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Why are behaviors of children suffering from various neuronopathic types of mucopolysaccharidoses different?
Get PDFMucopolysaccharidoses (MPS) are inherited metabolic disorders from the group of lysosomal storage diseases
(LSD). They arise from mutations causing dysfunction of one of enzymes involved in degradation of
glycosaminoglycans (GAGs) in lysosomes. Impaired degradation of these compounds results in their
accumulation in cells and dysfunction of most tissues and organs of patients. If heparan sulfate (HS) is
the sole or one of stored GAGs, brain functions are also affected. However, despite the fact that products
of incomplete degradation of the same chemical, HS, are accumulated in brains of patients suffering from
Hurler disease (MPS type I), Hunter disease (MPS type II), Sanfilippo disease (MPS type III) and Sly disease
(MPS type VII), and obvious deterioration of brain functions occur in these patients, their behavior is considerably
different between various types of MPS. Here we asked the question about biochemical reasons
of these differences. We performed theoretical analysis of products of incomplete HS degradation that
accumulate in tissues of patients diagnosed for these diseases. A correlation between chemical structures
of incompletely degraded HS and behaviors of patients suffering from particular MPS types was found.
We propose a hypothesis that particular chemical moieties occurring at the ends of incompletely
degraded HS molecules may determine characteristic behavioral disturbances, perhaps due to chemical
reactions interfering with functions of neurons in the brain. A possible experimental testing of this
hypothesis is also proposed. If the hypothesis is true, it might shed some new light on biochemical mechanisms
of behavioral problems occurring not only in MPS but also in some other diseases
RNA channelling by the eukaryotic exosome
Get PDFThe eukaryotic exosome is a key nuclease for the degradation, processing and quality control of a wide variety of RNAs. Here, we report electron microscopic reconstructions and pseudo-atomic models of the ten-subunit Saccharomyces cerevisiae exosome in the unbound and RNA-bound states. In the RNA-bound structures, extra density that is visible at the entry and exit sites of the exosome channel indicates that a substrate-threading mechanism is used by the eukaryotic exosome. This channelling mechanism seems to be conserved in exosome-like complexes from all domains of life, and might have been present in the most recent common ancestor
Transcription regulation of the Escherichia coli pcnB gene coding for poly(A) polymerase I: roles of ppGpp, DksA and sigma factors
Get PDFPoly(A) polymerase I (PAP I), encoded by the
pcnB gene, is a major enzyme responsible for RNA polyadenylation in Escherichia coli, a process involved in the global control of gene expression in this bacterium through inXuencing the rate of transcript degradation. Recent studies have suggested a complicated regulation of pcnB expression, including a complex promoter region, a control at the level of translation initiation and dependence on bacterial growth rate. In this report, studies on transcription regulation of the pcnB gene are described. Results of in vivo and in vitro experiments indicated that (a) there are three �70-dependent (p1, pB, and p2) and two �S-dependent (pS1 and pS2) promoters of the pcnB gene, (b) guanosine tetraphosphate (ppGpp) and DksA directly inhibit transcription from pB, pS1 and pS2, and (c) pB activity is drastically impaired at the stationary phase of growth. These results indicate that regulation of the pcnB gene transcription is a complex process, which involves several factors acting to ensure precise control of PAP I production. Moreover, inhibition of activities of pS1 and pS2 by ppGpp and DksA suggests that regulation of transcription from promoters requiring alternative � factors by these eVectors of the stringent response might occur according to both passive and active models
Why are behaviors of children suffering from various neuronopathic types of mucopolysaccharidoses different?
Get PDFMucopolysaccharidoses (MPS) are inherited metabolic disorders from the group of lysosomal storage diseases
(LSD). They arise from mutations causing dysfunction of one of enzymes involved in degradation of
glycosaminoglycans (GAGs) in lysosomes. Impaired degradation of these compounds results in their
accumulation in cells and dysfunction of most tissues and organs of patients. If heparan sulfate (HS) is
the sole or one of stored GAGs, brain functions are also affected. However, despite the fact that products
of incomplete degradation of the same chemical, HS, are accumulated in brains of patients suffering from
Hurler disease (MPS type I), Hunter disease (MPS type II), Sanfilippo disease (MPS type III) and Sly disease
(MPS type VII), and obvious deterioration of brain functions occur in these patients, their behavior is considerably
different between various types of MPS. Here we asked the question about biochemical reasons
of these differences. We performed theoretical analysis of products of incomplete HS degradation that
accumulate in tissues of patients diagnosed for these diseases. A correlation between chemical structures
of incompletely degraded HS and behaviors of patients suffering from particular MPS types was found.
We propose a hypothesis that particular chemical moieties occurring at the ends of incompletely
degraded HS molecules may determine characteristic behavioral disturbances, perhaps due to chemical
reactions interfering with functions of neurons in the brain. A possible experimental testing of this
hypothesis is also proposed. If the hypothesis is true, it might shed some new light on biochemical mechanisms
of behavioral problems occurring not only in MPS but also in some other diseases
Infuence of the Escherichia coli oxyR gene function on lambda prophage maintenance
Get PDFIn Escherichia coli hosts, hydrogen peroxide is
one of the factors that may cause induction of lambda prophage.
Here, we demonstrate that H2O2-mediated lambda prophage
induction is signiWcantly enhanced in the oxyR mutant host.
