S-adenosyl-L-homocysteine hydrolase (SAHase) is an essential enzyme involved in the regulation of methylation reactions. This applies to both, healthy host cells and their invading pathogens form. Therefore, selective inhibition of SAHases in targeted cells is an excellent possibility for a drug intervention at the molecular level of cell metabolism. SAHases are highly-conserved enzymes with almost identical organization of the active site. This fact practically precludes design of highly selective inhibitors against the enzymes of pathogenic origin that would not affect the human cells. Therefore, the aim of this study is not to focus on the active site but to elucidate mechanisms of substrate and inhibitor delivery to the substrate-binding pocket of SAHases. For this purpose, targets were selected from various prokaryotic and eukaryotic human pathogens. Phylogenetic relationships and sequence differences including extra inserts within a substrate-binding domain have been taken into account during enzyme selection. The premises about various mechanisms which regulate the accessibility of the substrate binding pocked are based on crystallographic studies of SAHases from various organisms. However, the chemical nature of the different regulation mechanisms has not yet been explained. Additionally, apart from the active site, a role of a non-conservative entrance to the substrate-binding pocked in substrate delivery to the active site is proposed.
This project is supported by a grant from the Polish National Science Center (No. UMO-2013/09/B/NZ1/01880).