independent descent of Eukaryotes and Akaryotes (archaea and bacteria) from the universal common ancestor (UCA) is the most probable as well as the most parsimonious hypothesis for the evolutionary origins of extant genomes. Reconstructions of ancestral proteomes by both Bayesian and ESP methods suggest that at least 70% of unique domain-superfamilies known in extant species were present in the UCA. In addition, identification of a vast majority (96%) of the mitochondrial superfamilies in the UCA proteome precludes a symbiotic hypothesis for the origin of eukaryotes. Accordingly, neither the archaeal origin of eukaryotes nor the bacterial origin of mitochondria is supported by the data. The proteomic complexity of the UCA suggests that the evolution of cellular phenotypes in the two primordial lineages, Akaryotes and Eukaryotes, was driven largely by duplication of common superfamilies as well as by loss of unique superfamilies. Finally, innovation of novel superfamilies has played a surprisingly small role in the evolution of Akaryotes and only a marginal role in the evolution of Eukaryotes.

  • 12.
    Harish, Ajith
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Kurland, Charles G.
    Lund Univ, Microbial Ecol Program, Dept Biol, Lund, Sweden..
    Empirical genome evolution models root the tree of life2017Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 138, s. 137-155Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A reliable phylogenetic reconstruction of the evolutionary history of contemporary species depends on a robust identification of the universal common ancestor (UCA) at the root of the Tree of Life (ToL). That root polarizes the tree so that the evolutionary succession of ancestors to descendants is discernable. In effect, the root determines the branching order and the direction of character evolution. Typically, conventional phylogenetic analyses implement time-reversible models of evolution for which character evolution is un-polarized. Such practices leave the root and the direction of character evolution undefined by the data used to construct such trees. In such cases, rooting relies on theoretic assumptions and/or the use of external data to interpret unrooted trees. The most common rooting method, the outgroup method is clearly inapplicable to the ToL, which has no outgroup. Both here and in the accompanying paper (Harish and Kurland, 2017) we have explored the theoretical and technical issues related to several rooting methods. We demonstrate (1) that Genome-level characters and evolution models are necessary for species phylogeny reconstructions. By the same token, standard practices exploiting sequence-based methods that implement gene-scale substitution models do not root species trees; (2) Modeling evolution of complex genomic characters and processes that are non-reversible and non-stationary is required to reconstruct the polarized evolution of the ToL; (3) Rooting experiments and Bayesian model selection tests overwhelmingly support the earlier finding that akaryotes and eukaryotes are sister clades that descend independently from UCA (Harish and Kurland, 2013); (4) Consistent ancestral state reconstructions from independent genome samplings confirm the previous finding that UCA features three fourths of the unique protein domain-superfamilies encoded by extant genomes.

  • 13.
    Hauryliuk, Vasili
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Zavialov, Andrey
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Kisselev, Lev
    Ehrenberg, Måns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Class-1 release factor eRF1 promotes GTP binding by class-2 release factor eRF32006Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 88, nr 7, s. 747-757Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In eukaryotes, termination of mRNA translation is triggered by the essential polypeptide chain release factors eRF1, recognizing all three stop codons, and eRF3, a member of the GTPase superfamily with a role that has remained opaque. We have studied the kinetic and thermodynamic parameters of the interactions between eRF3 and GTP, GDP and the non-hydrolysable GTP analogue GDPNP in the presence (K-D(GDP) = 1.3 +/- 0.2 mu M, K-D(GTP) approximate to 200 mu M and K-D(GDPNP) > 160 mu M) as well as absence (K-D(GDP) = 1.9 +/- 0.3 mu M, K-D(GTP) 0.7 +/- 0.2 mu M and K-D(GDPNP) approximate to 200 mu M) of eRF1. From the present data we propose that (i) free eRF3 has a strong preference to bind GDP compared to GTP (ii) eRF3 in complex with eRF1 has much stronger affinity to GTP than free eRF3 (iii) eRF3 in complex with PABP has weak affinity to GTP (iv) eRF3 in complex with eRF1 does not have strong affinity to GDPNP, implying that GDPNP is a poor analogue of GTP for eRF3 binding.

