Abstract
SAMHD1 in humans is vital in regulating many DNA-involved systems through its role as a dNTP triphosphohydrolase for cellular dNTP management. Not only does this ensure DNA replication, but it also ensures DNA repair to prevent cancer and viral replication through dNTP starvation. It can also function as a means to regulate immune cells through interferons. SAMHD1 is not catalytically active in its monomeric form, but through a metal and nucleotide-dependent process, it dimerizes then tetramerizes into the active form. To investigate modulation of Hs SAMHD1’s substrate promiscuity, a homologue form Leishmania tarentolae exhibits an extreme substrate specificity for only dCTP. The Lt SAMHD1 also presents another striking feature: d(GTP)'s affinity for the first allosteric site is almost two orders of magnitude greater than that of humans. The goal of this study was to determine the molecular underpinnings for these two phenomena for these two phenomena, as this opens up drug targets for parasites like Trypanosoma brucei. It also modulates the activity of Hs SAMHD1 to prevent unwanted catalysis of drugs, increase viral regulation, or even impact the immune response.