Formation of phosphate conjugates

Phosphate conjugates are rare compared to sulfates, yet they are of primary significance in the metabolism of anticancer and antiviral agents impacting on endogenous nucleotides. Indeed, phosphorylation is an essential metabolic step in the bioactivity of these agents, and numerous in vitro and in vivo studies document their stepwise phosphorylation to mono-, di-, and triphosphates. Such reactions are sometimes, and correctly, labeled as anabolic (i.e., biosynthetic) ones.68'69 They are known or postulated to be catalyzed by some among the very many phosphotransferases (EC 2.7), for example adenosine kinase (EC 2.7.1.20), thymidine kinase (2.7.1.21), uridine kinase (2.7.1.48), deoxycytidine kinase (EC 2.7.1.74), deoxyadenosine kinase (EC 2.7.1.76), nucleoside phosphotransferase (EC 2.7.1.77), creatine kinase (EC 2.7.3.2), adenylate kinase (EC 2.7.4.3), nucleoside-phosphate kinase (EC 2.7.4.4), guanylate kinase (EC 2.7.4.8), and (deoxy)nucleoside-phosphate kinase (EC 2.7.4.13).

A therapeutically relevant example is afforded by the well-known anti-HIVagent zidovudine (AZT) (36, Figure 14). The concentrations of its phosphate anabolites were measured in the peripheral blood mononuclear cells of AIDS patients treated with the drug.70 The monophosphate was the predominant compound, and the diphosphate and triphosphate were present in comparable amounts.

The unexpected (and mostly unexplored) activity of phosphotransferases toward xenobiotic substrates is forcefully illustrated by the recently reported activation of FTY720 (37, Figure 14), a novel immunomodulator showing great promise in transplantations and to treat autoimmunity.71 The agent itself appears inactive, being phosphorylated in rats and humans to the active monophosphate. Recent studies have implicated spingosine kinases as the catalysts and have shown that the reaction is highly product enantioselective. Indeed, FTY720 itself is prochiral (it bears two enantiotopic -CH2OH groups), and the enzymatic reaction results exclusively in the phosphorylated enantiomer of (S)-configuration (38), which is also the only active one.

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