  • 14.
    Kirsebom, Leif A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    RNase P RNA mediated cleavage: substrate recognition and catalysis2007Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 89, nr 10, s. 1183-1194Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The universally conserved endoribonuclease P consists of one RNA subunit and, depending on its origin, a variable number of protein subunits. RNase P is involved in the processing of a large variety of substrates in the cell, the preferred substrate being tRNA precursors. Cleavage activity does not require the presence of the protein subunit(s) in vitro. This is true for both prokaryotic and eukaryotic RNase P RNA suggesting that the RNA based catalytic activity has been preserved during evolution. Progress has been made in our understanding of the contribution of residues and chemical groups both in the substrate as well as in RNase P RNA to substrate binding and catalysis. Moreover, we have access to two crystal structures of bacterial RNase P RNA but we still lack the structure of RNase P RNA in complex with its substrate and/or the protein subunit. Nevertheless, these recent advancements put us in a new position to study the way and nature of interactions between in particular RNase P RNA and its substrate. In this review I will discuss various aspects of the RNA component of RNase P with an emphasis on our current understanding of the interaction between RNase P RNA and its substrate.

  • 15. Kurland, Charles G.
    et al.
    Canbäck, Björn
    Berg, Otto G.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    The origins of modem proteomes2007Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 89, nr 12, s. 1454-1463Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Distributions of phylogenetically related protein domains (fold superfamilies), or FSFs, among the three Superkingdoms (trichotomy) are assessed. Very nearly 900 of the 1200 FSFs of the trichotomy are shared by two or three Superkingdoms. Parsimony analysis of FSF distributions suggests that the FSF complement of the last common ancestor to the trichotomy was more like that of modem eukaryotes than that of archaea and bacteria. Studies of length distributions among members of orthologous families of proteins present in all three Superkingdoms reveal that such lengths are significantly longer among eukaryotes than among bacteria and archaea. The data also reveal that proteins lengths of eukaryotes are more broadly distributed than they are within archaeal and bacterial members of the same orthologous families. Accordingly, selective pressure for a minimal size is significantly greater for orthologous protein lengths in archaea and bacteria than in eukaryotes. Alignments of orthologous proteins of archaea, bacteria and eukaryotes are characterized by greater sequence variation at their N-terminal and C-terminal domains, than in their central cores. Length variations tend to be localized in the terminal sequences; the conserved sequences of orthologous families are localized in a central core. These data are consistent with the interpretation that the genomes of the last common ancestor (LUCA) encoded a cohort of FSFs not very different from that of modem eukaryotes. Divergence of bacterial and archaeal genomes from that common ancestor may have been accompanied by more intensive reductive evolution of proteomes than that expressed in eukaryotes. Dollo's Law suggests that the evolution of novel FSFs is a very slow process, while laboratory experiments suggests that novel protein genesis from preexisting FSFs can be relatively rapid. Reassortment of FSFs to create novel proteins may have been mediated by genetic recombination before the advent of more efficient splicing mechanisms.

  • 16.
    Kurland, Charles G.
    et al.
    Lund Univ, Dept Biol, Microbial Ecol, SE-22362 Lund, Sweden..
    Harish, Ajith
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Structural biology and genome evolution: An introduction2015Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 119, s. 205-208Artikkel i tidsskrift (Annet vitenskapelig)
  • 17.
    Kurland, Charles G.
    et al.
    Lund Univ, Microbial Ecol, Dept Biol, SE-22362 Lund, Sweden..
    Harish, Ajith
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    The phylogenomics of protein structures: The backstory2015Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 119, s. 284-302Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    In this introductory retrospective, evolution as viewed through gene trees is inspected through a lens compounded from its founding operational assumptions. The four assumptions of the gene tree culture that are singularly important to evolutionary interpretations are: a. that protein-coding sequences are molecular fossils; b. that gene trees are equivalent to species trees; c. that the tree of life is assumed to be rooted in a simple akaryote cell implying that akaryotes are primitive, and d. that the notion that all or most incongruities between alignment-based gene trees are due to horizontal gene transfer (HGT), which includes the endosymbiotic models postulated for the origins of eukaryotes. What has been unusual about these particular assumptions is that though each was taken on board explicitly, they are defended in the face of factual challenge by a stolid disregard for the conflicting observations. The factual challenges to the mainstream gene tree-inspired evolutionary view are numerous and most convincingly summarized as: Genome trees tell a very different story. Phylogeny inferred from genomic assortments of homologous protein structural-domains does not support any one of the four principle evolutionary interpretations of gene trees: a. 3D protein domain structures are the molecular fossils of evolution, while coding sequences are transients; b. Species trees are very different from gene trees; c. The ToL is rooted in a surprisingly complex universal common ancestor (UCA) that is distinct from any specific modern descendant and d. HGT including endosymbiosis is a negligible player in genome evolution from UCA to the present.

