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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antioxidant defence plays a crucial role in rapidly growing and multiplying organisms, including parasites and tumor cells. Apart from reactive oxygen species (ROS) produced in endogenous reactions, parasites are usually exposed to high ROS concentrations imposed by the host immune system. The glutathione and thioredoxin systems represent the two major antioxidant defence lines in most eukaryotes and prokaryotes. Trypanosomatids, however, are characterized by their unique trypanothione system. These systems are NADPH-dependent and based on the catalytic activity of the flavoenzymes glutathione reductase, trypanothione reductase and thioredoxin reductase (TrxR), respectively. TrxR reduces the 12-kDa protein thioredoxin (Trx), which in turn provides elcctrons to ribonucleotide reductase, thioredoxin peroxidases (TPxs), certain transcription factors and other target molecules. Comparing the thioredoxin systems of different parasites and their respective host cells enhances our understanding of parasite biology and evolution, of parasite-host interactions and mechanisms of drug resistance. It furthermore opens avenues for the development of novel antiparasitic compounds. Here we review the current knowledge on the Trx systems of eukaryotic parasites, finally focusing on the malarial parasite Plasmodium falciparum.
Cell Mol Life Sci 2002 Jun
PMID:The thioredoxin system of Plasmodium falciparum and other parasites. 1216 15

For growth under oxygen-free atmosphere, some strict or facultative anaerobes depend on a class III ribonucleotide reductase for the synthesis of deoxyribonucleotides, the DNA precursors. Prototypes for this class of enzymes are ribonucleotide reductases from Escherichia coli and bacteriophage T4. This review article describes their structural and mechanistic properties as well as their complex allosteric regulation. Their evolutionnary relationship to class I and class II ribonucleotide reductases is also discussed.
Prog Nucleic Acid Res Mol Biol 2002
PMID:Deoxyribonucleotide synthesis in anaerobic microorganisms: the class III ribonucleotide reductase. 1220 60

Diiron proteins are found throughout nature and have a diverse range of functions; proteins in this class include methane monooxygenase, ribonucleotide reductase, Delta(9)-acyl carrier protein desaturase, rubrerythrin, hemerythrin, and the ferritins. Although each of these proteins has a very different overall fold, in every case the diiron active site is situated within a four-helix bundle. Additionally, nearly all of these proteins have a conserved Glu-Xxx-Xxx-His motif on two of the four helices with the Glu and His residues ligating the iron atoms. Intriguingly, subtle differences in the active site can result in a wide variety of functions. To probe the structural basis for this diversity, we designed an A(2)B(2) heterotetrameric four-helix bundle with an active site similar to those found in the naturally occurring diiron proteins. A novel computational approach was developed for the design, which considers the energy of not only the desired fold but also alternatively folded structures. Circular dichroism spectroscopy, analytical ultracentrifugation, and thermal unfolding studies indicate that the A and B peptides specifically associate to form an A(2)B(2) heterotetramer. Further, the protein binds Zn(II) and Co(II) in the expected manner and shows ferroxidase activity under single turnover conditions.
J Mol Biol 2002 Aug 30
PMID:Computational de novo design, and characterization of an A(2)B(2) diiron protein. 1220 71

