Characterization of a peptide alpha-amidation activity in human plasma and tissues

Wand, Gary S.; Ney, Robert L.; Baylin, Stephen B.; Eipper, Betty A.; Mains, Richard E.

doi:10.1016/0026-0495(85)90077-0

Cited by 52 publications

(54 citation statements)

References 28 publications

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“…PAM shows the high- www.chemmedchem.org est expression level in the CNS and is the enzyme responsible for the activation of prodrug 5. [14,16] This selective activation pathway is assumed to contribute to a brain targeting.…”

Section: Activationmentioning

confidence: 99%

“…[14] Thus, this mode of activation could contribute to brain targeting. [16] Prodrug 8 is assumed to be a substrate for transporters resulting in an increased oral bioavailability by active uptake mechanisms. Despite many efforts to understand the exact substrate specificity of human transport systems, the knowledge is still very restricted and does not allow reliable predictions as to whether a newly discovered compound is a substrate or not.…”

Section: Introductionmentioning

confidence: 99%

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New Prodrugs of the Antiprotozoal Drug Pentamidine

Kotthaus

Schade

et al. 2011

ChemMedChem

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Pentamidine is an effective antimicrobial agent that is approved for the treatment of African trypanosomiasis but suffers from poor oral bioavailability and central nervous system (CNS) penetration. This work deals with the development and systematic characterisation of new prodrugs of pentamidine. For this reason, numerous prodrugs that use different prodrug principles were synthesised and examined in vitro and in vivo. Another objective of the study was the determination of permeability of the different pentamidine prodrugs. While some of the prodrug principles applied in this study are known, such as the conversion of the amidine functions into amidoximes or the O-alkylation of amidoximes with a carboxymethyl residue, others were developed more recently and are described here for the first time. These newly developed methods aim to increase the affinity of the prodrug for the transporters and mediate an active uptake via carrier systems by conjugation of amidoximes with compounds that improve the overall solubility of the prodrug. The different principles chosen resulted in several pentamidine prodrugs with various advantages. The objective of this investigation was the systematic characterisation and evaluation of eight pentamidine prodrugs in order to identify the most appropriate strategy to improve the properties of the parent drug. For this reason, all prodrugs were examined with respect to their solubility, stability, enzymatic activation, distribution, CNS delivery, and oral bioavailability. The results of this work have allowed reliable conclusions to be drawn regarding the best prodrug principle for the antiprotozoal drug pentamidine.

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Section: Activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New Prodrugs of the Antiprotozoal Drug Pentamidine

Kotthaus

Schade

et al. 2011

ChemMedChem

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“…5 PAM activity has been found in a number of endocrine tumors (secreting ␣-amidated peptides), such as medullary thyroid carcinoma, pheochromocytoma, 6 pancreatic tumors (secreting vasoactive intestinal peptide), 7 and human pituitary tumors. 8,9 The finding that PAM immunoreactivity was also detected in several unexpected cell types, such as ependyma, choroid plexus, oligodendroglia, and Schwann cells 10 prompted us to investigate whether PAM expression could be detected in gliomas.…”

mentioning

confidence: 99%

Neutralization of Adrenomedullin Inhibits the Growth of Human Glioblastoma Cell Lines in Vitro and Suppresses Tumor Xenograft Growth in Vivo

Ouafik¹,

Sauze²,

Boudouresque³

et al. 2002

The American Journal of Pathology

119

159

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Presently, there is no effective treatment for glioblastoma, the most malignant and common brain tumor. Growth factors are potential targets for therapeutic strategies because they are essential for tumor growth and progression. Peptidylglycine ␣-amidating monooxygenase is the enzyme producing ␣-amidated bioactive peptides from their inactive glycine-extended precursors. The high expression of peptidylglycine ␣-amidating monooxygenase mRNA in glioblastoma and glioma cell lines points to the involvement of ␣-amidated peptides in tumorigenic growth processes in the brain. After screening of amidated peptides, it was found that human glioblastoma cell lines express high levels of adrenomedullin (AM) mRNA, and that immunoreactive AM is released into the culture medium. AM is a multifunctional regulatory peptide with mitogenic and angiogenic capabilities among others. Real-time quantitative reverse transcriptase-polymerase chain reaction analysis showed that AM mRNA was correlated to the tumor type and grade, with high expression in all glioblastomas analyzed, whereas a low expression was found in anaplastic astrocytomas and barely detectable levels in low-grade astrocytomas and oligodendrogliomas. In the present study we also demonstrate the presence of mRNA encoding the putative AM receptors, calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CRLR/RAMP2; CRLR/RAMP3) in both glioma tissues and glioblastoma cell lines and further show that exogenously added AM can stimulate the growth of these glioblastoma cells in vitro. These findings suggest that AM may function as an autocrine growth factor for glioblastoma cells. One way to test the autocrine hypothesis is to interrupt the function of the endogenously produced AM. Herein, we demonstrate that a polyclonal antibody specific to AM, blocks the binding of the hormone to its cellular receptors and decreases by 33% (P < 0.001) the growth of U87 glioblastoma cells in vitro. Malignant glioblastomas are highly aggressive tumors with a median patient survival time of 9 to 14 months.

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“…In mammals, PAM activity has been found in the blood and in many tissues 15 , with the highest levels being found in pituitary, central nervous system and the atrium of the heart 7,14–16 . A large percentage of mammalian bioactive peptides, ~50%, possess an α-amidated C-terminus.…”

Section: Introductionmentioning

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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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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Characterization of a peptide alpha-amidation activity in human plasma and tissues

Cited by 52 publications

References 28 publications

New Prodrugs of the Antiprotozoal Drug Pentamidine

New Prodrugs of the Antiprotozoal Drug Pentamidine

Neutralization of Adrenomedullin Inhibits the Growth of Human Glioblastoma Cell Lines in Vitro and Suppresses Tumor Xenograft Growth in Vivo

Inactivation of peptidylglycineα-hydroxylating monooxygenase by cinnamic acid analogs

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