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New insights into copper monooxygenases and peptide amidation: structure, mechanism and function

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Many bioactive peptides must be amidated at their carboxy terminus to exhibit full activity. Surprisingly, the amides are not generated by a transamidation reaction. Instead, the hormones are synthesized from glycine-extended intermediates that are transformed into active amidated hormones by oxidative cleavage of the glycine N-Cα bond. In higher organisms, this reaction is catalyzed by a single bifunctional enzyme, peptidylglycine α-amidating monooxygenase (PAM). The PAM gene encodes one polypeptide with two enzymes that catalyze the two sequential reactions required for amidation. Peptidylglycine α-hydroxylating monooxygenase (PHM; EC catalyzes the stereospecific hydroxylation of the glycine α-carbon of all the peptidylglycine substrates. The second enzyme, peptidyl-α-hydroxyglycine α-amidating lyase (PAL; EC, generates α-amidated peptide product and glyoxylate. PHM contains two redox-active copper atoms that, after reduction by ascorbate, catalyze the reduction of molecular oxygen for the hydroxylation of glycine-extended substrates. The structure of the catalytic core of rat PHM at atomic resolution provides a framework for understanding the broad substrate specificity of PHM, identifying residues critical for PHM activity, and proposing mechanisms for the chemical and electron-transfer steps in catalysis. Since PHM is homologous in sequence and mechanism to dopamine β-monooxygenase (DBM; EC, the enzyme that converts dopamine to norepinephrine during catecholamine biosynthesis, these structural and mechanistic insights are extended to DBM.

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Received 7 December 1999; received after revision 24 February 2000; accepted 29 February 2000

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Prigge, S., Mains, R., Eipper, B. et al. New insights into copper monooxygenases and peptide amidation: structure, mechanism and function . CMLS, Cell. Mol. Life Sci. 57, 1236–1259 (2000).

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