Fig. S1.

Schematic overview of de novo and salvage dNTP biosynthetic pathways and the mechanism of action of dCK-dependent nucleoside analog prodrugs. (A) dNTPs are synthesized by the de novo pathway starting from glucose and amino acids, and by nucleoside salvage pathways starting with preformed deoxyribonucleosides (dNs). ADA, adenosine deaminase; dCK, deoxycytidine kinase; dGK, deoxyguanosine kinase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; PNP, purine nucleoside phosphorylase; RNR, ribonucleotide reductase; TK1, thymidine kinase 1; TK2, thymidine kinase 2. (B) Indicated nucleoside analog prodrugs are phosphorylated by dCK to their monophosphate forms and trapped inside the cells by dCK. Subsequent phosphorylation steps generate the active di- and triphosphate forms that induce anti-tumor effects via the indicated mechanisms.