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malfunction
disruption of AP-1-dependent late endosomal trafficking diminishes the ability of PAM to retain copper and produce amidated peptides. Impaired AP-1 function alters luminal copper delivery to PAM. Altered luminal cuproenzyme function may contribute to diseases associated with diminished AP-1 function. Reduced AP-1 function makes 18-kDa fragment amidation more sensitive to inhibition by bathocuproine disulfonate, a cell-impermeant Cu(I) chelator. The endocytic trafficking of PAM is altered, and PAM-1 accumulates on the cell surface when AP-1 levels are reduced
malfunction
disruption of AP-1-dependent late endosomal trafficking diminishes the ability of PAM to retain copper and produce amidated peptides. Impaired AP-1 function alters luminal copper delivery to PAM. Altered luminal cuproenzyme function may contribute to diseases associated with diminished AP-1 function. Reduced AP-1 function makes 18-kDa fragment amidation more sensitive to inhibition by bathocuproine disulfonate, a cell-impermeant Cu(I) chelator. The endocytic trafficking of PAM is altered, and PAM-1 accumulates on the cell surface when AP-1 levels are reduced
malfunction
mutating the His residues His364, His366, and His367 to Ala in the His-rich cluster (His-Gly-His-His) in the linker region connecting the enzyme's two catalytic domains affects enzyme trafficking. H3A mutation eliminates the ability of internalized PAM-1 to return to secretory granules
malfunction
the rs13175330 polymorphism of the PAM gene is selected from the ten single nucleotide polymorphisms (SNPs) most strongly associated with blood pressure. The presence of the G allele of the PAM rs13175330 A>G SNP is associated with a higher risk of hypertension after adjustments for age, sex, BMI, smoking, and drinking. The PAM rs13175330 A>G SNP is a candidate gene for hypertension in the Korean population. Additionally, the PAM rs13175330 G allele might be associated with insulin resistance and LDL atherogenicity in patients with hypertension. Phenotypes, overview
metabolism
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copper metabolism is altered by PAM
metabolism
the enzyme catalyzes the final reaction in the maturation of alpha-amidated peptide hormones
physiological function
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regulation of the hypothalamic-pituitary-thyroid axis and body temperature are selected for evaluation
physiological function
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essential for the synthesis of all amidated neuropeptides, mice lacking peptidylglycine alpha-amidating monooxygenase do not survive gestation
physiological function
most mammalian bioactive peptides possess a C-terminal amino acid amide moiety. Amidated peptides are produced in vivo by the enzymatic cleavage of a precursor with a C-terminal glycine residue. The enzyme catalyzes the key step in the oxidation of the glycine-extended precursors to the alpha-amidated peptide
physiological function
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the enzyme is a regulator of copper homeostasis in neuroendocrine cells
physiological function
decreasing luminal pH is thought to play a role in the entry of newly synthesized and endocytosed membrane proteins into secretory granules. Secretory granule membrane proteins are retrieved and reused or degraded after exocytosis. The two catalytic domains of peptidylglycine alpha-amidating monooxygenase (PAM) catalyze the sequential reactions that convert peptidyl-Gly substrates into amidated products. A conserved His-rich cluster (His-Gly-His-His) in the linker region connecting its two catalytic domains senses pH and is involved in enzyme trafficking
physiological function
in neuroendocrine cells, ATP7A provides copper to peptidylglycine alpha-amidating monooxygenase (PAM), an essential enzyme that requires copper to catalyze peptide amidation, one of the final steps in the production of bioactive peptides. Trafficking of Atp7a, a copper pump, and the cuproenzyme PAM-1 depend on adaptor protein-1 complex (AP-1). The enzyme is involved in the prohormone POMC processing pathway and constitutive-like secretion, overview. Production of the amidated products of POMC (18-kDa fragment-NH2, JP-NH2, and ACTH(1-13)NH2) requires both PAM and Atp7a
physiological function
in neuroendocrine cells, ATP7A provides copper to peptidylglycine alpha-amidating monooxygenase (PAM), an essential enzyme that requires copper to catalyze peptide amidation, one of the final steps in the production of bioactive peptides. Trafficking of Atp7a, a copper pump, and the cuproenzyme PAM-1 depend on adaptor protein-1 complex (AP-1). The enzyme is involved in the prohormone POMC processing pathway and constitutive-like secretion, overview. Production of the amidated products of POMC (18-kDa fragment-NH2, JP-NH2, and ACTH(1-13)NH2) requires both PAM and Atp7a, Atp7a concentrates in the Golgi region in pituitary cells
physiological function
PAM is a bifunctional enzyme, its copper-dependent peptidylglycine alpha-hydroxylating monooxygenase, PHM, domain converts peptidylglycine substrates to peptidyl-alpha-hydroxyglycine intermediates that are subsequently converted into amidated products plus glyoxylate by the zinc-dependent peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) domain. The reaction catalyzed by PHM results in the stereospecific incorporation of one atom of molecular oxygen into the substrate in a reaction that involves two single electron transfer steps. PAM-mediated C-terminal amidation occurs across a range of biologically active endocrine and nervous system peptides and in many cases has been shown to be required for normal biological activity in vivo. Peptidylglycine alpha-amidating monooxygenase (PAM) is solely responsible for catalysis of amidation, a biologically important posttranslational modification. Peptide substrate amidation is strikingly sensitive to the exposure of cells to moderate hypoxia, physiological effects of hypoxia may be PAM-dependent. Because PAM-dependent amidation is irreversible, bi-directional responses that rapidly upregulate and downregulate levels of amidation can only be observed on rapidly turned-over PAM substrates
