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Nitric Oxide : Biology and Chemistry Oct 2022Ribonucleotide reductase (RNR) is a multi-subunit enzyme responsible for catalyzing the rate-limiting step in the production of deoxyribonucleotides essential for DNA... (Review)
Review
Ribonucleotide reductase (RNR) is a multi-subunit enzyme responsible for catalyzing the rate-limiting step in the production of deoxyribonucleotides essential for DNA synthesis and repair. The active RNR complex is composed of multimeric R1 and R2 subunits. The RNR catalysis involves the formation of tyrosyl radicals in R2 subunits and thiyl radicals in R1 subunits. Despite the quaternary structure and cofactor diversity, all the three classes of RNR have a conserved cysteine residue at the active site which is converted into a thiyl radical that initiates the substrate turnover, suggesting that the catalytic mechanism is somewhat similar for all three classes of the RNR enzyme. Increased RNR activity has been associated with malignant transformation, cancer cell growth, and tumorigenesis. Efforts concerning the understanding of RNR inhibition in designing potent RNR inhibitors/drugs as well as developing novel approaches for antibacterial, antiviral treatments, and cancer therapeutics with improved radiosensitization have been made in clinical research. This review highlights the precise and potent roles of NO in RNR inhibition by targeting both the subunits. Under nitrosative stress, the thiols of the R1 subunits have been found to be modified by S-nitrosylation and the tyrosyl radicals of the R2 subunits have been modified by nitration. In view of the recent advances and progresses in the field of nitrosative modifications and its fundamental role in signaling with implications in health and diseases, the present article focuses on the regulations of RNR activity by S-nitrosylation of thiols (R1 subunits) and nitration of tyrosyl residues (R2 subunits) which will further help in designing new drugs and therapies.
Topics: Catalysis; Catalytic Domain; Ribonucleotide Reductases; Sulfhydryl Compounds; Tyrosine
PubMed: 35850377
DOI: 10.1016/j.niox.2022.07.002 -
Oncogene Apr 2015Accurate DNA replication and repair is essential for proper development, growth and tumor-free survival in all multicellular organisms. A key requirement for the... (Review)
Review
Accurate DNA replication and repair is essential for proper development, growth and tumor-free survival in all multicellular organisms. A key requirement for the maintenance of genomic integrity is the availability of adequate and balanced pools of deoxyribonucleoside triphosphates (dNTPs), the building blocks of DNA. Notably, dNTP pool alterations lead to genomic instability and have been linked to multiple human diseases, including mitochondrial disorders, susceptibility to viral infection and cancer. In this review, we discuss how a key regulator of dNTP biosynthesis in mammals, the enzyme ribonucleotide reductase (RNR), impacts cancer susceptibility and serves as a target for anti-cancer therapies. Because RNR-regulated dNTP production can influence DNA replication fidelity while also supporting genome-protecting DNA repair, RNR has complex and stage-specific roles in carcinogenesis. Nevertheless, cancer cells are dependent on RNR for de novo dNTP biosynthesis. Therefore, elevated RNR expression is a characteristic of many cancers, and an array of mechanistically distinct RNR inhibitors serve as effective agents for cancer treatment. The dNTP metabolism machinery, including RNR, has been exploited for therapeutic benefit for decades and remains an important target for cancer drug development.
Topics: Antineoplastic Agents; Carcinogenesis; DNA Repair; DNA Replication; Genomic Instability; Humans; Molecular Targeted Therapy; Neoplasms; Ribonucleotide Reductases
PubMed: 24909171
DOI: 10.1038/onc.2014.155 -
Expert Opinion on Therapeutic Targets Dec 2013Ribonucleotide reductase (RR) is a unique enzyme, because it is responsible for reducing ribonucleotides to their corresponding deoxyribonucleotides, which are the... (Review)
Review
INTRODUCTION
Ribonucleotide reductase (RR) is a unique enzyme, because it is responsible for reducing ribonucleotides to their corresponding deoxyribonucleotides, which are the building blocks required for DNA replication and repair. Dysregulated RR activity is associated with genomic instability, malignant transformation and cancer development. The use of RR inhibitors, either as a single agent or combined with other therapies, has proven to be a promising approach for treating solid tumors and hematological malignancies.
AREAS COVERED
This review covers recent publications in the area of RR, which include: i) the structure, function and regulation of RR; ii) the roles of RR in cancer development; iii) the classification, mechanisms and clinical application of RR inhibitors for cancer therapy and iv) strategies for developing novel RR inhibitors in the future.
EXPERT OPINION
Exploring the possible nonenzymatic roles of RR subunit proteins in carcinogenesis may lead to new rationales for developing novel anticancer drugs. Updated information about the structure and holoenzyme models of RR will help in identifying potential sites in the protein that could be targets for novel RR inhibitors. Determining RR activity and subunit levels in clinical samples will provide a rational platform for developing personalized cancer therapies that use RR inhibitors.
Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Ribonucleotide Reductases
PubMed: 24083455
DOI: 10.1517/14728222.2013.840293 -
Sub-cellular Biochemistry 2022Herein we present a multidisciplinary discussion of ribonucleotide reductase (RNR), the essential enzyme uniquely responsible for conversion of ribonucleotides to... (Review)
Review
Herein we present a multidisciplinary discussion of ribonucleotide reductase (RNR), the essential enzyme uniquely responsible for conversion of ribonucleotides to deoxyribonucleotides. This chapter primarily presents an overview of this multifaceted and complex enzyme, covering RNR's role in enzymology, biochemistry, medicinal chemistry, and cell biology. It further focuses on RNR from mammals, whose interesting and often conflicting roles in health and disease are coming more into focus. We present pitfalls that we think have not always been dealt with by researchers in each area and further seek to unite some of the field-specific observations surrounding this enzyme. Our work is thus not intended to cover any one topic in extreme detail, but rather give what we consider to be the necessary broad grounding to understand this critical enzyme holistically. Although this is an approach we have advocated in many different areas of scientific research, there is arguably no other single enzyme that embodies the need for such broad study than RNR. Thus, we submit that RNR itself is a paradigm of interdisciplinary research that is of interest from the perspective of the generalist and the specialist alike. We hope that the discussions herein will thus be helpful to not only those wanting to tackle RNR-specific problems, but also those working on similar interdisciplinary projects centering around other enzymes.
Topics: Animals; Deoxyribonucleotides; Mammals; Oxidoreductases; Ribonucleotide Reductases; Ribonucleotides
PubMed: 36151376
DOI: 10.1007/978-3-031-00793-4_5 -
Current Opinion in Chemical Biology Feb 2020Stereotyped as a nexus of dNTP synthesis, the dual-subunit enzyme - ribonucleotide reductase (RNR) - is coming into view as a paradigm of oligomerization and... (Review)
Review
Stereotyped as a nexus of dNTP synthesis, the dual-subunit enzyme - ribonucleotide reductase (RNR) - is coming into view as a paradigm of oligomerization and moonlighting behavior. In the present issue of 'omics', we discuss what makes the larger subunit of this enzyme (RNR-α) so interesting, highlighting its emerging cellular interactome based on its unique oligomeric dynamism that dictates its compartment-specific occupations. Linking the history of the field with the multivariable nature of this exceedingly sophisticated enzyme, we further discuss implications of new data pertaining to DNA-damage response, S-phase checkpoints, and ultimately tumor suppression. We hereby hope to provide ideas for those interested in these fields and exemplify conceptual frameworks and tools that are useful to study RNR's broader roles in biology.
Topics: Animals; DNA Damage; DNA Helicases; Deoxyadenosines; Humans; Models, Molecular; Protein Interaction Maps; Protein Structure, Quaternary; Ribonucleotide Reductases
PubMed: 31734537
DOI: 10.1016/j.cbpa.2019.09.003 -
Current Genetics Apr 2019The molecular chaperones Hsp70 and Hsp90 bind and fold a significant proportion of the proteome. They are responsible for the activity and stability of many... (Review)
Review
The molecular chaperones Hsp70 and Hsp90 bind and fold a significant proportion of the proteome. They are responsible for the activity and stability of many disease-related proteins including those in cancer. Substantial effort has been devoted to developing a range of chaperone inhibitors for clinical use. Recent studies have identified the oncogenic ribonucleotide reductase (RNR) complex as an interactor of chaperones. While several generations of RNR inhibitor have been developed for use in cancer patients, many of these produce severe side effects such as nausea, vomiting and hair loss. Development of more potent, less patient-toxic anti-RNR strategies would be highly desirable. Inhibition of chaperones and associated co-chaperone molecules in both cancer and model organisms such as budding yeast result in the destabilization of RNR subunits and a corresponding sensitization to RNR inhibitors. Going forward, this may form part of a novel strategy to target cancer cells that are resistant to standard RNR inhibitors.