  • 18.
    Lovmar, Martin
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Ehrenberg, Måns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Rate, accuracy and cost of ribosomes in bacterial cells2006Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 88, nr 8, s. 951-961Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent biochemical data on the rate of peptidyl-transfer and missense error levels associated with the E. coli ribosome in conjunction with direct measurements of diffusion constants for proteins in the E. coli cell have been used to discuss protein synthesis in the living E. coli cell in the perspective of a previously developed maximal fitness theory. With these improved experimental parameters, i.e. k(cat) similar to 50 s(-1) for protein elongation and k(cat)/K-M similar to 4 mu M-1 s(-1) for cognate ternary complex binding to the ribosomal A site, theory predicts the experimentally observed variations in protein elongation rate, ribosome and ternary complex concentrations with varying quality of the growth medium. The theoretically predicted average missense error level is close the error levels estimated in vitro for special isoacceptor combinations, i.e. error levels about I per million. The future prospect of extensive integration of biochemistry, cell physiology and population genetics is discussed in the light of the maximal fitness theory and other, similar, theoretical approaches.

  • 19.
    Lovmar, Martin
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylärbiologi.
    Vimberg, Vladimir
    Institute of Technology, University of Tartu, Tartu, Estonia.
    Lukk, Eliisa
    Institute of Technology, University of Tartu, Tartu, Estonia.
    Nilsson, Karin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylärbiologi.
    Tenson, Tanel
    Institute of Technology, University of Tartu, Tartu, Estonia.
    Ehrenberg, Måns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylärbiologi.
    Cis-acting resistance peptides reveal dual ribosome inhibitory action of the macrolide josamycin2009Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 91, nr 8, s. 989-995Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Macrolide antibiotics block the entrance of nascent peptides to the peptide exit tunnel of the large ribosomal subunit. Expression of specific cis-acting peptides confers low-level macrolide-resistance. We show that, in the case of josamycin, peptide expression does not eject josamycin from the ribosome, implying a peptide resistance mechanism different from that previously suggested for erythromycin. We find dipeptide formation and dipeptidyl-tRNA drop-off in the presence of josamycin to be much slower during translation of resistance than of control mRNAs. We demonstrate low-level josamycin resistance by over-expression of peptidyl-tRNA hydrolase. These findings suggest dual growth-inhibitory action of josamycin by (i) direct inhibition of peptide-elongation and (ii) indirect inhibition of peptide-elongation through rapid peptidyl-tRNA drop-off, leading to depletion of tRNA isoacceptors available for protein synthesis. We propose that josamycin resistance peptide expression brings ribosomes into a "quarantine" state with small drop-off rate, thereby eliminating the josamycin dependent depletion of tRNA isoacceptors in the protein-synthesis-active state.

