A mechanism of the C-S bond activation of S-adenosylmethionine (SAM) in biotin synthase is discussed from quantum mechanical/molecular mechanical (QM/MM) computations. The active site of the enzyme involves a [4Fe-4S] cluster, which is coordinated to the COO- and NH2 groups of the methionine moiety of SAM. The unpaired electrons on the iron atoms of the [4Fe-4S]2+ cluster are antiferromagnetically coupled, resulting in the S = 0 ground spin state. An electron is transferred from an electron donor to the [4Fe-4S]2+-SAM complex to produce the catalytically active [4Fe-4S]+ state. The SOMO of the [4Fe-4S]+-SAM complex is localized on the [4Fe-4S] moiety and the spin density of the [4Fe-4S] core is calculated to be 0.83. The C-S bond cleavage is associated with the electron transfer from the [4Fe-4S]+ cluster to the antibonding σ* C-S orbital. The electron donor and acceptor states are effectively coupled with each other at the transition state for the C-S bond cleavage. The activation barrier is calculated to be 16.0 kcal/mol at the QM (B3LYP/SV(P))/MM (CHARMm) level of theory and the C-S bond activation process is 17.4 kcal/mol exothermic, which is in good agreement with the experimental observation that the C-S bond is irreversibly cleaved in biotin synthase. The sulfur atom of the produced methionine molecule is unlikely to bind to an iron atom of the [4Fe-4S]2+ cluster after the C-S bond cleavage from the energetical and structural points of view.
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