Carboxymethylenebutenolidase Like Protein (CMBL)

CMBL (EC 3.1.1.45) is a cysteine hydrolase of the dienelactone hydrolase family that is highly expressed in liver cytosol.CMBL hydrolyzed the angiotensin receptor (AGTR1) blocker olmesartan medoxomil to the bioavailable molecule olmesartan with simple Michaelis-Menten kinetics. It also catalyzed the hydrolytic activation of other medoxomil-ester prodrugs with the medoxomil moiety linked to an oxygen atom, but not those with medoxomil linked to a nitrogen atom. CMBL appeared to prefer cyclic esters over simple esters and amides, and it did not hydrolyze typical esterase substrates. Inhibitor studies showed that CMBL was sensitive to a carboxylesterase inhibitor and a free thiol modifier, indicating that CMBL is a cysteine hydrolase. Site-directed mutagenesis confirmed that cys132 is the catalytic cysteine in CMBL.