  • 20. Lu, Anrui
    et al.
    Li, Xuquan
    Hillyer, Julian E.
    Beerntsen, Brenda T.
    Söderhäll, Kenneth
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Jämförande fysiologi.
    Ling, Erjun
    Recombinant Drosophila prophenoloxidase 1 is sequentially cleaved by alpha-chymotrypsin during in vitro activation2014Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 102C, s. 154-165Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insect prophenoloxidase (PPO) is an essential innate immunity protein to induce pathogen into melanization. In Bombyx mori, pro-phenoloxidase-activating enzyme (PPAE) can directly cleave and activate PPO. However, PPO in Manduca sexta cannot be cleaved into active phenoloxidase (PO) by serine proteases unless cofactors are involved, which indicates that PPO activation is complicated. Here we use recombinant Drosophila melanogaster prophenoloxidase 1 (rPPO1) to study the mechanism of PPO activation induced by a typical serine protease, alpha-chymotrypsin. Small amounts of alpha-chymotrypsin cleave rPPO1 at the N- and C-terminus to produce a large fragment rPPO1(N1/C1) that needs further cleavage by alpha-chymotrypsin to produce a smaller fragment rPO1(60-kD) with PO activity. rPO1(60-kD) oxidizes dopamine without being affected by high temperature, or by having salt and Ethylene diamine tetraacetic acid (EDTA) in the solution. After incubation with dopamine, rPO1(60-kD) cannot be detected using reducing SDS-PAGE due to formation of a large complex. Trypsin, another typical serine protease, cleaves rPPO1 at the N- and C-terminus to produce a small fragment rPPO1(N'/C') without PO activity. Several rPPO1 mutants were created through over-expressing active fragments that have direct PO activity. They are easily cleaved by low amounts of alpha-chymotrypsin without increasing PO activity. Therefore, rPPO1 can be sequentially cleaved in at least three places by alpha-chymotrypsin to produce activated rPO1(60-kD). 

  • 21.
    Ntika, Stelia
    et al.
    Sodertalje Hosp, Dept Res, STS Biovat, SE-15286 Sodertalje, Sweden;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Thombare, Ketan
    Sodertalje Hosp, Dept Res, STS Biovat, SE-15286 Sodertalje, Sweden.
    Aryapoor, Masood
    Sodertalje Hosp, Dept Res, STS Biovat, SE-15286 Sodertalje, Sweden.
    Kristinsson, Hjalti
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Krizhanovskii, Camilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Sodertalje Hosp, Dept Res, STS Biovat, SE-15286 Sodertalje, Sweden;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Oleate increase neutral lipid accumulation, cellular respiration and rescues palmitate-exposed GLP-1 secreting cells by reducing ceramide-induced ROS2019Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 159, s. 23-35Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Fatty acids (FAs), and especially monounsaturated FAs (MUFAs) stimulate GLP-1 release. However, lipotoxicity is indicated in GLP-1 secreting cells following long-term exposure to elevated levels of saturated FAs (SFAs) in vivo and in vitro, where in vitro studies indicate that cosupplementation with MUFAs confers lipoprotection. SFAs and MUFAs differentially affect the fate of cells in ways that depend on the cell type, concentration and ratio of the FAs. The present study was designed to further elucidate the mechanisms underlying the effects of SFAs/MUFAs on GLP-1-producing cells in terms of lipotoxicity/lipoprotection and GLP-1 secretion.

    Methods: Cultured GLP-1 secreting cells were exposed to hyperlipidemia simulated by SFA-albumin complexes where the molar ratio was 2:1. The cellular response to simulated hyperlipidemia was assessed in the presence/absence of MUFA cosupplementation by determining intracellular ceramide, ROS, neutral lipid accumulation, and cellular respiration. The role for cellular respiration in GLP-1 secretion in response to SFAs/MUFAs was assessed.

    Results: Generation of intracellular ceramide mediate a detrimental increased in ROS production following long term exposure to SFAs in GLP-1-secreting cells. Cosupplementation with MUFAs increases cellular respiration, triglyceride synthesis, and the expression of ceramide kinase, while reducing ceramide synthesis and attenuating ROS production, caspase-3 activity and DNA fragmentation. Further, acute secretory effects of unsaturated FAs are independent of FAO, but mediated by a FFAR1 induced increase in cellular respiration.

    Conclusion: This study demonstrates novel data supporting effects of MUFAs on the ceramide biosynthetic pathway, triglyceride storage respiration and secretion in GLP-1 secreting cells. These findings may be of value for nutritional interventions, as well as for identification of novel targets, to help preserve L-cell mass and potentiate GLP-1 secretion in diabesity.

