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

Citation
St. Prigge et al., New insights into copper monooxygenases and peptide amidation: structure, mechanism and function, CELL MOL L, 57(8-9), 2000, pp. 1236-1259
Citations number
169
Language
INGLESE
art.tipo
Review
Categorie Soggetti
Cell & Developmental Biology
Journal title
CELLULAR AND MOLECULAR LIFE SCIENCES
ISSN journal
1420-682X → ACNP
Volume
57
Issue
8-9
Year of publication
2000
Pages
1236 - 1259
Database
ISI
SICI code
1420-682X(200008)57:8-9<1236:NIICMA>2.0.ZU;2-X
Abstract
Many bioactive peptides must be amidated at their carboxy terminus to exhib it full activity. Surprisingly, the amides are not generated by a transamid ation reaction. Instead, the hormones are synthesized from glycine-extended intermediates that are transformed into active amidated hormones by oxidat ive cleavage of the glycine N-C alpha bond. In higher organisms, this react ion is catalyzed by a single bifunctional enzyme, peptidylglycine alpha-ami dating monooxygenase (PAM). The PAM gene encodes one polypeptide with two e nzymes that catalyze the two sequential reactions required for amidation. P eptidylglycine alpha-hydroxylating monooxygenase (PHM; EC 1.14.17.3) cataly zes the stereospecific hydroxylation of the glycine alpha-carbon of all the peptidylglycine substrates. The second enzyme, peptidyl-alpha-hydroxyglyci ne alpha-amidating lyase (PAL; EC 4.3.2.5), generates alpha-amidated peptid e product and glyoxylate. PHM contains two redox-active copper atoms that, after reduction by ascorbate, catalyze the reduction of molecular oxygen fo r the hydroxylation of glycine-extended substrates. The structure of the ca talytic core of rat PHM at atomic resolution provides a framework for under standing the broad substrate specificity of PHM, identifying residues criti cal for PHM activity, and proposing mechanisms for the chemical and electro n-transfer steps in catalysis. Since PHM is homologous in sequence and mech anism to dopamine beta-monooxygenase (DBM; EC 1.14.17.1), the enzyme that c onverts dopamine to norepinephrine during catecholamine biosynthesis, these structural and mechanistic insights are extended to DBM.