Phosphoribosyl pyrophosphate analogues

Huckel s method of molecular orbitals. II. Analogues of the orotic acid in the reaction with phosphoribosyl-pyrophosphate. J. Theor. Biol., 26, 29-32 (1970)... 

The crystal structure of hypoxanthine phosphoribosyltransferase has been solved in a ternary complex of the enzyme with the substrate 5-phosphoribosyl 1-pyrophosphate (PRPP) and an analogue of hypoxanthine with a carbon atom in place of As with PNP and OPRTase, these structures showed many contacts with... 

The first reaction is catalysed by orotate phosphoribosyltransferase (orotidine 5 -phosphate pyrophosphate phosphoribosyltransferase, EC 2.4.2.10) which is readily reversible. The equilibrium constant for the forward reaction [109] is about 0.1. The reaction is specific for orotate (the enzyme usually does not accept uracil) and some synthetic analogues of orotic acid (Chapter 6). Orotate phosphoribosyltransferase activity was found in many animal tissues [110] and there are several phosphoribosyl-transferases of broad specifity which are distinct from the enzyme involved in the orotate pathway [111-113]. 

An alternative mechanism of SAB action could involve its known effects on de novo purine biosynthesis (1, S) and/or nucleoside transport (5). The combined inhibitory effects of SAB and purine analogues on purine biosynthesis could result in sufficient depletion of intracellular nucleotide pools to result in enhanced cellular cytotoxicity. In addition, these effects would lead to an increased bioavailability of 5-phosphoribosyl-l-pyrophosphate (PRPP), the first enzymic product in the de novo pathway. Increased PRPP levels would enhance the activity of hypoxanthine phosphoribosyl transferase, leading to increased salvage of purine analogues. 

A short synthesis of the carbocyclic analogue of S-phosphoribosyl-1-pyrophosphate from the known (C.R. Johnson et al.. Tetrahedron, 1984, 40, 1225) chiral ketone 72 has been described. Syntheses of carba-a-D-arabinofuranose and of the carba-nucleosides (+)-cyclaradine and (+)- caH>a>P-D-arabinofuranosyluraciI from key intermediate nitro-compound 73 have been reported. A short synthesis of Ohno s lactone, 74 in 54% overall yield from (+)-(lR)-e/u/o-5-norbomene-2-carboxylic acid, as a useful carbocyclic nucleoside precursor, has been reported." See Chapter 20 for the synthesis of carbocyclic tiazofurin and other carbocyclic nucleosides. 

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