title: A novel clade of unique eukaryotic ribonucleotide reductase R2 subunits is exclusive to apicomplexan parasites.
abstract: Apicomplexa are protist parasites of tremendous medical and economic importance, causing millions of deaths and billions of dollars in losses each year. Apicomplexan-related diseases may be controlled via inhibition of essential enzymes. Ribonucleotide reductase (RNR) provides the only de novo means of synthesizing deoxyribonucleotides, essential precursors for DNA replication and repair. RNR has long been the target of antibacterial and antiviral therapeutics. However, targeting this ubiquitous protein in eukaryotic pathogens may be problematic unless these proteins differ significantly from that of their respective host. The typical eukaryotic RNR enzymes belong to class Ia, and the holoenzyme consists minimally of two R1 and two R2 subunits (α₂β₂). We generated a comparative, annotated, structure-based, multiple-sequence alignment of R2 subunits, identified a clade of R2 subunits unique to Apicomplexa, and determined its phylogenetic position. Our analyses revealed that the apicomplexan-specific sequences share characteristics with both class I R2 and R2lox proteins. The putative radical-harboring residue, essential for the reduction reaction by class Ia R2-containing holoenzymes, was not conserved within this group. Phylogenetic analyses suggest that class Ia subunits are not monophyletic and consistently placed the apicomplexan-specific clade sister to the remaining class Ia eukaryote R2 subunits. Our research suggests that the novel apicomplexan R2 subunit may be a promising candidate for chemotherapeutic-induced inhibition as it differs greatly from known eukaryotic host RNRs and may be specifically targeted.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Munro
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Jacob
authors.forename: Joana C
authors.initials: JC
authors.lastname: Silva
mesh_terms: D016782:Apicomplexa / Q000201:enzymology* / Q000235:genetics; D001105:Archaea / Q000201:enzymology; D001419:Bacteria / Q000201:enzymology; D004261:DNA Replication; D010802:Phylogeny; D012264:Ribonucleotide Reductases / Q000737:chemistry* / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D012264:Ribonucleotide Reductases; C108427:ribonucleotide reductase R2 subunit
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