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Novel Substrates And Inhibitors Of Peptidylglycine Alpha-amidating Monooxygenase.

A. Katopodis, S. May
Published 1990 · Chemistry, Medicine

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Peptidylglycine alpha-amidating monooxygenase (PAM, EC 1.14.17.3) catalyzes the formation of alpha-amidated peptides from their glycine-extended precursors, thus playing a key role in the processing of peptide neurohormones. We now report that PAM readily catalyzes three alternate monooxygenase reactions--sulfoxidation, amine N-dealkylation, and O-dealkylation. Thus, (4-nitrobenzyl)thioacetic acid is converted to the analogous sulfoxide, N-(4-nitrobenzyl)glycine is converted to 4-nitrobenzylamine and glyoxylate, and [(4-nitrobenzyl)oxy]acetic acid is converted to 4-nitrobenzyl alcohol and glyoxylate. All these new activities display the characteristics expected for the normal PAM-catalyzed reductive oxygenation pathway and produce an equimolar amount of glyoxylate together with the heteroatom-containing dealkylation products. The ester [(4-methoxybenzoyl)oxy]acetic acid is not a PAM substrate, but is instead a good competitive inhibitor (KI = 0.48 mM). In addition, we report that the olefinic substrate analogues trans-benzoylacrylic acid and 4-phenyl-3-butenoic acid are potent time-dependent inactivators of PAM, with inactivation exhibiting the characteristics expected for mechanism-based inhibition. Monoethyl fumarate is also a time-dependent inactivator of PAM. Finally, we introduce several small non-peptide substrates for PAM by demonstrating that PAM catalyzes the transformation of hippuric acid and several ring-substituted derivatives to the corresponding benzamides and glyoxylic acid, with the most facile substrate of this class being 4-nitrohippuric acid. These compounds are the smallest amide substrates yet reported for PAM, and it is thus apparent that only the minimal structure of an acylglycine is required for PAM-catalyzed oxygenative amidation.
This paper references
10.1016/0006-291X(86)91080-6
Tissue distribution and characterization of peptide C-terminal α-amidating activity in rat
J. Sakata (1986)
10.1021/BI00539A032
Chiral sulfoxidations catalyzed by rat liver cytochromes P-450.
D. Waxman (1982)
Dopamine beta-hydroxylase. Comparative specificities and mechanisms of the oxygenation reactions.
S. May (1981)
10.1146/ANNUREV.BI.57.070188.003003
Dopamine beta-hydroxylase of adrenal chromaffin granules: structure and function.
L. C. Stewart (1988)
10.1021/JA00211A033
New oxyfunctionalization capabilities for .omega.-hydroxylases. Asymmetric aliphatic sulfoxidation and branched ether demethylation
A. Katopodis (1988)
10.1021/JA00373A053
Electron transfer from nitrogen in microsomal oxidation of amine and amide. Simulation of microsomal oxidation by anodic oxidation
T. Shono (1982)
10.1021/BI00342A021
Olefin oxygenation and N-dealkylation by dopamine beta-monooxygenase: catalysis and mechanism-based inhibition.
S. Padgette (1985)
Dopamine beta-hydroxylase. Demonstration of enzymatic ketonization of the product enantiomer S-octopamine.
S. May (1981)
10.1016/0006-291X(88)90767-X
Cloning of cDNA encoding a new peptide C-terminal α-amidating enzyme having a putative membrane-spanning domain from Xenopuslaevis skin
K. Ohsuye (1988)
10.1146/ANNUREV.PH.50.030188.002001
Peptide alpha-amidation.
B. Eipper (1988)
10.1016/0006-291X(83)91274-3
Dopamine-B-hydroxylase: suicide inhibition by the novel olefinic substrate, 1-phenyl-1-aminomethylethene.
