Disease relevance of ARR2

• ACR2 was cloned into a bacterial expression vector and expressed in E. coli as a C-terminally histidine-tagged protein that was purified by sequential metal chelate affinity and gel filtration chromatography [1].

High impact information on ARR2

• We have identified a single gene in the Arabidopsis thaliana genome, ACR2, with moderate sequence homology to yeast arsenate reductase [2].
• RNA interference reduced ACR2 protein expression in Arabidopsis to as low as 2% of wild-type levels [2].
• Expression of ACR2 cDNA in Escherichia coli complemented the arsenate-resistant and arsenate-sensitive phenotypes of various bacterial ars operon mutants [2].
• In vitro band shift experiments demonstrated binding of Nrg1 to the 5. end of the ARR2 region [3].
• Previous functional analysis of the ENA1 promoter revealed a calcineurin-independent pH responsive region (ARR2, 83 nucleotides) [3].

Chemical compound and disease context of ARR2

• As postulated for Acr2p and R773 ArsC, rSynArsC formed a covalent complex with glutathione in an arsenate-dependent manner. rSynArsC contains three essential cysteine residues like pI258 ArsC, whereas the yeast and E. coli enzymes require only one cysteine for catalysis [4].

Biological context of ARR2

• The presence of ACR3 together with ACR2 on a multicopy plasmid was conducive to increased arsenate resistance [5].
• Homology searches revealed a cluster of three new open reading frames named ACR1, ACR2 and ACR3 [6].
• Substrate specificity as well as sensitivity toward inhibitors for the fern AR (phosphate as a competitive inhibitor, arsenite as a noncompetitive inhibitor) was also similar to Acr2p [7].
• The yeast Acr2p has an active site motif HC(X)(5)R that is conserved in protein phosphotyrosine phosphatases and rhodanases, suggesting that these three groups of enzymes may have evolved from an ancestral oxyanion-binding protein [8].

Anatomical context of ARR2

• The ARR2 and ARR3 genes encoding the cytoplasmic arsenate reductase and the plasma membrane arsenite transporter are functionally interchangeable in both yeast species [9].
• The combination of chimeric MBP-Acr2-6H protein and yeast cytosol from an ACR2-disrupted strain exhibited arsenate reductase activity [10].

Associations of ARR2 with chemical compounds

• In Saccharomyces cerevisiae, expression of the ACR2 and ACR3 genes confers arsenical resistance [1].
• In contrast, acr1, acr3, and acr4 mutants were resistant to papulacandin B (an antibiotic containing a disaccharide linked to two fatty acid chains that also inhibits beta-glucan synthesis), but acr2 mutants were susceptible to this antibiotic [11].
• Acr2p also has a third cysteine residue at position 106 [12].
• Here we show that creation of a phosphate binding motif through the introduction of glycines at positions 79, 81, and 84 in Acr2p resulted in a gain of phosphotyrosine phosphatase activity and a loss of arsenate reductase activity [13].
• An arsenate reductase (AR) in the fern showed a reaction mechanism similar to the previously reported Acr2p, an AR from yeast (Saccharomyces cerevisiae), using glutathione as the electron donor [7].

Other interactions of ARR2

• This suggests that during the catalytic cycle, Acr2p forms a mixed disulfide with GSH before being reduced by glutaredoxin to regenerate the active Acr2p reductase [1].
• Yap8p is demonstrated to reside in the nucleus where it mediates enhanced expression of the arsenic detoxification genes ACR2 and ACR3 [14].
• Acr2p is not a phosphatase but is a homologue of CDC25 phosphatases [13].
• The ACR2 gene of Saccharomyces cerevisiae was disrupted by insertion of a HIS3 gene [10].

Analytical, diagnostic and therapeutic context of ARR2

• Crystallization and preliminary X-ray diffraction analysis of Saccharomyces cerevisiae Ygr203p, a homologue of Acr2 arsenate reductase [15].

References