physiological function
PAM is a bifunctional enzyme, its copper-dependent peptidylglycine alpha-hydroxylating monooxygenase, PHM, domain converts peptidylglycine substrates to peptidyl-alpha-hydroxyglycine intermediates that are subsequently converted into amidated products plus glyoxylate by the zinc-dependent peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) domain. The reaction catalyzed by PHM results in the stereospecific incorporation of one atom of molecular oxygen into the substrate in a reaction that involves two single electron transfer steps. PAM-mediated C-terminal amidation occurs across a range of biologically active endocrine and nervous system peptides and in many cases has been shown to be required for normal biological activity in vivo. Peptidylglycine alpha-amidating monooxygenase (PAM) is solely responsible for catalysis of amidation, a biologically important posttranslational modification. Peptide substrate amidation is strikingly sensitive to the exposure of cells to moderate hypoxia, physiological effects of hypoxia may be PAM-dependent. Because PAM-dependent amidation is irreversible, bi-directional responses that rapidly upregulate and downregulate levels of amidation can only be observed on rapidly turned-over PAM substrates
physiological function
PAM is the only known enzyme responsible for the bioconversion of glycine C-terminal prohormones into des-glycine alpha-amidated products and glyoxylate. PAM is a bifunctional, type-II copper monooxygenase that consists of two independent catalytic domains, PHM and PAL. The PAM reaction is a two-step process. Initially, PHM removes the pro-S hydrogen to allow hydroxylation of the alpha-glycyl carbon, resulting in an alpha-hydroxylated intermediate. PHM is a molecular oxygen, Cu(II) and ascorbate (reductant) dependent enzyme. The second catalytic domain, PAL, dealkylates the alpha-hydroxylated intermediate, yielding the alpha-amidated product and glyoxylate. PAM is responsible for the posttranslational modification of many important neuropeptides, including oxytocin, vasopressin, ACTH, alphaMSH, VIP, substance P, neuropeptide Y, cholecystokinin, gastrin, and a large number of other molecules. Hypoglycemic effect of the alpha-amidated analogue of recombinant human insulin
physiological function
peptidylglycine alpha-amidating monooxygenase (PAM) is a bifunctional enzyme that catalyzes the final reaction in the maturation of alpha-amidated peptide hormones. Peptidylglycine alpha-hydroxylating monooxygenase (PHM) is the PAM domain responsible for the copper-, ascorbate- and O2-dependent hydroxylation of glycine-extended precursor peptides to the active alpha-amidated peptide and glyoxylate. Peptidylamidoglycolate lyase, EC 4.3.2.5, is the PAM domain responsible for the Zn(II)-dependent dealkylation of the alpha-hydroxyglycine-containing precursor to the final alpha-amidated peptide
physiological function
peptidylglycine alpha-amidating monooxygenase (PAM) is solely responsible for catalysis of amidation, a biologically important posttranslational modification. Peptide substrate amidation is strikingly sensitive to the exposure of cells to moderate hypoxia, physiological effects of hypoxia may be PAM-dependent. PHM-dependent amidation of POMC peptides is sensitive to oxygen in AtT20 cells. Enzyme PHM is essential for development in Drosophila melanogaster. Peptidylglycine alpha-amidating monooxygenase (PAM) is solely responsible for catalysis of amidation, a biologically important posttranslational modification. Peptide substrate amidation is strikingly sensitive to the exposure of cells to moderate hypoxia, physiological effects of hypoxia may be PAM-dependent. Because PAM-dependent amidation is irreversible, bi-directional responses that rapidly upregulate and downregulate levels of amidation can only be observed on rapidly turned-over PAM substrates
physiological function
peptidylglycine alpha-hydroxylating monooxygenase catalyzes the generation of C-terminal carboxamides of peptide hormones, neurotransmitters, and growth factors for biological activation. The enzyme is a noninteracting bicopper enzyme that stereospecifically hydroxylates the terminal glycine of small peptides for its later amidation. Neuroendocrine messengers, such as oxytocin, rely on the biological activity of this enzyme. Each catalytic turnover requires one oxygen molecule, two protons from the solvent, and two electrons
physiological function
peptidylglycine-alpha-amidating monooxygenase (PAM) may play a role in the secretion of atrial natriuretic peptide (ANP), which is a hormone involved in the maintenance of blood pressure. Enzyme PAM is involved in regulation of blood pressure and hypertension
additional information
solvent-exposed active site of enzyme PHM
additional information
structure of the PHM enzyme active site taken from PDB ID 1OPM structure with bound substrate diiodotyrosylglycine: the H-site coordinates to the Ndelta atom of H107, H108, and Nepsilon of H172, and the oxygen binding (catalytic) M-site coordinates to Nepsilon of H242 and H244 and the thiother S of M314. The side chain of the conserved E313 forms an H-bond to the main chain amide nitrogen of H244
additional information
substrate binding triggers oxygen activation in peptidylglycine monooygenase
additional information
the protease-resistant catalytic core of PHM (PHMcc) is followed by a well conserved cluster of three His residues. This His cluster is included in the final exon encoding PHMcc and is followed by a poorly conserved, protease-sensitive region encoded by a short exon present in each of the major splice variants of PAM. The non-catalytic linker region between PHM and PAL includes a 315-nt exon in PAM-1. Exon 16 plays an important role in PAM-1 trafficking and in the ability of PAM-1 to participate in transmembrane signaling