The mRNA levels for cI gene expression were increased in
a lambda lysogen in the presence of H2O2. On the other hand,
stimulation of the pM promoter by cI857 overproduced
from a multicopy plasmid was decreased in the lambda oxyR
mutant in the presence of H2O2 but not under normal
growth conditions. The puriWed OxyR protein did bind
speciWcally to the pM promoter region. This binding
impaired eYciency of interaction of the cI protein with the OR3 site, while stimulating such a binding to OR2 and
OR1 sites, in the regulatory region of the pM promoter. We
propose that changes in cI gene expression, perhaps in
combination with moderately induced SOS response, may
be responsible for enhanced lambda prophage induction by
hydrogen peroxide in the oxyR mutant. Therefore, OxyR
seems to be a factor stimulating lambda prophage maintenance
under conditions of oxidative stress. This proposal is discussed in the light of eYciency of induction of lambdoid
prophages bearing genes coding for Shiga toxins
Backbone dynamics of TFE-induced native-like fold of region 4 of Escherichia coli RNA polymerase sigma70 subunit.
No full textFolding of a recombinant protein rECsigma(70) (4) comprising domain 4 of E. coli RNA polymerase sigma(70) subunit, upon addition of 2,2,2-trifluoroethanol (TFE) to its aqueous solution, was monitored by heteronuclear NMR spectroscopy. The TFE-induced migration of resonance signals in a series of (15)N-HSQC spectra displayed sequence-dependent heterogeneity. A common trend of uniform upfield shift in both (1)H and (15)N dimensions, indicative of generation of helical structures, breaks down for some residues almost cooperatively at 10-15% TFE (v/v), pointing to the buildup of non-helical regions separating the initially induced helices. The preferences of residues to assume either helical or non-helical conformation are correlated with the location in the sequence rather than with their type. CSI descriptors and (15)N relaxation data obtained for the protein at 10% TFE allowed characterization of the stability of the pre-folded state of rECsigma(70) (4). By all the criteria applied, three highly populated alpha-helical regions separated by much more flexible residues forming a loop and a turn in the DNA-binding HLHTH motif were identified. The location of the secondary structure elements along the protein sequence coincides with those found in homologous proteins, and with the helix nucleation regions determined in unfolded rECsigma(70) (4) at low pH. The bimodal distribution of the (15)N relaxation parameters enabled identification of residues forming a framework of the folded protein strictly corresponding to the HLHTH motif, bracketed by unfolded terminal regions. Thus, in respect to rECsigma(70) (4) in aqueous solution TFE acts not only as a strong helix inducer, but also as a folding agent
Effect of the ΔPhe residue configuration on a didehydropeptides conformation: A combined CD and NMR study
Get PDFGenistein: a natural isoflavone with a potential for treatment of genetic diseases
Get PDFGenistein [4�,5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one] is a
natural isoflavone occurring in many plants known to possess various biological activities, ranging from
phyto-oestrogenic to antioxidative actions. Recent studies indicated that this isoflavone can also be
considered as a drug for as yet untreatable genetic diseases. In the present review, we discuss a plausible
use of genistein in treatment of two genetic disorders: CF (cystic fibrosis) and MPS (mucopolysaccharidosis).
Although various biological actions of genistein are employed in these two cases, in vitro studies, tests on
animal models and pilot clinical trials suggest that this plant-derived compound might be a real hope for
patients suffering from severe inherited disorders with relatively complicated pathomechanisms, including
those affecting the central nervous system
The human core exosome interacts with differentially localized processive RNases: hDIS3 and hDIS3L.
Get PDFThe eukaryotic RNA exosome is a ribonucleolytic complex involved in RNA processing and turnover. It consists of a nine-subunit catalytically inert core that serves a structural function and participates in substrate recognition. Best defined in Saccharomyces cerevisiae, enzymatic activity comes from the associated subunits Dis3p (Rrp44p) and Rrp6p. The former is a nuclear and cytoplasmic RNase II/R-like enzyme, which possesses both processive exo- and endonuclease activities, whereas the latter is a distributive RNase D-like nuclear exonuclease. Although the exosome core is highly conserved, identity and arrangements of its catalytic subunits in different vertebrates remain elusive. Here, we demonstrate the association of two different Dis3p homologs--hDIS3 and hDIS3L--with the human exosome core. Interestingly, these factors display markedly different intracellular localizations: hDIS3 is mainly nuclear, whereas hDIS3L is strictly cytoplasmic. This compartmental distribution reflects the substrate preferences of the complex in vivo. Both hDIS3 and hDIS3L are active exonucleases; however, only hDIS3 has retained endonucleolytic activity. Our data suggest that three different ribonucleases can serve as catalytic subunits for the exosome in human cells
Full Repression of RNA Polymerase III Transcription Requires Interaction between Two Domains of Its Negative Regulator Maf1
Get PDFMaf1, first identified in yeast Saccharomyces cerevisiae, is a general negative regulator of RNA polymerase III (Pol III). Transcription regulation by Maf1 is important under stress conditions and during the switch between fermentation and respiration. Maf1 is composed of two domains conserved during evolution. We report here that these two domains of human Maf1 are resistant to mild proteolysis and interact together as shown by pull-down and size-exclusion chromatography and that the comparable domains of yeast Maf1 interact in a two-hybrid assay. Additionally, in yeast, a mutation in the N-terminal domain is compensated by mutations in the C-terminal domain. Integrity of both domains and their direct interaction are necessary for Maf1 dephosphorylation and subsequent inhibition of Pol III transcription on a nonfermentable carbon source. These data relate Pol III transcription inhibition to Maf1 structural changes