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PAM  -  peptidylglycine alpha-amidating monooxygenase

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High impact information on PAM

  • The subcellular distribution of glutaminyl cyclase corresponded to the one of peptidylglycine alpha-amidating monooxygenase believed to catalyze C-terminal amidations during posttranslational precursor processing [1].
  • Carboxyl-terminal amidation, a required post-translational modification for the bioactivation of many neuropeptides, entails sequential enzymatic action by peptidylglycine monooxygenase (PAM, EC and peptidylamidoglycolate lyase (PGL, EC [2].
  • The monooxygenase, PAM, first catalyzes conversion of a glycine-extended pro-peptide to the corresponding alpha-hydroxyglycine derivative, and the lyase, PGL, then catalyzes breakdown of this alpha-hydroxyglycine derivative to the amidated peptide plus glyoxylate [2].
  • Kinetic experiments with the ascorbate-dependent copper monooxygenases, PAM and dopamine-beta-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 [2].
  • The NH2-terminal third of the PAM precursor contains the first enzyme, peptidylglycine alpha-hydroxylating monooxygenase (PHM), a copper, molecular oxygen, and ascorbate-dependent enzyme [3].

Biological context of PAM


Anatomical context of PAM

  • High levels of PAM mRNA were found in bovine pituitary and cerebral cortex [4].
  • In marked contrast, an AtT-20 cell line transfected with a cDNA encoding a truncated, soluble form of bPAM had elevated levels of PAM activity, but levels of SPAM activity were not increased compared to wild-type cells [7].
  • A new facile trinitrophenylated substrate for peptide alpha-amidation and its use to characterize PAM activity in chromaffin granules [8].
  • We now report that the two enzymes essential for amidation, peptidylglycine alpha-monooxygenase (PAM) and peptidylamidoglycolate lyase (PGL), are present in both the cytosol and membrane fractions of cultured bovine aortic endothelial cells [9].
  • Qualitative and quantitative expression of m.RNA coding for Peptidyl-Glycine alpha-Amidating Monooxygenase (PAM) in the developing rat pancreas was investigated by Northern and dot blot hybridization, with a bovine PAM c.DNA probe (0.7 kb fragment) [10].

Associations of PAM with chemical compounds

  • An NH2-terminal signal sequence and short propeptide precede the NH2 terminus of purified PAM [4].
  • The monooxygenase first catalyzes formation of the alpha-hydroxyglycine derivative of the glycine-extended precursor, and the lyase subsequently catalyzes breakdown of the PAM product to the amidated peptide and glyoxylate [5].
  • 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 [11].
  • 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 [11].
  • We report here that in the presence of molecular O2, copper and PAM substrate, NN-dimethyl-1,4-phenylenediamine (DMPD) serves as the requisite electron donor for the mono-oxygenase, being oxidized in the process to a stable and highly chromophoric cation radical [12].

Other interactions of PAM

  • One of the questions addressed was the suitability of the AF islet neuropeptide Y-like peptide, aPY-Gly, as a substrate for the islet PAM [13].

Analytical, diagnostic and therapeutic context of PAM

  • Following differential centrifugation of rat atrial homogenates, most of the PAM activity was associated with crude granule fractions, with lesser amounts of activity associated with crude microsomal fractions [14].
  • In rat anterior pituitary this factor (denoted SPAM for stimulator of PAM activity) was a soluble protein with a mol wt of 44 K by gel filtration; its stimulatory activity could be reduced or eliminated by trypsin digestion or boiling [7].
  • Partially purified PAM from AF islet secretory granules was incubated with [125I] aPY-Gly and the resulting products were analyzed by HPLC [13].
  • A colorimetric assay for measuring peptidylglycine alpha-amidating monooxygenase using high-performance liquid chromatography [15].


  1. Identification of a mammalian glutaminyl cyclase converting glutaminyl into pyroglutamyl peptides. Fischer, W.H., Spiess, J. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  2. Pyruvate-extended amino acid derivatives as highly potent inhibitors of carboxyl-terminal peptide amidation. Mounier, C.E., Shi, J., Sirimanne, S.R., Chen, B.H., Moore, A.B., Gill-Woznichak, M.M., Ping, D., May, S.W. J. Biol. Chem. (1997) [Pubmed]
  3. Peptidyl-alpha-hydroxyglycine alpha-amidating lyase. Purification, characterization, and expression. Eipper, B.A., Perkins, S.N., Husten, E.J., Johnson, R.C., Keutmann, H.T., Mains, R.E. J. Biol. Chem. (1991) [Pubmed]
  4. Structure of the precursor to an enzyme mediating COOH-terminal amidation in peptide biosynthesis. Eipper, B.A., Park, L.P., Dickerson, I.M., Keutmann, H.T., Thiele, E.A., Rodriguez, H., Schofield, P.R., Mains, R.E. Mol. Endocrinol. (1987) [Pubmed]
  5. Functional and structural characterization of peptidylamidoglycolate lyase, the enzyme catalyzing the second step in peptide amidation. Katopodis, A.G., Ping, D.S., Smith, C.E., May, S.W. Biochemistry (1991) [Pubmed]
  6. A novel enzyme from bovine neurointermediate pituitary catalyzes dealkylation of alpha-hydroxyglycine derivatives, thereby functioning sequentially with peptidylglycine alpha-amidating monooxygenase in peptide amidation. Katopodis, A.G., Ping, D., May, S.W. Biochemistry (1990) [Pubmed]
  7. pH-dependent stimulation of peptidylglycine alpha-amidating monooxygenase activity by a granule-associated factor. Perkins, S.N., Husten, E.J., Mains, R.E., Eipper, B.A. Endocrinology (1990) [Pubmed]
  8. A new facile trinitrophenylated substrate for peptide alpha-amidation and its use to characterize PAM activity in chromaffin granules. Katopodis, A.G., May, S.W. Biochem. Biophys. Res. Commun. (1988) [Pubmed]
  9. Peptide amidating enzymes are present in cultured endothelial cells. Oldham, C.D., Li, C., Girard, P.R., Nerem, R.M., May, S.W. Biochem. Biophys. Res. Commun. (1992) [Pubmed]
  10. Ontogenetic expression of peptidyl-glycine alpha-amidating monooxygenase mRNA in the rat pancreas. Maltese, J.Y., Giraud, P., Kowalski, C., Ouafik, L.H., Salers, P., Pelen, F., Oliver, C. Biochem. Biophys. Res. Commun. (1989) [Pubmed]
  11. Novel substrates and inhibitors of peptidylglycine alpha-amidating monooxygenase. Katopodis, A.G., May, S.W. Biochemistry (1990) [Pubmed]
  12. NN-dimethyl-1,4-phenylenediamine as an alternative reductant for peptidylglycine alpha-amidating mono-oxygenase catalysis. Li, C., Oldham, C.D., May, S.W. Biochem. J. (1994) [Pubmed]
  13. Kinetic analyses of peptidylglycine alpha-amidating monooxygenase from pancreatic islets. Noe, B.D., Katopodis, A.G., May, S.W. Gen. Comp. Endocrinol. (1991) [Pubmed]
  14. Membrane-associated peptidylglycine alpha-amidating monooxygenase in the heart. Eipper, B.A., May, V., Braas, K.M. J. Biol. Chem. (1988) [Pubmed]
  15. A colorimetric assay for measuring peptidylglycine alpha-amidating monooxygenase using high-performance liquid chromatography. Chikuma, T., Hanaoka, K., Loh, Y.P., Kato, T., Ishii, Y. Anal. Biochem. (1991) [Pubmed]
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