Type II Dehydroquinase

Dehydroquinase (3-dehydroquinate dehydratase, DHQ, EC 4.2.1.10) is the third enzyme in the shikimic acid pathway. This route involves seven enzymes that catalyze the sequential conversion of erythrose-4-phosphate and phosphoenolpyruvate to chorismic acid, which is the precursor in the synthesis of aromatic amino acids, L-Phe, L-Tyr and L-Thr, and other important aromatic compounds such as folate cofactors, ubiquinone and vitamins E and K. The enzymes involved in the shikimic acid pathway are present in bacteria, fungi and higher plants, but they are absent in mammals. Some of these enzymes have also been detected in Toxoplasma gondii (which causes malaria) and Plasmodium falciparum extracts.

There are two types of DHQ enzymes, namely type I DHQ (DHQ1) and type II DHQ (DHQ2). Both enzymes catalyze the reversible dehydration of 3-dehydroquinic acid (1) to form 3-dehydroshikimic acid (2) but the reaction mechanism is completely different in each case.

DHQ2 is essential in pathogenic bacteria such as Mycobacterium tuberculosis (aroD gene), which is responsible for tuberculosis, and Helicobacter pylori (aroD/aroQ gene), which is the causative agent of gastric and duodenal ulcers and has also been classified as a type I carcinogen.

DHQ2 catalyzes the anti elimination of water through the loss of the more acidic pro-S hydrogen from C2 of 3-dehydroquinic acid (1) via an enolate intermediate, compound 3 (Scheme 1).

Scheme 1. Reaction catalyzed by the DHQ2 enzyme and structural requeriments for catalysis.

Based on the enzyme mechanism, we have developed compounds able to interfere and/or block the action of essential residues in the catalysis. We have developed four series of very potent competitive inhibitors of the dehydroquinase enzyme that bock the entrance of the essential arginine (Scheme 2):

a) analogues of the natural substrate

b) mimetics of the reaction intermediate involved in the catalysis.

Scheme 2. Selected view of several crystal structures of the binary complex of DHQ2 from H. pylori and M. tuberculosis with enolate mimetics and substrate analogs that are potent competitive reversible inhibitors.