  • 22. Olson, Steven T.
    et al.
    Richard, Benjamin
    Izaguirre, Gonzalo
    Schedin-Weiss, Sophia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Gettins, Peter G. W.
    Molecular mechanisms of antithrombin-heparin regulation of blood clotting proteinases. A paradigm for understanding proteinase regulation by serpin family protein proteinase inhibitors2010Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 92, nr 11, s. 1587-1596Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Serpin family protein proteinase inhibitors regulate the activity of serine and cysteine proteinases by a novel conformational trapping mechanism that may itself be regulated by cofactors to provide a finely-tuned time and location-dependent control of proteinase activity. The serpin, antithrombin, together with its cofactors, heparin and heparan sulfate, perform a critical anticoagulant function by preventing the activation of blood clotting proteinases except when needed at the site of a vascular injury. Here, we review the detailed molecular understanding of this regulatory mechanism that has emerged from numerous X-ray crystal structures of antithrombin and its complexes with heparin and target proteinases together with mutagenesis and functional studies of heparin-antithrombin-proteinase interactions in solution. Like other serpins, antithrombin achieves specificity for its target blood clotting proteinases by presenting recognition determinants in an exposed reactive center loop as well as in exosites outside the loop. Antithrombin reactivity is repressed in the absence of its activator because of unfavorable interactions that diminish the favorable RCL and exosite interactions with proteinases. Binding of a specific heparin or heparan sulfate pentasaccharide to antithrombin induces allosteric activating changes that mitigate the unfavorable interactions and promote template bridging of the serpin and proteinase. Antithrombin has thus evolved a sophisticated means of regulating the activity of blood clotting proteinases in a time and location-dependent manner that exploits the multiple conformational states of the serpin and their differential stabilization by glycosaminoglycan cofactors.

  • 23.
    Patrick, Michael
    et al.
    Univ Wisconsin Madison, Dept Med Genet, Madison, WI USA..
    Dennis, Patrick P.
    Howard Hughes Med Inst, Ashburn, VA USA..
    Ehrenberg, Måns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Bremer, Hans
    Univ Texas Dallas, Dept Mol & Cell Biol, Dallas, TX 75230 USA..
    Free RNA polymerase in Escherichia coli2015Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 119, s. 80-91Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The frequencies of transcription initiation of regulated and constitutive genes depend on the concentration of free RNA polymerase holoenzyme [R-f] near their promoters. Although RNA polymerase is largely confined to the nucleoid, it is difficult to determine absolute concentrations of [R-f] at particular locations within the nucleoid structure. However, relative concentrations of free RNA polymerase at different growth rates, [R-f](rel), can be estimated from the activities of constitutive promoters. Previous studies indicated that the rrnB P2 promoter is constitutive and that [R-f](rel) in the vicinity of rrnB P2 increases with increasing growth rate. Recently it has become possible to directly visualize Rf in growing Escherichia col cells. Here we examine some of the important issues relating to gene expression based on these new observations. We conclude that: (i) At a growth rate of 2 doublings/h, there are about 1000 free and 2350 non-specifically DNA-bound RNA polymerase molecules per average cell (12 and 28%, respectively, of 8400 total) which are in rapid equilibrium. (ii) The reversibility of the non-specific binding generates more than 1000 free RNA polymerase molecules every second in the immediate vicinity of the DNA. Of these, most rebind non-specifically to the DNA within a few ms; the frequency of non-specific binding is at least two orders of magnitude greater than specific binding and transcript initiation. (iii) At a given amount of RNA polymerase per cell, [R-f] and the density of non-specifically DNA-bound RNA polymerase molecules along the DNA both vary reciprocally with the amount of DNA in the cell. (iv) At 2 doublings/h an E. coli cell contains, on the average, about 1 non-specifically bound RNA polymerase per 9 kbp of DNA and 1 free RNA polymerase per 20 kbp of DNA. However some DNA regions (i.e. near active rRNA operons) may have significantly higher than average [R-f].

  • 24.
    Rath, Devashish
    et al.
    Bhabha Atom Res Ctr, Div Mol Biol, Mumbai 400085, Maharashtra, India..
    Amlinger, Lina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi. Uppsala Univ, Dept Cell & Mol Biol, SE-75124 Uppsala, Sweden..
    Rath, Archana
    Univ Mumbai, Dept Biotechnol, Mumbai 400098, Maharashtra, India..
    Lundgren, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    The CRISPR-Cas immune system: Biology, mechanisms and applications2015Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 117, s. 119-128Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Viruses are a common threat to cellular life, not the least to bacteria and archaea who constitute the majority of life on Earth. Consequently, a variety of mechanisms to resist virus infection has evolved. A recent discovery is the adaptive immune system in prokaryotes, a type of system previously thought to be present only in vertebrates. The system, called CRISPR-Cas, provide sequence-specific adaptive immunity and fundamentally affect our understanding of virus host interaction. CRISPR-based immunity acts by integrating short virus sequences in the cell's CRISPR locus, allowing the cell to remember, recognize and clear infections. There has been rapid advancement in our understanding of this immune system and its applications, but there are many aspects that await elucidation making the field an exciting area of research. This review provides an overview of the field and highlights unresolved issues.

