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Nucleotide Metabolism and DNA Replication

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  • Authors: Digby F. Warner1, Joanna C. Evans2, Valerie Mizrahi3
  • Editors: Graham F. Hatfull4, William R. Jacobs Jr.5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Center of Excellence for Biomedical TB Research, Institute of Infectious Disease and Molecular Medicine, and Division of Medical Microbiology, University of Cape Town, P/Bag X3 Rondebosch 7700, South Africa; 2: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Center of Excellence for Biomedical TB Research, Institute of Infectious Disease and Molecular Medicine, and Division of Medical Microbiology, University of Cape Town, P/Bag X3 Rondebosch 7700, South Africa; 3: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Center of Excellence for Biomedical TB Research, Institute of Infectious Disease and Molecular Medicine, and Division of Medical Microbiology, University of Cape Town, P/Bag X3 Rondebosch 7700, South Africa; 4: University of Pittsburgh, Pittsburgh, PA; 5: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY
  • Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0001-2013
  • Received 08 April 2013 Accepted 22 July 2013 Published 05 September 2014
  • V. Mizrahi, valerie.mizrahi@uct.ac.za
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  • Abstract:

    The development and application of a highly versatile suite of tools for mycobacterial genetics, coupled with widespread use of “omics” approaches to elucidate the structure, function, and regulation of mycobacterial proteins, has led to spectacular advances in our understanding of the metabolism and physiology of mycobacteria. In this article, we provide an update on nucleotide metabolism and DNA replication in mycobacteria, highlighting key findings from the past 10 to 15 years. In the first section, we focus on nucleotide metabolism, ranging from the biosynthesis, salvage, and interconversion of purine and pyrimidine ribonucleotides to the formation of deoxyribonucleotides. The second part of the article is devoted to DNA replication, with a focus on replication initiation and elongation, as well as DNA unwinding. We provide an overview of replication fidelity and mutation rates in mycobacteria and summarize evidence suggesting that DNA replication occurs during states of low metabolic activity, and conclude by suggesting directions for future research to address key outstanding questions. Although this article focuses primarily on observations from , it is interspersed, where appropriate, with insights from, and comparisons with, other mycobacterial species as well as better characterized bacterial models such as . Finally, a common theme underlying almost all studies of mycobacterial metabolism is the potential to identify and validate functions or pathways that can be exploited for tuberculosis drug discovery. In this context, we have specifically highlighted those processes in mycobacterial DNA replication that might satisfy this critical requirement.

  • Citation: Warner D, Evans J, Mizrahi V. 2014. Nucleotide Metabolism and DNA Replication. Microbiol Spectrum 2(5):MGM2-0001-2013. doi:10.1128/microbiolspec.MGM2-0001-2013.

Key Concept Ranking

DNA Polymerase III
0.504
DNA Synthesis
0.47940093
DNA Replication Proteins
0.4787819
Bacterial DNA Replication
0.44565102
0.504

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/content/journal/microbiolspec/10.1128/microbiolspec.MGM2-0001-2013
2014-09-05
2017-09-19

Abstract:

The development and application of a highly versatile suite of tools for mycobacterial genetics, coupled with widespread use of “omics” approaches to elucidate the structure, function, and regulation of mycobacterial proteins, has led to spectacular advances in our understanding of the metabolism and physiology of mycobacteria. In this article, we provide an update on nucleotide metabolism and DNA replication in mycobacteria, highlighting key findings from the past 10 to 15 years. In the first section, we focus on nucleotide metabolism, ranging from the biosynthesis, salvage, and interconversion of purine and pyrimidine ribonucleotides to the formation of deoxyribonucleotides. The second part of the article is devoted to DNA replication, with a focus on replication initiation and elongation, as well as DNA unwinding. We provide an overview of replication fidelity and mutation rates in mycobacteria and summarize evidence suggesting that DNA replication occurs during states of low metabolic activity, and conclude by suggesting directions for future research to address key outstanding questions. Although this article focuses primarily on observations from , it is interspersed, where appropriate, with insights from, and comparisons with, other mycobacterial species as well as better characterized bacterial models such as . Finally, a common theme underlying almost all studies of mycobacterial metabolism is the potential to identify and validate functions or pathways that can be exploited for tuberculosis drug discovery. In this context, we have specifically highlighted those processes in mycobacterial DNA replication that might satisfy this critical requirement.

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FIGURE 1

Pathways for the formation of dTTP in . The steps for which homologs are absent are shown in gray, and enzymes that are essential for growth are shown in shaded boxes. Adapted from references 64 and 62 . doi:10.1128/microbiolspec.MGM2-0001-2013.f1

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0001-2013
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TABLE 1

Genes involved in purine and pyrimidine salvage pathways in

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0001-2013
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TABLE 2

Genes known to be involved in DNA replication in

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0001-2013

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