Probing the Catalytic Mechanism and Inhibition of SAMHD1 Using the Differential Properties of R_p- and S_p-dNTPαS Diastereomers.

ABSTRACT: SAMHD1 is a fundamental regulator of cellular dNTPs that catalyzes their hydrolysis into 2'-deoxynucleoside and triphosphate, restricting the replication of viruses, including HIV-1, in CD4⁺ myeloid lineage and resting T-cells. SAMHD1 mutations are associated with the autoimmune disease Aicardi-Goutières syndrome (AGS) and certain cancers. More recently, SAMHD1 has been linked to anticancer drug resistance and the suppression of the interferon response to cytosolic nucleic acids after DNA damage. Here, we probe dNTP hydrolysis and inhibition of SAMHD1 using the R_p and S_p diastereomers of dNTPαS nucleotides. Our biochemical and enzymological data show that the α-phosphorothioate substitution in S_p-dNTPαS but not R_p-dNTPαS diastereomers

SUBMITTER: Morris ER 

PROVIDER: S-EPMC8173608 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature