Disease relevance of MET22

• The recent visualization at the atomic level of the inhibitory site of sodium in the known target Hal2 has helped identify the interactions determining Na(+) toxicity [1].
• This protein is homologous to the HAL2 and CysQ phosphatases of yeast and Escherichia coli, respectively [2].

High impact information on MET22

• A salt-sensitive 3'(2'),5'-bisphosphate nucleotidase involved in sulfate activation [3].
• Here we report that pAp accumulation in HAL2 mutants inhibits the 5'-->3' exoribonucleases Xrn1p and Rat1p [4].
• Overexpression of Hal2p confers lithium resistance in yeast, and its activity is inhibited by submillimolar amounts of Li+ in vitro [4].
• Complementation analysis demonstrated that HAL2 is identical to MET22, a gene involved in methionine biosynthesis [5].
• In the yeast Saccharomyces cerevisiae we have isolated a gene, HAL2, which upon increase in gene dosage improves growth under NaCl and LiCl stresses [5].

Chemical compound and disease context of MET22

• X-ray structure of yeast Hal2p, a major target of lithium and sodium toxicity, and identification of framework interactions determining cation sensitivity [6].

Biological context of MET22

• The substrate specificity and kinetics of RHL enzyme are very similar to the Chlorella 3'(2'),5'-diphosphonucleoside 3'(2')-phosphohydrolase (DPNPase) [7].
• We used a biochemical genomics approach to identify two yeast phosphatases that can convert Appr1p to ADP-ribose: the product of ORF YBR022w (now Poa1p), which is completely unrelated to other known phosphatases; and Hal2p, a known 3'-phosphatase of 5',3'-pAp [8].

Associations of MET22 with chemical compounds

• Hal2p is an enzyme that converts pAp (adenosine 3',5' bisphosphate), a product of sulfate assimilation, into 5' AMP and Pi [4].
• The activity of Xrn1p is naturally inhibited in the presence of 3'-phosphoadenosine 5'-phosphate (pAp), a metabolite produced during sulfate assimilation that is quickly metabolized to AMP by the enzymatic activity of Hal2p [9].
• The common core was used to align the sequences of several other proteins that share significant similarity to inositol monophosphate phosphatase, including proteins encoded by fungal qa-X and qutG, bacterial suhB and cysQ (identical to amtA), and yeast met22 (identical to hal2) [10].
• The yeast halotolerance gene HAL2 encodes a nucleotidase that dephosphorylates 3'-phosphoadenosine 5'-phosphate (PAP) and 3'-phosphoadenosine 5'-phosphosulfate (PAPS), intermediates of the sulfate assimilation pathway [11].
• The enzyme 3'(2'),5'-bisphosphate nucleotidase catalyses a reaction that converts 3'-phosphoadenosine-5'-phosphate (PAP) to adenosine-5'-phosphate (AMP) and inorganic phosphate (Pi) [12].

Other interactions of MET22

• We have shown that yeast cells can better adapt to the presence of sodium than lithium because of their ability to reduce pAp accumulation by activating HAL2 expression in a Gcn4p-dependent response, a regulatory loop that is likely to be conserved in different yeast species [9].

Analytical, diagnostic and therapeutic context of MET22

• Several residues that are essential for the activity of this enzyme were identified by site-directed mutagenesis, and the possible role of DPNPase in salt tolerance is discussed [7].
• Molecular cloning and biochemical characterization of a 3'(2'),5'-bisphosphate nucleotidase from Debaryomyces hansenii [12].

References