Amino acids at conserved sites in the residue sequence of 10 ancient proteins, from 844 phylogenetically diverse sources, were used to specify their time of origin in the interval before species divergence from the last common ancestor (LCA). The order of amino acid addition to the genetic code, based on biosynthesis path length and other molecular evidence, provided a reference for evaluating the 'code age' of each residue profile examined. Significantly earlier estimates were obtained for conserved amino acid residues in these proteins than non-conserved residues. Evidence from the primary structure of 'fossil' proteins thus corroborated the biosynthetic order of amino acid addition to the code.Low potential ferredoxin (Fdxn) had the earliest residue profile among the proteins in this study. A phylogenetic tree for 82 prokaryote Fdxn sequences was rooted midway between bacteria and archaea branches. LCA Fdxn had a 23-residue antecedent whose residue profile matched mid-expansion phase codon assignments and included an amide residue. It contained a highly acidic N-terminal region and a non-charged C-terminal region, with all four cysteine residues. This small protein apparently anchored a [4Fe-4S] cluster, ligated by C-terminal cysteines, to a positively charged mineral surface, consistent with mediating e(-) transfer in a primordial surface system before cells appeared. Its negatively charged N-terminal 'attachment site' was highly mutable during evolution of ancestral Fdxn for Bacteria and Archaea, consistent with a loss of function after cell formation. An initial glutamate to lysine substitution may link 'attachment site' removal to early post-expansion phase entry of basic amino acids to the code. As proteins evidently anchored non-charged amide residues initially, surface attachment of cofactors and other functional groups emerges as a general function of pre-cell proteins.A phylogenetic tree of 107 proteolipid (PL) helix-1 sequences from H(+)-ATPase of bacteria, archaea and eukaryotes had its root between prokaryote branches. LCA PL h1 residue profile optimally fit a late expansion phase codon array. Sequence repeats in transmembrane PL helices h1 and h2 indicated formation of the archetypal PL hairpin structure involved successive tandem duplications, initiated within the gene for an 11-residue (or 4-residue) hydrophobic peptide. Ancestral PL h1 lacked acidic residues, in a fundamental departure from the prototype pre-cell protein. By this stage, proteins with a hydrophobic domain had evolved. Its non-polar, late expansion phase residue profile point to ancestral PL being a component of an early permeable cell membrane. Other indicators of cell formation about this stage of code evolution include phospholipid biosynthesis path length, FtsZ residue profile, and late entry of basic amino acids into the genetic code. Estimates based on conserved residues in prokaryote cell septation protein, FtsZ, and proteins involved with synthesis, transcription and replication of DNA revealed FtsZ, ribonucleotide reductase, RNA polymerase core subunits and 5'-->3' flap exonuclease, FEN-1, originated soon after cells putatively evolved. While reverse transcriptase and topoisomerase I, Topo I, appeared late in the pre-divergence era, when the genetic code was essentially complete. The transition from RNA genes to a DNA genome seemingly proceeded via formation of a DNA-RNA heteroduplex. These results suggest formation of DNA awaited evolution of a catalyst with a hydrophobic domain, capable of sequestering radical bearing intermediates in its synthesis from ribonucleotide precursors. Late formation of topology altering protein, Topo I, further suggests consolidation of genes into chromosomes followed synthesis of comparatively thermostable DNA strands.
Prog Biophys Mol Biol
PMID:Molecular evolution before the origin of species. 1222 77

The phylogeny of 13 viral species in the genera Granulovirus and Nucleopolyhedrovirus (family Baculoviridae) was reconstructed on the basis of 22 conserved protein families shared by all species, and a comprehensive homology search and phylogenetic analysis of the complete genomes of these viruses was used to test for horizontal gene transfer from cellular organisms. Statistically significant evidence of horizontal transfer was found in the case of six protein families (DNA ligase, ribonucleotide reductase 1, SNF2 global transactivator, inhibitor of apoptosis, chitinase, and UDP-glucosyltransferase). Three of these families are known to play key roles in the infection of insect hosts by these viruses. There was evidence that two of these (inhibitor of apoptosis and UDP-glucosyltransferase) were derived from the insect host. By contrast, the gene encoding chitinase in these viruses was evidently derived from a group of bacteria (the gamma subdivision of proteobacteria), which use chitinase to break down fungal chitins.
Mol Biol Evol 2003 Jun
PMID:Genome-wide survey for genes horizontally transferred from cellular organisms to baculoviruses. 1271 88

Cigarette smoking causes profound suppression of pulmonary T cell responses, which is associated with increased susceptibility to respiratory tract infections and decreased tumor surveillance. Hydroquinone (HQ) and catechol, at concentrations comparable to those found in cigarette smoke, are potent inhibitors of T cell activation and proliferation. We have previously shown that HQ and catechol inhibit ribonucleotide reductase, the rate-limiting enzyme in DNA synthesis. In this report we demonstrate that HQ and catechol also inhibit blastogenesis by interfering with T cell cycle entry and progression through the G(1) phase. In an attempt to localize the point in the cell cycle where arrest occurred, a set of key markers of activation and cell cycle progression were examined, including induction of c-Myc, up regulation of RNA synthesis, surface expression of CD71, and induction of E2F-dependent gene expression. Addition of HQ or catechol prior to stimulation inhibited each of these events without decreasing cell viability. However, production of IL-2 and surface expression of CD69 and CD25 were not affected, indicating that HQ and catechol inhibit only certain cell cycle events. These studies provide further indication of the regulatory pathways by which cigarette smoke inhibits T cell responses in the lungs of smokers.
Mol Immunol 2003 Jun
PMID:Hydroquinone and catechol interfere with T cell cycle entry and progression through the G1 phase. 1274 6

The three-dimensional structure of the large subunit of the first member of a class Ib ribonucleotide reductase, R1E of Salmonella typhimurium, has been determined in its native form and together with three allosteric effectors. The enzyme contains the characteristic ten-stranded alpha/beta-barrel with catalytic residues at a finger loop in its center and with redox-active cysteine residues at two adjacent barrel strands. Structures where the redox-active cysteine residues are in reduced thiol form and in oxidized disulfide form have been determined revealing local structural changes. The R1E enzyme differs from the class Ia enzyme, Escherichia coli R1, by not having an overall allosteric regulation. This is explained from the structure by differences in the N-terminal domain, which is about 50 residues shorter and lacks the overall allosteric binding site. R1E has an allosteric substrate specificity regulation site and the binding site for the nucleotide effectors is located at the dimer interface similarly as for the class Ia enzymes. We have determined the structures of R1E in the absence of effectors and with dTTP, dATP and dCTP bound. The low affinity for ATP at the specificity site is explained by a tyrosine, which hinders nucleotides containing a 2'-OH group to bind.
J Mol Biol 2003 Jun 27
PMID:Structure of the large subunit of class Ib ribonucleotide reductase from Salmonella typhimurium and its complexes with allosteric effectors. 1281 4

The cdc22+ gene of the fission yeast, Schizosaccharomyces pombe, encodes the large subunit of ribonucleotide reductase, and is periodically expressed during the mitotic cell cycle, transcript abundance reaching a maximum at the G1-S boundary. This regulation of expression is controlled by a transcription factor complex called DSC1, which binds to MCB motifs (ACGCGT) present in the promoter of cdc22+. cdc22+ has a complex pattern of MCBs, including two clusters of four motifs each, one of which is located within the transcribed region. We show that both clusters of MCBs contribute to the regulation of cdc22+ expression during the cell cycle, each having a different role. The MCB cluster within the transcribed region has the major role in regulating cdc22+, as its removal results in loss of transcription. The upstream cluster, instead, controls cell cycle-specific transcription through a negative function, as its removal results in expression of cdc22+ throughout the cell cycle. Both MCB clusters bind DSC1. We show that the interaction of DSC1 with the MCB cluster within the transcribed region has a high "on-off" rate, suggesting a mechanism by which DSC1 could activate expression, and still allow RNA polymerase to pass during transcription. Finally, we show that both clusters are orientation-dependent in their function. The significance of these results, in the context of MCB-mediated regulation of G1-S expression in fission yeast, is discussed.
Mol Genet Genomics 2003 Sep
PMID:MCB-mediated regulation of cell cycle-specific cdc22+ transcription in fission yeast. 1289 17

The ribonucleotide reductase (RR) 2 gene of the HSV-2 strain G was cloned, sequenced, and expressed in an E. coli cell. The RR2 gene was located on the PstI 2.4 kb fragment, which was cloned and sequenced. The ORF of the gene was 1,011 bp and its termination codon was TAG; also, the CATATAA sequence was present in the promoter of the RR2 gene. A Poly A signal sequence (AATAAA) was found in the 3'-noncoding region. The RR2 proteins that were produced in the E. coli and Vero cells were confirmed using a Western blot analysis. SDS-PAGE revealed that the molecular weights of the fusion-RR2 that was produced in the E. coli cells were approximately 24 kDa and 38 kDa in the Vero cells. The RR2 proteins were soluble. The differences in the molecular weights might be due to modifications in the Vero cells.
J Biochem Mol Biol 2003 Sep 30
PMID:Cloning of a ribonucleotide reductase gene of the herpes simplex virus type 2 strain G. 1453 37

Hydroxyurea is considered an antineoplastic drug, which also plays an important role in the treatment of sickle cell anemia patients. We evaluated and compared the clastogenic and cytotoxic effects of hydroxyurea, using chromosomal aberrations and mitotic index, respectively, as endpoints. In vitro short-term cultures of lymphocytes were exposed to several concentrations of this drug, at various cell cycle phases. There was a significant increase in the cytotoxicity of hydroxyurea at G1 and G1/S as well in the G2 phase of the cell cycle. Hydroxyurea did not significantly increase chromosome aberrations. There was an S-dependent cytotoxic effect of hydroxyurea, which is expected based on the known activity of hydroxyurea as an inhibitor of ribonucleotide reductase.
Genet Mol Res 2003 Sep 30
PMID:Evaluation of the mutagenic activity of hydroxyurea on the G1-S-G2 phases of the cell cycle: an in vitro study. 1496 81


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