The catalytic metal ions in Metal MACiE can carry out one, or more than one, three main functions :
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1) ACTIVATION OF REACTING SPECIES
The metal-induced activation exploits, most often, the Lewis acidity of the cations. When the substrate/cofactor coordinates the metal, the metal withdraws electrons from the ligand atom, inducing polarization of the bonds involving the ligand and activating it to the catalytic reaction. The following examples explain the 4 activation mechanisms in Metal MACiE which exploit the Lewis acidity of metals
A) Increases the electrophilicity of a reacting species
This occurs, for instance, in 6-hydroxymethyl-7,8-dihydropterin pyrophokinase (M0151) where Mg coordination by ATP causes polarization of the beta-phosphate P-O bond, enhancing the electrophilic character of the phosphorous atom and activating it for attack by the negatively charged pterin.
B) Increases the acidity of a reacting species
This occurs, for instance, in 3-dehydroquinate synthase (M0059) where Zn coordination results in increasing the acidity of the substrate. The proton release determines the electronic rearrangement of the species, activating it to the catalytic reaction.
C) Increases the nucleophilicity of a reacting species
This function is an alternative mechanism of activation deriving from the increase of acidity of species (see B). This occurs, for instance, in peptide deformylase (M0098) where a divalent ion promotes the proton release from water, determining the formation of a reactive hydroxyl ion.
D) Promotes heterolysis
This function is quite rare in Metal MACiE. This occurs, for instance, in pentalenene synthase (M0089) where the magnesium ion promotes the heterolytic cleavage of a C-O bond and the formation of a carbocation
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2) TRANSFER OF ELECTRON(S) FROM/TO THE REACTING SPECIES
In these cases Nature exploits the redox properties of transition metal ions which take part in one or more steps of the enzymatic reaction donating and/or accepting electrons to/from other reacting species. For instance, iron in isopenicillin N synthase (M0145) passes through the +2, +3 and +4 oxidation states.
It is worth noting that the function of iron in the first step of this reaction may be also regarded as an additional mechanism of substrate (i.e. dioxygen) activation, relying on the redox activity of the metal ion rather than on its Lewis acid properties.
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3) PROMOTION OF HOMOLYSIS TO OBTAIN RADICAL FORMATION
In B12-dependent enzymes such as methylaspartate mutase (M0063), the catalytic reaction proceeds through a free-radical mechanism promoted by the homolysis of the Co(III)-carbon of cobalamin to generate Co(II) and a carbon radical. In these cases, the metal is assigned the function of promoting homolysis.
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4) ELECTROSTATIC STABILIZATION OF INTERMEDIATES AND TRANSITION STATES
In these cases, the residual positive charge present on the metal ion is used to counterbalance local negative charges formed in the active site in the course of the reaction, such as in phosphoinositide phospholipase C (M0028), stabilizing the intermediates/transition states.
