Meta-Biol

• Pathways

Cellular uptake of decitabine or 5‑aza‑2′‑deoxycytidine is mediated by the equilibrative nucleoside transporters hENT1, hENT2, and hENT3, which also mediate cytosine uptake. Decitabine is a prodrug that has to be converted into a nucleoside triphosphate to become an active drug (reviewed in Raynal NJM & Issa JPJ 2016). The activation of the prodrug relies on three successive phosphorylation steps. The first phosphorylation is catalyzed by the deoxycytidine kinase (DCK) to produce the monophosphorylated form of decitabine or 5‑aza‑deoxycytidine‑5′‑monophosphate (5‑aza‑dCMP). Subsequently, two additional phosphorylation reactions catalyzed by the deoxycytidine‑5′‑monophosphate (dCMP) kinase and the nucleoside diphosphokinase will produce 5‑aza‑deoxycytidine‑5′‑diphosphate (5‑aza‑dCDP) and 5‑aza‑deoxycytidine‑5′‑triphosphate (5‑aza‑dCTP), respectively. Once in its triphosphate form, the active drug can be incorporated into the DNA of dividing cells by DNA polymerase, in the reaction annotated here. DNA polymerase has similar affinities for dCTP and 5‑aza‑dCTP (Raynal NJM & Issa JPJ 2016).