Thymidylate Kinase: An Old Topic Brings New Perspectives

Abstract

Thymidylate kinase (TMPK) is a key enzyme for pyrimidine synthesis that catalyzes the phosphorylation of thymidine 5'-monophosphate (dTMP) in the presence of ATP and Mg(2+) to form thymidine 5'-diphosphate (dTDP), which is then converted to thymidine 5'-triphosphate (dTTP) by nucleoside-diphosphate kinase (NDK). TMPK has an important function in cell proliferation and its enzyme kinetics and related structures have been determined in various organisms. TMPK is well recognized as a potential drug target, with the most notable function being in the activation of anti-HIV nucleoside prodrugs. Recent studies have shown that TMPK is a validated target for antibiotic development against gram-positive bacterium of Staphylococcus aureus. In addition, inhibition of human TMPK increases the potential of anticancer agent doxorubicin toward colon cancer cells regardless of p53 status. Following the rapid expanding knowledge on TMPKs and the rising interests in TMPKs as a drug target, in this review we try to describe current research on TMPKs in various organisms of eukaryotes, prokaryotes and viruses and to provide information for designing new potential inhibitors against TMPKs.

Elaboration of a proprietary thymidylate kinase inhibitor motif towards anti-tuberculosis agents

“…In two more analogues (7 and 8) the piperidine ring was substituted for a pyrrolidine ring. To explore the effect of additional distance and flexibility between the thymine and piperidinyl or pyrrolidinyl rings, analogues having a methylene linkage inserted between these heterocycles (9)(10)(11)(12) were prepared.…”

A combined systems and structural modeling approach repositions antibiotics for Mycoplasma genitalium

“…Tmk is an essential metabolic enzyme, which phosphorylates dTMP, producing dTDP Cui et al (2013), an important step in dTTP synthesis for DNA replication. Several reports have suggested that Tmk is a promising antibacterial target for multiple microorganisms including M. tuberculosis (Vanheusden et al, 2002), Pseudomonas aeruginosa (Choi et al, 2012), and Bacillus anthracis (Byun et al, 2008).…”

Nucleoside Analogs and Tuberculosis: New Weapons Against an Old Enemy

“…TMPK has already been considered as an interesting target for the synthesis of inhibitors both as anticancer [108] and as antiviral agents [109], and it recently attracted interest also for the development of antitubercular agents that could selectively target the M.tb isoform TMPKmt. In fact, TMPKmt appeared to be essential for mycobacterial DNA synthesis and biochemical and structural characterizations revealed only a 22% of sequence homology with the human isozyme (hTMPK) [110].…”