Reaction mechanisms between methylamine and a few Schiff bases: Ab initio potential energy surfaces of a catalytic step in semicarbazide sensitive amino oxidases (SSAO)

The potential energy surfaces for the transamination reaction catalyzed by SSAO were explored for some of the possible reactants considered in a preli minary investigation (Comput Chem 2000, 24, 311). The proton transfer to me thylamine (as a model of the catalytic base belonging to the enzyme active site)-either from the keto or enol form of the reactant Schiff bases with o ne of the possible cofactors, pyridoxal phosphate, PLP (using as a model th e pyridoxal ring protonated at N)-was investigated. The enol form seems to be preferred in the region of the neutral intermediate, because even the ke to form undergoes a spontaneous rearrangement to the enol form once the C-a lpha proton is delivered to methylamine, producing methylammonium. When the proton is returned back to the Schiff base (on C-1), the adduct is about 1 .4 kcal/mol more stable than the reactants, while a canonical electron dist ribution is obtainable only for the enol form. The proton transfer to methy lamine was also studied in the presence of the other possible cofactor (par a or ortho) topaquinone, TQ. A steep uphill pathway, similar to the keto-py ridoxal Schiff base one, is obtained using the Schiff base with pTQ, which requires a rearrangement to the final intermediate. On the contrary, using the oTQ structures with the quinonoid O on the same side of methylamine, th e proton abstracted from the Schiff base goes spontaneously onto the other quinonoid oxygen. The effect an the barrier heights produced by the presenc e of a variety of functional groups in the vicinity of the pyridoxal ring n itrogen was also examined. (C) 2001 John Wiley & Sons, Inc.