Uridine diphosphate acid hydrolysis

Typical reactions catalyzed by UGT enzymes require the cofactor uridine diphosphate-glucuronic acid, UDPGA. However, the C-terminus of all UGT enzymes contains a membrane-spanning domain that anchors the enzyme in the endoplasmic reticulum, and the enzyme faces the lumen of the endoplasmic reticulum, where it is ideally placed to conjugate lipophilic xenobiotics and their metabolites generated by oxidation, reduction, or hydrolysis. The lumenal... 

Fig. 4 Formation of uridine diphosphate glucuronic acid (UDP-GA) and its conjugation with clofibric acid. Inversion takes place during conjugation, the a-D-glucuronic acid forming a P-D-glucuronide. At a more alkaline pH, such glu-curonides may undergo intramolecular rearrangement to forms resistant to enzymic hydrolysis by P-glucuronidase.

Mechanistic studies of the hydrolysis of phosphate diesters indicate similar possibilities, with alkyl metaphosphate (ROP02)-like transition states and 5 n2(P) pathways. The hydrolysis of m-nitrobenzyl uridine 3 -diphosphate, whose two potential leaving groups have equal pK s, is associated with isomerisation to the 2 -isomer in weakly acidic solution, which requires pseudorotation of a (probably neutral) phosphorane. ... 

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