Biosynthesis of the C-terminal amide in peptide hormones

Bradbury, A. F.; Smyth, Derek G.

doi:10.1007/bf01122123

Cited by 82 publications

(38 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PAM enzymes catalyse the conversion of carboxy-terminal glycine extended peptides to an ~-amidated product. This occurs concomitantly with secretion and is essential for full biological potency of some pro-hormones (for reviews see [9,10]). Biochemical similarities between DBH and PAM include the following.…”

Section: Discussionmentioning

confidence: 99%

Sequence similarity between dopamine β‐hydroxylase and peptide α‐amidating enzyme: Evidence for a conserved catalytic domain

Southan¹,

Kruse²

1989

FEBS Letters

View full text Add to dashboard Cite

A comparison of human dopamine fl-hydroxylase (EC 1.14.17.1) with bovine peptide C-terminal ~t-amidating enzyme (EC 1.14.17.3), revealed a 28% identity extending throughout a common catalytic domain of approximately 270 residues. The shared biochemical properties of these two enzymes from neurosecretory granules suggests that the sequence similarity reflects a genuine homology and provides a structural basis for a new family of copper type II, ascorbate-dependent monooxygenases.

show abstract

Section: Discussionmentioning

confidence: 99%

Sequence similarity between dopamine β‐hydroxylase and peptide α‐amidating enzyme: Evidence for a conserved catalytic domain

Southan¹,

Kruse²

1989

FEBS Letters

View full text Add to dashboard Cite

show abstract

“…Post-translational amide modification of the C-terminal amino acid is common among neuropeptides and is essential to their bioactivity (Bradbury and Smyth, 1987;Escher et al, 1982;Eipper and Mains, 1988). Such enzymatic amidation may prevent the carboxy terminus of peptides from becoming ionized, therefore making them more hydrophobic and better able to bind to their receptors.…”

Section: Structure-activity Relationships Of Neuromedin Umentioning

confidence: 99%

Neuromedin U and Its Receptors: Structure, Function, and Physiological Roles

Brighton

Szekeres²,

Willars³

2004

Pharmacol Rev

248

219

View full text Add to dashboard Cite

“…One such processing event is carboxyl-terminal amidation, a very prevalent post-translational modification essential to the bioactivity of many neuropeptides (1,2). We and others (3)(4)(5)(6)(7)(8) have demonstrated that formation of peptide amides from their glycine-extended precursors is a two-step process, entailing sequential enzymatic action by peptidylglycine monooxygenase (PAM, 1 EC 1.14.17.3) and peptidylamidoglycolate lyase (PGL, EC 4.3.2.5).…”

mentioning

confidence: 99%

Pyruvate-extended Amino Acid Derivatives as Highly Potent Inhibitors of Carboxyl-terminal Peptide Amidation

Mounier

Shi

Sirimanne

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

Carboxyl-terminal amidation, a required post-translational modification for the bioactivation of many neuropeptides, entails sequential enzymatic action by peptidylglycine monooxygenase (PAM, EC 1.14.17.3) and peptidylamidoglycolate lyase (PGL, EC 4.3.2.5). The monooxygenase, PAM, first catalyzes conversion of a glycine-extended pro-peptide to the corresponding ␣-hydroxyglycine derivative, and the lyase, PGL, then catalyzes breakdown of this ␣-hydroxyglycine derivative to the amidated peptide plus glyoxylate. We now introduce the first potent inhibitors for peptidylamidoglycolate lyase. These inhibitors, which can be viewed as pyruvate-extended N-acetyl amino acids, constitute a novel class of compounds. They were designed to resemble likely transient species along the reaction pathway of PGL catalysis. A general synthetic procedure for preparation of pyruvate-extended N-acetyl amino acids or peptides is described. Since these compounds possess the 2,4-dioxo-carboxylate moiety, their solution tautomerization was investigated using both NMR and high performance liquid chromatography analyses. The results establish that freshly prepared solutions of N-AcPhe-pyruvate consist predominantly of the enol tautomer, which then slowly tautomerizes to the diketo form when left standing for several days in an aqueous medium; upon acidification, formation of the hydrate tautomer occurs. Kinetic experiments established that these novel compounds are highly potent, pure competitive inhibitors of PGL. Kinetic experiments with the ascorbate-dependent copper monooxygenases, PAM and dopamine-␤-monooxygenase, established that these compounds also bind competitively with respect to ascorbate; however, pyruvate-extended N-acyl-amino acid derivatives possessing hydrophobic side chains are much more potent inhibitors of PGL than of PAM. Selective targeting of N-Ac-Phe-pyruvate so as to inhibit the lyase, but not the monooxygenase, domain was demonstrated with the bifunctional amidating enzyme of Xenopus laevis. The availability of potent inhibitors of PGL should facilitate studies regarding the possible biological role of ␣-hydroxyglycine-extended peptides.Neuropeptides, which are critical mediators of intercellular communication, are generated biosynthetically from larger precursors via a variety of post-translational modifications. One such processing event is carboxyl-terminal amidation, a very prevalent post-translational modification essential to the bioactivity of many neuropeptides (1, 2). We and others (3-8) have demonstrated that formation of peptide amides from their glycine-extended precursors is a two-step process, entailing sequential enzymatic action by peptidylglycine monooxygenase (PAM, 1 EC 1.14.17.3) and peptidylamidoglycolate lyase (PGL, EC 4.3.2.5). The monooxygenase, PAM, first catalyzes formation of the ␣-hydroxyglycine derivative of the glycine-extended precursor, in a process dependent upon ascorbate, copper, and molecular oxygen (3, 4, 9). The lyase, PGL, then catalyzes the breakdown of this ␣-hydroxyglycine de...

show abstract

Biosynthesis of the C-terminal amide in peptide hormones

Cited by 82 publications

References 26 publications

Sequence similarity between dopamine β‐hydroxylase and peptide α‐amidating enzyme: Evidence for a conserved catalytic domain

Sequence similarity between dopamine β‐hydroxylase and peptide α‐amidating enzyme: Evidence for a conserved catalytic domain

Neuromedin U and Its Receptors: Structure, Function, and Physiological Roles

Pyruvate-extended Amino Acid Derivatives as Highly Potent Inhibitors of Carboxyl-terminal Peptide Amidation

Contact Info

Product

Resources

About