Strain within N5,N10-bridged tetrahydropterins influences stereochemistry of hydride transfer

The stereoselectivity of hydride transfer reactions involving N5,N10-methylenetetra- hydromethanopterin and N5,N10-methylenetetrahydrofolate exhibits a striking contrast between enzymatic and non-enzymatic environments. Enzymatic reactions consistently favor the Re face of the imidazolidine ring, while non-enzymatic reductions with NaBH4 show near-absolute selectivity for the Si face. This study employs computational methods to investigate the underlying factors driving the non-enzymatic stereoselectivity, focusing on the role of the charge of the hydride donor and structural features of the pterin ring. Transition state structures and energy decomposition analysis reveal that structural strain promotes the Si pathway. Although the anionic nature of the hydride donor influences selectivity, intrinsic structural rigidity emerges as a dominant factor. These results deepen our understanding of pterin reactivity and its implications for enzymatic catalysis and metabolic processes.