Phosphonoacetyl-L-aspartate PALA

In practice, these considerations usually reduce A G si,- i er by > three orders of magnitude (> — 4 kcal mol-1) since observed effective concentrations > 105 M are rarely if ever seen in bisubstrate inhibitors. For example, N-phosphonoacetyl-L-aspartate (PALA),1241 in clinical trials in the 1980s, is a typical bisubstrate analog1251 with Kt = 27 nM (Fig. 11) and an observed effective concentration of > 17 M (equa-... 

Figure 7.6 (a) The first step in the biosynthesis of pyrimidines, (b) The proposed transition state for the carbamoyl phosphate/aspartic acid stage in pyrimidine synthesis, (c) The structure of sodium N-phosphonoacetyl-L-aspartate (PALA)... 

A particularly intuitive application of this concept may be the experimental anticancer drug N-(phosphonoacetyl)-L-aspartate (PALA). The first step in the de novo biosynthesis of the pyrimidine nucleotide formation in the cell involves the condensation of carbamoyl phosphate with L-aspartic acid catalyzed by the enzyme aspartate transcarbamylase (Eq. 2.14).2 One can postulate a transition state, as shown in Eq. 2.14. 

Dynamics of proteins are in general important to their functions (Frauenfelder et al. 1979 Karplus and McCammon, 1983, Capeillere-Blandin and Albani, 1987). It was shown for example, that binding of cytidine 5 -triphosphate (CTP) and N-(phosphonoacetyl)-L-aspartate (PALA) to aspartate transcarbamylase (ATCase) from Escherichia coli induces a modification in the dynamics behavior of the two Trp residues of the protein (Royer et al. 1987). 

Fig. 1. Sites of action of cytostatic agents. PALA = N-phosphonoacetyl-L-aspartate.

The pyrimidine antagonists inhibit the biosynthesis of pyrimidine nucleotides or interfere with vital cellular functions, such as the synthesis or function of nucleic acids. The analogues of deoxycytidine and thymidine that are used are inhibitors of DNA synthesis while 5-fluorouracil (5-FU) an analogue of uracil, is an inhibitor of both RNA function and of the synthesis of thymidylate (see Fig. 2). PALA (N-phosphonoacetyl-L-aspartate), an inhibitor of as-... 

Glode, J., Gross, H., Henklein, P, Niedrich, H., Tanneberger, S., and Tschiersch, B., Synthesis of N-(phosphonoacetyl)-L-aspartic acid (PALA), Pharmazie, 43, 434, 1988. 

Figure 7. Interactions at the active site of aspartate transcarbamylase (ATCase). N-phosphonoacetyl-L-asparate (PALA) is a bisubstrate analog of the two natural substrates of ATCase, carbamyl phosphate and L-aspartate. PALA is shown bound in the active site of ATCase. Noncovalent interactions between PALA and side-chains of the protein are shown as dashed lines. Specific residues are indicated by their one letter abbreviation and by their position in the protein sequence (e.g., HI 34 = histidine at position 134). The active site is composed of residues from two separate polypeptide chains (denoted by primed and unprimed residue numbers). Note the complimentarity of the site and the ligand. The same interactions are used to align and catalyze the condensation of ATCase s natural substrates (Monaco et al., 1978).

FIGURE 51-1 Summary of the mechanisms and sites of action of some chemotherapeutic agents useful in neoplastic disease. PALA = A-phosphonoacetyl-L-aspartate TMP = thymidine monophosphate. 

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