S. May (1983)
10.1016/0006-291X(86)90322-0
Peptide C-terminal α-amidating enzyme purified to homogeneity from Xenopuslaevis skin
Kazuhiko Mizuno (1986)
10.1021/JA00354A044
MNDO calculation of kinetic isotope effects in model cytochrome P-450 oxidations
J.Paul Shea (1983)
10.1021/JA00538A080
Asymmetric sulfoxidation by dopamine .beta.-hydroxylase, an oxygenase heretofore considered specific for methylene hydroxylation
S. May (1980)
10.1210/ENDO-118-6-2262
Purification and characterization of a peptidyl glycine monooxygenase from porcine pituitary.
J. S. Kizer (1986)
10.1111/J.1432-1033.1987.TB13648.X
Enzyme‐catalysed peptide amidation
A. Bradbury (1987)
10.1016/S0040-4039(00)78745-4
Kinetic study on enzymatic s-oxygenation promoted by a reconstituted system with purified cytochrome P-450
Y. Watanabe (1980)
10.1021/JA00189A065
Dopamine .beta.-monooxygenase-catalyzed aromatization of 1-(2-aminoethyl)-1,4-cyclohexadiene: redirection of specificity and evidence for a hydrogen-atom-transfer mechanism
K. Wimalasena (1989)
10.1007/BF01122123
Biosynthesis of the C-terminal amide in peptide hormones
A. Bradbury (1987)
10.1039/JR9400000769
143. Studies in peroxidase action. Part II. The oxidation of p-toluidine
B. Saunders (1940)
10.1021/JA00233A032
Formation of peptide amides by peptidylglycine .alpha.-amidating monooxygenase: a new assay and stereochemistry of hydrogen loss
S. E. Ramer (1988)
Purification and characterization of peptidylglycine alpha-amidating monooxygenase from bovine neurointermediate pituitary.
A. Murthy (1986)
10.1002/chin.198543146
CYTOCHROME P-450 CATALYZED OXIDATION OF QUADRICYCLANE. EVIDENCE FOR A RADICAL CATION INTERMEDIATE
R. Stearns (1985)
10.1038/298686A0
Mechanism of C-terminal amide formation by pituitary enzymes
A. Bradbury (1982)
10.1016/0006-291X(88)90621-3
A new facile trinitrophenylated substrate for peptide alpha-amidation and its use to characterize PAM activity in chromaffin granules.
A. Katopodis (1988)
10.1021/BI00539A031
Studies on the chirality of sulfoxidation catalyzed by bacterial flavoenzyme cyclohexanone monooxygenase and hog liver flavin adenine dinucleotide containing monooxygenase.
D. Light (1982)
10.1021/JA00543A053
Ruthenium(II) tris(bipyrazyl) dication: a new photocatalyst
R. Crutchley (1980)
The catalytic mechanism of cytochrome P-450. Spin-trapping evidence for one-electron substrate oxidation.
O. Augusto (1982)
10.1016/0006-291X(82)91937-4
Bioactivation of Catha edulis alkaloids: enzymatic ketonization of norpseudoephedrine.
S. May (1982)
10.1021/BI00535A035
Destruction of cytochrome P-450 by vinyl fluoride, fluroxene, and acetylene. Evidence for a radical intermediate in olefin oxidation.
P. R. Ortiz de Montellano (1982)
Kinetic isotope effects on cytochrome P-450-catalyzed oxidation reactions. The oxidative O-dealkylation of 7-ethoxycoumarin.
G. Miwa (1984)
10.1021/BI00380A021
Ascorbate depletion as a consequence of product recycling during dopamine beta-monooxygenase catalyzed selenoxidation.
S. May (1987)
10.1016/0006-291X(83)91573-5
The amidating enzyme in pituitary will accept a peptide with C-terminal D-alanine as substrate.
A. E. Landymore-Lim (1983)
10.1021/AR00097A002
Chemical mechanisms of catalysis by cytochromes P-450: a unified view
F. Guengerich (1984)
10.1021/JO00428A004
Facile synthesis of amino acid and peptide esters under mild conditions via cesium salts.
