Hydride Transfer Stereospecificity in Methenyl-Tetrahydromethanopterin: Donor-Dependent Effects

Pterin derivatives play crucial roles in various biological processes across organisms from bacteria to mammals. Despite extensive research, intriguing questions remain, especially regarding hydride transfer reactions involving molecules like methylene-tetrahydromethanopterin and methylene-tetrahydrofolate. These reactions are catalyzed by dehydrogenases such as MtdA, MtdB, and the F420-dependent enzyme, yet their catalytic mechanisms, the origins of their stereospecificity and the contrasting stereochemistry of analogous non-enzymatic reactions are not yet fully understood. In this study, we modeled the behavior of a simplified version of methylene-tetrahydromethanopterin in aqueous solution and investigated non-enzymatic hydride transfer from various donors to an equally simple methenyl-tetrahydromethanopterin model, in order to identify factors influencing activation energy and stereospecificity. Our findings show that methylene-tetrahydromethanopterin adopts a conformation enhancing C-H bond reactivity in the pro-S orientation. On the other hand, its cationic derivative preferentially accepts hydride units on the Si face from smaller donors, a preference that decreases and even reverses with larger donors like 1,4-dihydropyridines. These insights enhance the understanding of pterin-related enzymatic catalysis and might be useful in the design of pterin-based biocatalysts.