The key idea is that hydrolytic enzymes do not carry out redox chemistry — they cleave bonds by delivering water or hydroxide. The metal's job is to act as a Lewis acid: to polarise the substrate carbonyl or phosphate, and to lower the pK_a of a bound water molecule so that a nucleophilic hydroxide is available at physiological pH.

That job description calls for ions with a fixed oxidation state, so that no unwanted electron transfer occurs. Zn²⁺, Mg²⁺ and Ca²⁺ are exactly such ions — all redox inert, all good Lewis acids.

Zn²⁺ is the classic hydrolytic cofactor: carbonic anhydrase, carboxypeptidase A and the matrix metalloproteinases all use it, and its d¹⁰ configuration means no ligand-field preference, allowing flexible coordination geometry at the active site.

Mg²⁺ is central to phosphate hydrolysis — ATPases, phosphatases, and the ribozymes — where it stabilises the developing negative charge of the transition state.

Ca²⁺ appears in enzymes such as phospholipase A₂ and in nucleases, again as a structural and polarising centre.

The other sets all contain redox-active metals. Cu²⁺, Fe²⁺, Co²⁺, Mn²⁺ and Ni²⁺ readily change oxidation state, and that is precisely why biology places them in oxidases, oxygenases, catalases and electron-transfer proteins rather than in hydrolases — a redox-active ion in a hydrolytic site would risk damaging side reactions.

Hence the metal ions commonly found at hydrolytic active sites are Zn²⁺, Mg²⁺ and Ca²⁺.