Wang S-S (1977)
10.1021/JA00230A059
Facile stereoselective allylic hydroxylation by dopamine .beta.-monooxygenase
S. Sirimanne (1988)
The allantoin content of blood.
A. Christman (1944)
10.1021/JA00247A033
Mechanistic studies on dopamine .beta.-monooxygenase catalysis: N-dealkylation and mechanism-based inhibition by benzylic-nitrogen-containing compounds. Evidence for a single-electron-transfer mechanism
K. Wimalasena (1987)
10.1073/PNAS.80.16.5144
Identification in pituitary tissue of a peptide alpha-amidation activity that acts on glycine-extended peptides and requires molecular oxygen, copper, and ascorbic acid.
B. Eipper (1983)
10.1246/BCSJ.54.1163
Enzymatic Oxidation of Alkyl Sulfides by Cytochrome P-450 and Hydroxyl Radical
Y. Watanabe (1981)
10.1021/JA00187A088
Enzymatic peptidyl .alpha.-amidation proceeds through formation of an .alpha.-hydroxyglycine intermediate
S. D. Young (1989)
10.1016/0003-9861(87)90563-7
Mechanism-based inhibitors of dopamine β-hydroxylase
P. Fitzpatrick (1987)
10.1246/BCSJ.55.188
Mechanisms of enzymatic S-oxygenation of thioanisole derivatives and O-demethylation of anisole derivatives promoted by both microsomes and a reconstituted system with purified cytochrome P-450.
Y. Watanabe (1982)
10.1021/JO00366A024
The formation and metabolism of N-hydroxymethyl compounds. Part 8. The oxidative decarboxylation of N-aroylglycines to N-(acetoxymethyl)benzamides and N-formylbenzamides with lead(IV) acetate
A. P. Gledhill (1986)
10.1016/0003-9861(88)90102-6
Purification of a peptidylglycine alpha-amidating enzyme from transplantable rat medullary thyroid carcinomas.
N. M. Mehta (1988)
10.1210/MEND-1-11-777
Structure of the precursor to an enzyme mediating COOH-terminal amidation in peptide biosynthesis.
B. Eipper (1987)



This paper is referenced by
10.1074/jbc.M513886200
Role for an Essential Tyrosine in Peptide Amidation*
M. De (2006)
10.1016/S0169-5002(99)00015-X
Autocrine growth loops dependent on peptidyl alpha-amidating enzyme as targets for novel tumor cell growth inhibitors.
N. Iwai (1999)
10.1152/ajpcell.1997.273.6.C1908
Amidative peptide processing and vascular function.
C. D. Oldham (1997)
10.1126/SCIENCE.278.5341.1300
Amidation of bioactive peptides: the structure of peptidylglycine alpha-hydroxylating monooxygenase.
S. Prigge (1997)
10.1038/13351
Substrate-mediated electron transfer in peptidylglycine α-hydroxylating monooxygenase
S. Prigge (1999)
10.1016/S0076-6879(97)79007-4
Peptidylglycine alpha-amidating monooxygenase: an ascorbate-requiring enzyme.
A. Kolhekar (1997)
In vivo inhibition of peptidylglycine-alpha-hydroxylating monooxygenase by 4-phenyl-3-butenoic acid.
G. Mueller (1999)
Design, synthesis, kinetic analysis, molecular modeling, and pharmacological evaluation of novel inhibitors of peptide amidation
M. Foster (2008)
10.1016/0005-2728(93)90108-R
The secretory-vesicle ascorbate-regenerating system: a chain of concerted H+/e(-)-transfer reactions.
