Diphosphates as leaving groups

The nucleotide cyclic AMP (3, 5 -cyclic adenosine monophosphate, cAMP) is a cyclic phosphate ester of particular biochemical significance. It is formed from the triester ATP by the action of the enzyme adenylate cyclase, via nucleophilic attack of the ribose 3 -hydroxyl onto the nearest P=0 group, displacing diphosphate as leaving group. It is subsequently inactivated by hydrolysis to 5 -AMP through the action of a phosphodiesterase enzyme. 

Note that the first step in Figure 21.6—reaction of the carboxylate with ATP to give an acyl adenylate—is itself a nucleophilic acyl substitution on phosphorus. The carboxylate first adds to a P=0 bond, giving a five-coordinate phosphorus intermediate that expels diphosphate ion as leaving group. 

Figure 11.15 Biosynthesis of geraniol from dimethylallyl diphosphate. Two Sfvjl reactions occur, both with diphosphate ion as the leaving group.

The S il reaction occurs when the substrate spontaneously dissociates to a carbocation in a slow rate-limiting step, followed by a rapid reaction with the nucleophile. As a result, SN1 reactions are kinetically first-order and take place with racemization of configuration at the carbon atom. They are most favored for tertiary substrates. Both S l and S 2 reactions occur in biological pathways, although the leaving group is typically a diphosphate ion rather than a halide. 

The compounds geranyl diphosphate, farnesyl diphosphate, and geranylgeranyl diphosphate are biochemical precursors of monoterpenes, sesquiterpenes, and diterpenes respectively, and virtually all subsequent modifications of these precursors involve initial formation of an allylic cation through loss of diphosphate as the leaving group. 

The fatty acid is initially converted into an acyl-AMP derivative by attack of the carboxylate as a nucleophile onto the P=0 system of ATP, with loss of diphosphate as a leaving group. This reaction is far from favourable, and the equilibrium is disturbed by subsequent pyrophosphatase-catalysed hydrolysis of diphosphate into two molecules of phosphate. 

Addition of new nucleotide units to the growing chain occurs in the 5 to C direction, and is catalysed by the enzyme DNA polymerase. The most important step is the addition of a 5 -mononucleoside triphosphate to the free 3 -hydroxyl group of the growing chain as the 3 -hydroxyl attacks the triphosphate and expels a diphosphate leaving group. 

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