Q7(c). Choice of metal ions in enzymes and proteins

(i) Redox enzymes: Mn, Fe, Co rather than Zn, Ga, Ca

1. A redox enzyme must take up and give up electrons, so its metal needs two or more stable oxidation states close in energy: Mn(II)/(III)/(IV), Fe(II)/(III)/(IV), Co(I)/(II)/(III).
2. Zn²⁺ (d¹⁰), Ga³⁺ (d¹⁰) and Ca²⁺ (noble-gas core) each have only one oxidation state under biological conditions: no redox chemistry is possible. Their roles are structural or Lewis-acid catalysis.
3. The potentials of the open-shell metals can be tuned by the ligands (porphyrin, Fe–S, corrin) across the whole biological range, and Fe and Co are abundant and taken up readily.

(ii) Protein folding: Ca²⁺, Zn²⁺, Cu²⁺ rather than Al³⁺, Cr³⁺

1. Folding control needs ions that bind reversibly and quickly to side-chain donors, so that a protein can fold, unfold and respond to signals.
2. Ca²⁺: hard, fast-exchanging, no geometric preference (6 to 8 O donors from carboxylates), so it binds and leaves on the timescale of signalling (calmodulin). Zn²⁺: no ligand-field preference, labile, binds Cys/His in tetrahedral sites that hold a fold (zinc fingers). Cu²⁺: strongest binder (top of the Irving–Williams series) and still labile; Cu is linked to the folding of prion and amyloid proteins.
3. Al³⁺ and Cr³⁺: high charge density, so their aqua ions hydrolyse and precipitate as hydroxides near pH 7; they bind phosphate and carboxylate too strongly and would lock a misfolded chain. Cr³⁺ (d³) is also kinetically inert: ligand exchange takes hours or longer, far too slow to control folding. Al³⁺ is toxic for these reasons.

(iii) Why Zn²⁺ in hydrolytic enzymes

1. Strong Lewis acid for its size: bound water is made acidic (in carbonic anhydrase its pKₐ falls from 15.7 for bulk water to about 7), giving a Zn–OH⁻ nucleophile at neutral pH; it also polarises the C=O of a peptide or ester.
2. d¹⁰: no ligand-field stabilisation, so no preferred geometry: coordination number 4 or 5 changes easily during catalysis, and ligand exchange is fast (rapid turnover, about 10⁶ s⁻¹ for carbonic anhydrase).
3. No redox activity: Zn(II) cannot be oxidised or reduced, so it cannot start radical reactions that damage the substrate or protein.
4. Borderline hard/soft: binds N (His), O (Glu, water) and S (Cys) donors; it is abundant and available. Examples: carbonic anhydrase, carboxypeptidase, alkaline phosphatase.

(iv) Manganese in photosystem II

OECMn₄CaO₅ clusterCYCLEfour photons, four electrons, one O₂DRIVERP680⁺, about 1.3 V

1. Many accessible oxidation states: Mn(II) to Mn(V) at high, positive potentials. Water oxidation, 2H₂O → O₂ + 4H⁺ + 4e⁻, needs four oxidising equivalents; the four Mn atoms store them one photon at a time through the states S₀ to S₄, then release O₂ together.
2. Hard oxido ligands: Mn(III), Mn(IV) and Mn(V) are hard ions, well matched to the oxido and carboxylate O donors of the cluster; bridging oxide ions stabilise the high oxidation states and help form the O–O bond. Ca²⁺, which stays +2, binds the incoming water.
3. Copper and nickel have only Cu(I)/(II) and Ni(II) (Ni(I), Ni(III) occasionally) under biological conditions: they cannot store four equivalents at the required potential, their higher states would be unstable, and they prefer softer N and S donors.
4. Availability: Mn is abundant and its Mn(II) ion is soluble, so the cluster can be rebuilt each time the D1 protein is replaced after oxidative damage.

Application. these principles guide the design of bio-inspired catalysts: manganese–oxido and cobalt–oxido clusters are studied as cheap catalysts for water oxidation in artificial photosynthesis, and zinc complexes as artificial hydrolases.