D. Njus (1993)
10.1002/0470028637.MET282
Peptidyl‐α‐Hydroxyglycine α‐Amidating Lyase (PAL)
E. Chufán (2010)
The evaluation of novel anti-inflammatory compounds in cell culture and experimental arthritis and identification of an inhibitor to early-stage loblolly pine somatic embryo growth
Jacob Lucrezi (2013)
10.1002/ARCH.940260104
Peptide amidation in an invertebrate: purification, characterization, and inhibition of peptidylglycine alpha-hydroxylating monooxygenase from the heads of honeybees (Apis mellifera).
T. Zabriskie (1994)
10.1016/0010-8545(92)80033-N
Oxygen insertion in organic substrates catalyzed by copper compounds
E. Spodine (1992)
10.1016/0016-6480(91)90022-X
Kinetic analyses of peptidylglycine α-amidating monooxygenase from pancreatic islets
B. D. Noe (1991)
10.1016/j.bmcl.2012.10.004
Prohormone-substrate peptide sequence recognition by peptidylglycine α-amidating monooxygenase and its reflection in increased glycolate inhibitor potency.
K. M. Morris (2012)
10.1007/s10637-015-0254-2
Amidation inhibitors 4-phenyl-3-butenoic acid and 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester are novel HDAC inhibitors with anti-tumorigenic properties
A. Ali (2015)
10.1007/978-1-4615-4793-8_76
A pathway for the biosynthesis of fatty acid amides.
K. Merkler (1999)
10.1021/BI00478A001
A novel enzyme from bovine neurointermediate pituitary catalyzes dealkylation of alpha-hydroxyglycine derivatives, thereby functioning sequentially with peptidylglycine alpha-amidating monooxygenase in peptide amidation.
A. Katopodis (1990)
10.1007/978-1-4613-9783-0_4
Dioxygen Reactivity in Copper Proteins and Complexes
S. Fox (1995)
Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function Running title : Effects of PAM on beta cell function
Anne Raimondo (2017)
10.1016/j.str.2009.05.008
Amidation of bioactive peptides: the structure of the lyase domain of the amidating enzyme.
E. Chufán (2009)
10.1016/0960-894X(96)00041-8
Unsaturated thioacetic acids as novel mechanism-based inhibitors of peptidylglycine α-hydroxylating monooxygenase
P. Casara (1996)
10.1124/MOL.55.6.1067
Differential regulation of peptide alpha-amidation by dexamethasone and disulfiram.
W. Driscoll (1999)
10.1006/ABBI.1999.1611
The enzymatic formation of novel bile acid primary amides.
L. King (2000)
10.1007/978-94-011-6875-5_16
The Enzymology of Peptide Amidation
D. J. Merkler (1993)
10.1002/cmdc.201000214
Probing the Peptidylglycine α‐Hydroxylating Monooxygenase Active Site with Novel 4‐Phenyl‐3‐butenoic Acid Based Inhibitors
E. Langella (2010)
10.1007/s000110050335
Pharmacological evaluation of 1-(carboxymethyl)-3,5-diphenyl-2-methylbenzene, a novel arylacetic acid with potential anti-inflammatory properties
S. J. Cutler (1998)
10.1111/J.1527-3466.2007.00004.X
Oleamide: a fatty acid amide signaling molecule in the cardiovascular system?
C. Hiley (2007)
Steady State and Theoretical Investigations of Peptidylglycine α-Amidating Monooxygenase (PAM)
Edward W. Lowe (2008)
10.1080/12265071.1998.9647415
Absence of an Essential Thiol in Human Glutaminyl Cyclase: Implications for Mechanism
Jeffrey S. Temple (1998)
10.1016/J.MEHY.2003.11.012
A new proposal for the mechanism of glycine hydroxylation as catalyzed by peptidylglycine alpha-hydroxylating monooxygenase (PHM).
T. C. Owen (2004)
10.1021/BI00239A016
Functional and structural characterization of peptidylamidoglycolate lyase, the enzyme catalyzing the second step in peptide amidation.
A. Katopodis (1991)
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