Looking glass mechanism-based inhibition of peptidylglycine α-amidating monooxygenase

Foster, Michael S.; Oldham, Charlie D.; May, Sheldon W.

doi:10.1016/j.tetasy.2011.01.006

Cited by 5 publications

(4 citation statements)

References 50 publications

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“…We find that inactivated PHM is indistinguishable from untreated enzyme and find no evidence for cinnamate oxidation during the inactivation reaction. The reversible Michael addition of an active site nucleophile to cinnamate could account for our data and may explain the inactivation of PHM by a variety of acrylates 20,30,35 , and the 2- and 3-alkenoates 32 as well as provide an explanation for the lack of PHM-labeling by 3 H-PBA 37 .…”

Section: Introductionmentioning

confidence: 57%

“…Other olefinic inactivators of PHM include monoethyl fumarate 25 , styrylthioa-cetate 38 , 2- and 3-alkenoates 32 , vinylglycine 32 , 3-substituted acrylates 32 , substituted 4-oxo-2-hexenoates 30 , and D-Phe-L-Phe-L-vinylglycine 64 . Other monooxygenases, P 450 and dopamine β-monooxygenase (DβM, structurally and mechanistically related to PHM), are inactivated by olefins 65–68 .…”

Section: Discussionmentioning

confidence: 99%

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Inactivation of peptidylglycineα-hydroxylating monooxygenase by cinnamic acid analogs

McIntyre

Lowe

Battistini

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Peptidylglycine α-amidating monooxygenase (PAM) is a bifunctional enzyme that catalyzes the final reaction in the maturation of α-amidated peptide hormones. Peptidylglycine α-hydroxylating monooxygenase (PHM) is the PAM domain responsible for the copper-, ascorbate- and O2-dependent hydroxylation of a glycine-extended peptide. Peptidylamidoglycolate lyase is the PAM domain responsible for the Zn(II)-dependent dealkylation of the α-hydroxyglycine-containing precursor to the final α-amidated peptide. We report herein that cinnamic acid and cinnamic acid analogs are inhibitors or inactivators of PHM. The inactivation chemistry exhibited by the cinnamates exhibits all the attributes of a suicide-substrate. However, we find no evidence for the formation of an irreversible linkage between cinnamate and PHM in the inactivated enzyme. Our data support the reversible formation of a Michael adduct between an active site nucleophile and cinnamate that leads to inactive enzyme. Our data are of significance given that cinnamates are found in foods, perfumes, cosmetics and pharmaceuticals.

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Section: Introductionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Inactivation of peptidylglycineα-hydroxylating monooxygenase by cinnamic acid analogs

McIntyre

Lowe

Battistini

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The first report of a PHM inactivator was trans ‐4‐phenyl‐3‐butenoate (PBA) (Bradbury, Mistry, Roos, et al, 1990) (Figure 3h). In addition to PBA and ring‐substituted PBAs (Langella et al, 2010), other PHM inactivators include trans ‐styrylthioacetate (Casara et al, 1996), 2‐[(phenylethynyl)thio]acetate (Casara et al, 1996), acrylates (Foster et al, 2011; Katopodis & May, 1990b; Rhodes & Honsinger, 1993), monoethyl fumarate (Katopodis & May, 1990b), 2‐, 3‐, and 2,4‐alkenoates (Rhodes & Honsinger, 1993), cinnamate and ring‐substituted cinnamates (Bradbury, Mistry, & Smyth, 1990; McIntyre et al, 2016), N ‐formyl amides (Klinge et al, 1994), and peptides with a C‐terminal vinylglycine (Zabriskie et al, 1994). Treatment of cultured mammalian cells and rats with PBA inhibits PHM activity and the biosynthesis of α‐amidated peptides (Abou‐Mohamed et al, 2000; Ogonowski et al, 1997).…”

Section: Phm Inactivatorsmentioning

confidence: 99%

Peptidylglycine α‐amidating monooxygenase as a therapeutic target or biomarker for human diseases

Merkler

Hawley

Eipper

et al. 2022

British J Pharmacology

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Peptides play a key role in controlling many physiological and neurobiological pathways. Many bioactive peptides require a C‐terminal α‐amide for full activity. The bifunctional enzyme catalysing α‐amidation, peptidylglycine α‐amidating monooxygenase (PAM), is the sole enzyme responsible for amidated peptide biosynthesis, from Chlamydomonas reinhardtii to Homo sapiens. Many neuronal and endocrine functions are dependent upon amidated peptides; additional amidated peptides are growth promoters in tumours. The amidation reaction occurs in two steps, glycine α‐hydroxylation followed by dealkylation to generate the α‐amide product. Currently, most potentially useful inhibitors target the first reaction, which is rate‐limiting. PAM is a membrane‐bound enzyme that visits the cell surface during peptide secretion. PAM is then used again in the biosynthetic pathway, meaning that cell‐impermeable inhibitors or inactivators could have therapeutic value for the treatment of cancer or psychiatric abnormalities. To date, inhibitor design has not fully exploited the structures and mechanistic details of PAM.

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“…The first report of a PHM inactivator wastrans -4-phenyl-3-butenoate (PBA) (A. F. Bradbury, Mistry, Roos, et al, 1990). In addition to PBA and ring-substituted PBAs (Langella et al, 2010), other PHM inactivators includetrans -styrylthioacetate (Casara et al, 1996), 2-[(phenylethynyl)thio]acetate (Casara et al, 1996), acrylates (Foster, Oldham, & May, 2011;Rhodes & Honsinger, 1993), monoethyl fumarate (A. G. , 2-, 3-, and 2,4-alkenoates (Rhodes & Honsinger, 1993), cinnamate and ring-substituted cinnamates (A. F. N.R. McIntyre et al, 2016), N -formyl amides (Klinge, Cheng, Zabriske, & Vederas, 1994), and peptides with a C-terminal vinylglycine (Zabriskie et al, 1994).…”

Section: Phm Inactivatorsmentioning

confidence: 99%

Peptidylglycine α-amidating monooxygenase as a therapeutic target or biomarker

Merkler

Hawley

Eipper

et al. 2021

Preprint

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Peptides play a key role in controlling many physiological and neurobiological pathways. Many bioactive peptides require a C-terminal α-amide for full activity. The bifunctional enzyme catalyzing α-amidation, peptidylglycine α-amidating monooxygenase (PAM), is the sole enzyme responsible for amidated peptide biosynthesis, from Chlamydomonas reinhardtii to Homo sapiens. Many neuronal and endocrine functions are dependent upon amidated peptides; additional amidated peptides are growth promoters in tumors. The amidation reaction occurs in two steps, glycine α-hydroxylation followed by dealkylation to generate the α-amide product. Currently, most potentially useful inhibitors target the first reaction, which is rate-limiting. PAM is a membrane-bound enzyme that visits the cell surface during peptide secretion. PAM is then used again in the biosynthetic pathway, meaning that cell-impermeable inhibitors or inactivators could have therapeutic value for the treatment of cancer or psychiatric abnormalities. To date, inhibitor design has not fully exploited the structures and mechanistic details of PAM.

show abstract

Looking glass mechanism-based inhibition of peptidylglycine α-amidating monooxygenase

Cited by 5 publications

References 50 publications

Inactivation of peptidylglycineα-hydroxylating monooxygenase by cinnamic acid analogs

Inactivation of peptidylglycineα-hydroxylating monooxygenase by cinnamic acid analogs

Peptidylglycine α‐amidating monooxygenase as a therapeutic target or biomarker for human diseases

Peptidylglycine α-amidating monooxygenase as a therapeutic target or biomarker

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