Topics: Animals; Antineoplastic Agents; DNA Damage; DNA Replication; Enzyme Activation; Gene Expression Regulation; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Neoplasms; Protein Binding; Proteomics; Ribonucleotide Reductases
PubMed: 30519713
DOI: 10.1007/s00294-018-0916-7 -
Current Issues in Molecular Biology 2012Malaria is caused by species in the apicomplexan genus Plasmodium, which infect hundreds of millions of people each year and kill close to one million. While malaria is... (Review)
Review
Malaria is caused by species in the apicomplexan genus Plasmodium, which infect hundreds of millions of people each year and kill close to one million. While malaria is the most notorious of the apicomplexan-caused diseases, other members of eukaryotic phylum Apicomplexa are responsible for additional, albeit less well-known, diseases in humans, economically important livestock, and a variety of other vertebrates. Diseases such as babesiosis (hemolytic anemia), theileriosis and East Coast Fever, cryptosporidiosis, and toxoplasmosis are caused by the apicomplexans Babesia, Theileria, Cryptosporidium and Toxoplasma, respectively. In addition to the loss of human life, these diseases are responsible for losses of billions of dollars annually. Hence, the research into new drug targets remains a high priority. Ribonucleotide reductase (RNR) is an essential enzyme found in all domains of life. It is the only means by which de novo synthesis of deoxyribonucleotides occurs, without which DNA replication and repair cannot proceed. RNR has long been the target of antiviral, antibacterial and anti-cancer therapeutics. Herein, we review the chemotherapeutic methods used to inhibit RNR, with particular emphasis on the role of RNR inhibition in Apicomplexa, and in light of the novel RNR R2_e2 subunit recently identified in apicomplexan parasites.
Topics: Amino Acid Sequence; Animals; Antiprotozoal Agents; Apicomplexa; Humans; Molecular Sequence Data; Molecular Targeted Therapy; Parasites; Protozoan Infections; Ribonucleotide Reductases
PubMed: 21791713
DOI: No ID Found -
Advances in Enzyme Regulation 1989Although they are proliferatively quiescent, the cells in the intact adult rat liver express the gene coding for the M1 subunit of ribonucleotide reductase. But since... (Review)
Review
Although they are proliferatively quiescent, the cells in the intact adult rat liver express the gene coding for the M1 subunit of ribonucleotide reductase. But since they do not need deoxyribonucleotides, they promptly inactivate the 88 to 90 kDa M1 products and degrade them into 40 kDa fragments. Partial hepatectomy signals the remaining cells to start proliferating. Two hours before the onset of DNA replication, around 16 to 18 hr after partial hepatectomy, the cells start accumulating a large pool of functional ribonucleotide reductase M2 subunits. Near the end of the G1 build-up the cells step up M1 gene expression, stop inactivating, and reduce the degradation of the M1 products. The accumulating functional 88 to 90 kDa M1 subunits, each with more than one catalytic site, couple with functional M2 subunits to produce active ribonucleotide reductase holoenzyme which accumulates in the outer nuclear membrane from which they supply deoxyribonucleotide precursors to intranuclear replication enzymes. At the end of the S phase, the cell reduces M1 gene expression and resumes degrading 88 to 90 kDa M1 subunits. At least some of the 40 kDa M1 fragments are still active and can form partially active "holoenzymes" when mixed with a standard preparation of functional M2 subunits. The M1 control mechanism appears not to operate in hepatoma cells and Ehrlich ascites tumor cells, both of which maintain a pool of undegraded 88 to 90 kDa M1 components.
Topics: Animals; Cell Line; DNA Polymerase II; Liver; Liver Regeneration; Lymphoma; Macromolecular Substances; Mice; Rats; Ribonucleotide Reductases; Tumor Cells, Cultured
PubMed: 2696342
DOI: 10.1016/0065-2571(89)90067-8 -
Trends in Genetics : TIG Sep 1990
Review
Topics: Animals; Cell Cycle; Gene Expression Regulation, Enzymologic; Ribonucleotide Reductases; Yeasts
PubMed: 2238081
DOI: 10.1016/0168-9525(90)90214-q -
Genes Jul 2021Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the... (Review)
Review
Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the cycle by inducing replication stress. It is a well-known and widely used drug, one which has proved to be effective in treating chronic myeloproliferative disorders and which is considered a staple agent in sickle anemia therapy and-recently-a promising factor in preventing cognitive decline in Alzheimer's disease. The reversibility of HU-induced replication inhibition also makes it a common laboratory ingredient used to synchronize cell cycles. On the other hand, prolonged treatment or higher dosage of hydroxyurea causes cell death due to accumulation of DNA damage and oxidative stress. Hydroxyurea treatments are also still far from perfect and it has been suggested that it facilitates skin cancer progression. Also, recent studies have shown that hydroxyurea may affect a larger number of enzymes due to its less specific interaction mechanism, which may contribute to further as-yet unspecified factors affecting cell response. In this review, we examine the actual state of knowledge about hydroxyurea and the mechanisms behind its cytotoxic effects. The practical applications of the recent findings may prove to enhance the already existing use of the drug in new and promising ways.
Topics: Animals; DNA Replication; Humans; Hydroxyurea; Ribonucleotide Reductases; S Phase
PubMed: 34356112
DOI: 10.3390/genes12071096