    Fulltekst (pdf)
    fulltext
  • 25.
    Spillmann, Dorothe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Heparan sulfate: anchor for viral intruders?2001Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 83, nr 8, s. 811-817Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Heparan sulfates (HS) are ubiquitous, polyanionic carbohydrate chains linked to core proteins in cell membranes and extracellular matrices of all eukaryotes. Due to the complex nature of the HS-biosynthesis, a wealth of different structures are produced. These seem to have a well defined distribution in different tissues and cells throughout development. Binding of endogenous proteins with different functional properties such as growth factors, adhesion molecules or enzymes, is one of the functions of HS. Besides interaction with endogenous factors, glycosaminoglycans (GAG) and especially HS have also been demonstrated to function as receptors for a number of different pathogens. What roles may HS play in the pathogenesis and tropism of different intruders like parasites or viruses? What implications does binding of viruses to HS have for the development of drugs or the application of viral vectors for gene targeting? In this review an attempt is made to collect our present knowledge on viral usage of HS and the implications that follow.

  • 26.
    Thuresson, Ann-Charlotte
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Kirsebom, Leif A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Virtanen, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Inhibition of poly(A) polymerase by aminoglycosides2007Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 89, nr 10, s. 1221-1227Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aminoglycosides are potent inhibitors of bacterial growth and are used clinically as antibiotics. However, their usage has declined in recent years due to the emergence of resistance and severe toxic side effects. Here we show that human poly(A) polymerase gamma (PAPgamma) is inhibited by aminoglycosides. The inhibition was pH dependent and could be released by Mg(II) ions in a competitive manner suggesting that electrostatic interactions are important for inhibition and that the binding sites for aminoglycosides overlap with Mg(II) ion binding sites. Kinetic analysis revealed that aminoglycosides of the neomycin and kanamycin families behaved as mixed non-competitive inhibitors for the PAPgamma substrates oligoA15 and ATP. Interestingly, sisomicin and 5-epi-sisomycin showed a competitive mechanism of inhibition for the oligoA15 whereas they inhibited the ATP substrate mixed non-competitive. This implies that different aminoglycosides bind in different ways to a common binding pocket and suggests that the binding sites for related aminoglycosides are not overlapping even if they may share molecular determinants. Our study emphasizes the possibility that aminoglycoside toxicity could be due to interference with housekeeping enzymes involved in breaking and forming phosphodiester bonds.

  • 27.
    Tomkinson, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Tripeptidyl-peptidase II: Update on an oldie that still counts2019Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 166, s. 27-37Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The huge exopeptidase, tripeptidyl-peptidase II (TPP II), appears to be involved in a large number of important biological processes. It is present in the cytosol of most eukaryotic cells, where it removes tripeptides from free amino termini of longer peptides through a 'molecular ruler mechanism'. Its main role appears to be general protein degradation, together with the proteasome. The activity is increased by stress, such as during starvation and muscle wasting, and in tumour cells. Overexpression of TPP II leads to accelerated cell growth, genetic instability and resistance to apoptosis, whereas inhibition or down-regulation of TPP II renders cells sensitive to apoptosis. Although it seems that humans can survive without TPP II, it is not without consequences. Recently, patients with loss-of-function mutations in the TPP2 gene have been identified. They suffer from autoimmunity leading to leukopenia and other consequences. Furthermore, a missense mutation in the TPP2 gene is associated with a sterile brain inflammation condition mimicking multiple sclerosis. This review will summarise what is known today regarding the activity and structure of this very large enzyme complex, and its potential function in various cellular processes. It is clear that more research is needed to identify natural substrates and/or interaction partners of TPP II, which can explain the observed effects in different cellular contexts.

    Fulltekst (pdf)
    FULLTEXT01
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