The charged residues bind either one or two metal ions that are required for catalysis; under physiological conditions these are magnesium ions, but manganese also usually supports enzymatic activity, while calcium may inhibit it. Although two-metal-ion catalytic mechanisms are very common in enzymes involved in phosphate biochemistry, it has been a subject of debate in the literature whether one or two ions are used in RNase H catalysis. In either proposed mechanism, at least one water molecule participates in the reaction.