Thymidylate kinase (A48R) (A48R)

The Monkeypox A48R protein, also known as thymidylate kinase (tmk), is a vital enzyme for the Monkeypox virus (MPXV) replication cycle (UniProt: Q8V4Y0). It belongs to the nucleoside monophosphate kinase family and catalyzes the conversion of deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP) using ATP as a phosphate donor (PubMed: 36253421). This step is essential for the de novo synthesis of deoxythymidine triphosphate (dTTP), which is a critical precursor for viral DNA synthesis. Since poxviruses replicate in the host cell's cytoplasm, they must encode their own enzymes for nucleotide metabolism to ensure an adequate supply of DNA building blocks (NCBI: Gene ID 928965). A48R is a validated therapeutic target because its inhibition leads to the depletion of dTTP pools, effectively halting viral genome replication and progeny production. While there are currently no FDA-approved drugs specifically targeting A48R, it is a major focus for the development of novel small-molecule inhibitors and nucleoside analogs designed to selectively target the viral enzyme over its human counterpart (PubMed: 35914481). The structural differences between the viral A48R and human thymidylate kinase provide a basis for achieving high drug selectivity and reducing potential toxicity.

Other names

MPXV-A48RdTMP kinaseThymidylate monophosphate kinaseA48R proteinDeoxythymidylate kinase

Inhibition of the thymidylate kinase enzyme prevents the conversion of deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), thereby depleting the pool of deoxythymidine triphosphate (dTTP) required for viral DNA synthesis and halting viral replication.