Ribonucleotide Reductase

Mitochondrial DNA depletion syndromes (MDSs) form a group of autosomal recessive disorders characterized by profoundly decreased mitochondrial DNA copy numbers in affected tissues. Three main clinical presentations are known: myopathic, encephalomyopathic and hepatocerebral. The first is associated with mutations in thymidine kinase 2 (TK2) and p53-induced ribonucleotide reductase B subunit (RRM2B); the second with mutations in succinate synthase A (SUCLA2) and B (SUCLG1); the third with mutations in Twinkle (PEO1), pol-γA (POLG1), deoxyguanosine kinase (DGUOK) and MPV17 (MPV17). In this work, we review the MDS-associated phenotypes and present our own experience of 32 MDS patients, with the aim of defining the mutation frequency of the known genes, the clinical spectrum of the diseases, and the genotype–phenotype correlations. Five of our patients carried previously unreported mutations in one of the eight MDS genes.

During the last years, several reports have indicated genotoxic effects of paracetamol, a widely used non-prescription analgesic and antipyretic drug. Thus, a careful evaluation of a possible genotoxic effect related to paracetamol use is warranted. Studies in vitro and in vivo indicate that the reactive metabolite of paracetamol can bind irreversibly to DNA and cause DNA strand breaks. Paracetamol inhibits

Background: Drugs for the treatment of AIDS have been directed to specific events in the human immunodeficiency virus (HIV-1) life cycle, aimed to stop viral replication by inhibition of reverse transcriptase or protease activity. Studies showing that oxidative stress and iron may be important in the activation of HIV-1 have focused attention on the potential therapeutic use of iron chelators. Objectives: The goal of this review is to describe several possibilities as to how iron is involved in the replication of HIV and how iron chelation may interfere in this process. Study design: First some physico-chemical properties of iron concerning solubility, oxidation–reduction potential, catalysis, and chelation will be discussed. In the second part, the role of iron in various biochemical systems is explained. Results: Nuclear factor kappa B (NF-κB) activation, regulating proviral transcription, can be influenced by iron through the production of reactive oxygen species. A second route by which iron chelation could influence HIV replication, is by inhibition of DNA synthesis through inactivation of iron-dependent ribonucleotide reductase. Another strategy which can be employed in targeting iron chelators against HIV-1, is direct oxidative viral RNA/DNA attack. This could be achieved by bleomycin, a cytostatic agent with the ability to form a complex with DNA and RNA. Conclusion: Chelation may withhold iron from viral metabolism but on the other hand may also favor catalysis of reactive oxygen species directed to viral constituents. In combination with existing antivirals, iron chelation could add to improve the treatment of HIV-disease.

Several known mammalian ribonucleotide reductase inhibitors featuring a polyhydroxyphenyl and/or hydroxamate moiety as the active group were screened for potency in inhibiting growth of the malaria parasite Plasmodium falciparum. Compounds containing a 2,3- or 3,4-dihydroxyphenyl group as well as benzohydroxamate appear to be the most effective inhibitors of the malaria parasite.

In the genomes of two baculoviruses, Spodoptera exigua and S. littoralis multicapsid nucleopolyhedroviruses (SeMNPV and SpliMNPV, respectively), an open reading frame (ORF) encoding the large subunit of ribonucleotide reductase (RR1) was identified. The predicted amino acid sequences of SeMNPV and SpliMNPV RR1 showed high homology to RR1 proteins from eukaryotes (ca. 70% and 80% similarity, respectively). The amino acid residues thought to be involved in catalytic function were conserved in the baculoviral RR1 ORFs. The RR1 ORFs in SeMNPV and SpliMNPV were located in different genomic positions. In SeMNPV, the RR1 ORF was located upstream of the polyhedrin gene, in an anti-genomic orientation. In SpliMNPV, the RR1 ORF preceded the p74 gene. By searching databanks, sequences homologous to the N terminus of RR1 were also detected upstream of the polyhedrin gene of three other baculoviruses, Mamestra brassicae multicapsid NPV, Panolis flammea multicapsid NPV and Orgyia pseudotsugata si...