AMIDATION OF BIOACTIVE PEPTIDES - THE STRUCTURE OF PEPTIDYLGLYCINE ALPHA-HYDROXYLATING MONOOXYGENASE

Many neuropeptides and peptide hormones require amidation at the carbo xyl terminus for activity. Peptidylglycine alpha-amidating monooxygena se (PAM) catalyzes the amidation of these diverse physiological regula tors. The amino-terminal domain of the bifunctional PAM protein is a p eptidylglycine alpha-hydroxylating monooxygenase (PHM) with two copper s that cycle through cupric and cuprous oxidation states. The anomalou s signal of the endogenous coppers was used to determine the structure of the catalytic core of oxidized rat PHM with and without bound pept ide substrate. These structures strongly suggest that the PHM reaction proceeds via activation of substrate by a copper-bound oxygen species . The mechanistic and structural insight gained from the PHM structure s can be directly extended to dopamine beta-monooxygenase.