Naturally Occurring Mutations to Muscle-Type Creatine Kinase Impact Its Canonical and Pharmacological Activities in a Substrate-Dependent Manner In Vitro.

ABSTRACT: Tenofovir (TFV) is a key component of human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP). TFV is a nucleotide analog reverse-transcriptase inhibitor prodrug that requires two separate phosphorylation reactions by intracellular kinases to form the active metabolite tenofovir-diphosphate (TFV-DP). Muscle-type creatine kinase (CKM) has previously been demonstrated to be the kinase most responsible for the phosphorylation of tenofovir-monophosphate (TFV-MP) to the active metabolite in colon tissue. Because of the importance of CKM in TFV activation, genetic variation in CKM may contribute to interindividual variability in TFV-DP levels. In the present study, we report 10 naturally occurring CKM mutations that reduced TFV-MP phosphorylation in vitro: T35I, R43Q, I92M, H97Y, R130

SUBMITTER: Mosher EP 

PROVIDER: S-EPMC8626780 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature