H

Aspartate Transition state

FIGURE 2.3 Inhibition of aspartate transcarbamoylase by PALA.

phosphoribosyl pyrophosphate (PRPP) to give orotidylate. Finally, uridylic acid (uridine monophosphate, UMP) is generated by decarboxylation (Fig. 2.2). UMP is the precursor to other pyrimidine nucleotides, after its conversion to the corresponding nucleoside triphosphate (UTP).

Among the many compounds known to inhibit reactions of this pathway, we will only mention N-phosphonoacetyl-l-aspartate (PALA), an inhibitor of aspartate transcarbamoylase that acts as a transition state analog (Fig. 2.3). This compound has undergone some clinical trials, normally in combination with 5-fluorouracil (5-FU), another pyrimidine antimetabolite.1

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