Diphosphate leaving group

The compound dimethylallyl diphosphate provides an excellent example of a natural product with a diphosphate leaving group that can be displaced in a nucleophilic substitution reaction. Suitable nucleophiles are hydroxyl groups, e.g. a phenol, though frequently an electron-rich nucleophilic carbon is employed. Dimethylallyl diphosphate is a precursor of many natural products that contain in their structures branched-chain C5 subunits termed isoprene units. 

A common intermediate for all the nucleotides is 5-phosphoribosyl-l-diphosphate (PRPP), produced by successive ATP-dependent phosphorylations of ribose. This has an a-diphosphate leaving group that can be displaced in Sn2 reactions. Similar Sn2 reactions have been seen in glycoside synthesis (see Section 12.4) and biosynthesis (see Box 12.4), and for the synthesis of aminosugars (see Section 12.9). For pyrimidine nucleotide biosynthesis, the nucleophile is the 1-nitrogen of uracil-6-carboxylic acid, usually called orotic acid. The product is the nucleotide orotidylic acid, which is subsequently decarboxylated to the now recognizable uridylic acid (UMP). 

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. 

Bond formation occurs by attack of the 3 hydroxyl group on the 5 triphosphate, with loss of a diphosphate leaving group. 

Bowers, K.E., and Fierke, C. A. (2004). Positively charged side chains in protein farnesyltransferase enhance catalysis by stabilizing the formation of the diphosphate leaving group. Biochemistry 43 5256-5265. 

Figure 4 Electrophilic aromatic substitution, constituting the most likely mechanism for DMAT synthase. The diphosphate moiety dissociates to generate the allylic carbocation, which then attacks the activated carbon-4 of the indole ring system. Approach of the aromatic C-4 is opposite the diphosphate leaving group, as indicated by experiments with specifically mono-tritiated (T) DMAPP (Shibuya et al., 1990). 

Section 24.9 Carbon-carbon bond formation between isoprene units can be understood on the basis of nucleophilic attack of the tt electrons of a double bond on a carbocation or an allylic carbon that bears a diphosphate leaving group. 

Loss of the diphosphate leaving group forms a resonance-stabilized carbocation in Step [1], which reacts with the nucleophilic double bond of the 1° diphosphate to form a new C-C bond and a 3° carbocation in Step [2]. 

Nucleophilic attack with diphosphate forms neryl diphosphate, a stereoisomer of geranyl diphosphate. The diphosphate leaving group of neryl diphosphate is now in closer proximity to the doubie bond at the other end of the chain, so that intramolecular cyclization can occur. 

An acyl phosphate is formed by nucleophilic attack of a carboxylate ion on the y-phosphorus (the phosphorus farthest away from the adenosyl group) of ATP. Attack of the nucleophile breaks the phosphoanhydride bond (rather than the tt bond), so an intermediate is not formed. Essentially, it is an Sn2 reaction with an adenosine diphosphate leaving group. 

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