Page - (000029) - in Biomedical Chemistry: Current Trends and Developments

Phosphate and acyl group transfer reactions, key pieces in metabolic pathways, are also nucleophilic substitution reactions although with some differences. In the phosphorylation of glucose a phosphate group is transferred from ATP to glucose with a phosphorus atom undergoing a nucleophilic substitution (Scheme 1.1.8). Scheme 1.1.8: Glucose phosphorylation. In this reaction, the phosphorus electrophilicity is reinforced trough chelation with two Mg2+ ions present in the phosphoryl transferase enzyme. In the complex, the most representative resonance structure places a positive formal charge in the P atom and negative charges on the O atoms. This makes the tetrahedral phosphate easy to be attacked by the oxygen atom from the 6-hydroxyl group in glucose, while a base captures the released proton. The mechanism shown in Scheme 1.1.8 is a simplified version of what has been observed. The preferred reaction path is not well defined in biological systems, since it is highly dependent on the nature of the nucleophile and the enzyme scaffold. Intermediates may or may not be involved. Either a pentavalent trigonal bipyramidal (associative intermediate) or a metaphosphate (dissociative intermediate) intermediate may be formed (Scheme 1.1.9). A concerted reaction mechanism has also been observed, where the substitution is done smoothly in one step (i.e. SN2 like).