Gene Symbol: Pam
Description: peptidylglycine alpha-amidating monooxygenase
Alias: PHM, peptidyl-glycine alpha-amidating monooxygenase
Species: rat
Products:     Pam

Top Publications

  1. Ouafik L, Stoffers D, Campbell T, Johnson R, Bloomquist B, Mains R, et al. The multifunctional peptidylglycine alpha-amidating monooxygenase gene: exon/intron organization of catalytic, processing, and routing domains. Mol Endocrinol. 1992;6:1571-84 pubmed
    Peptidylglycine alpha-amidating monooxygenase (PAM; EC is a multifunctional protein containing two enzymes that act sequentially to catalyze the alpha-amidation of neuroendocrine peptides...
  2. Kolhekar A, Bell J, Shiozaki E, Jin L, Keutmann H, Hand T, et al. Essential features of the catalytic core of peptidyl-alpha-hydroxyglycine alpha-amidating lyase. Biochemistry. 2002;41:12384-94 pubmed
    ..Analysis of mutants that were efficiently secreted identified three His residues along with single Asp residue that may play a role in catalysis. These essential residues occur in a pattern unique to PAL. ..
  3. Murthy V, Han S, Beauchamp R, Smith N, Haddad L, Ito N, et al. Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex. J Biol Chem. 2004;279:1351-8 pubmed
    ..Tuberin and hamartin function together as a complex in mammals and Drosophila. We report here the association of Pam, a protein identified as an interactor of Myc, with the tuberin-hamartin complex in the brain...
  4. May V, Eipper B. Regulation of peptide amidation in cultured pituitary cells. J Biol Chem. 1985;260:16224-31 pubmed
    ..and high levels of a copper and ascorbate-dependent peptidylglycine alpha-amidating monooxygenase (PAM) capable of converting peptides terminating in -X-Gly into amidated products (-X-NH2)...
  5. Beaudry G, Mehta N, Ray M, Bertelsen A. Purification and characterization of functional recombinant alpha-amidating enzyme secreted from mammalian cells. J Biol Chem. 1990;265:17694-9 pubmed
    ..0-10.0. The availability of large amounts of readily purified, active recombinant alpha-AE should allow detailed probing of reaction mechanism, copper coordination chemistry, and turn-over-based inactivation events. ..
  6. Prohaska J, Broderius M. Plasma peptidylglycine alpha-amidating monooxygenase (PAM) and ceruloplasmin are affected by age and copper status in rats and mice. Comp Biochem Physiol B Biochem Mol Biol. 2006;143:360-6 pubmed
    ..neonatal development experiments compared two plasma cuproenzymes, peptidylglycine alpha-amidating monooxygenase (PAM ), an enzyme involved in peptide posttranslational activation, to ceruloplasmin (Cp), a ferroxidase involved in ..
  7. El Meskini R, Delfino C, Boudouresque F, Oliver C, Martin P, Ouafik L H -. Evidence of high expression of peptidylglycine alpha-amidating monooxygenase in the rat uterus: estrogen regulation. Proc Natl Acad Sci U S A. 1998;95:7191-6 pubmed
    In the present study, high levels of peptidylglycine alpha-amidating monooxygenase (PAM), which catalyzes the two-step formation of bioactive alpha-amidated peptides from their glycine-extended precursors, have been found in the uterus...
  8. Chen L, Johnson R, Milgram S. P-CIP1, a novel protein that interacts with the cytosolic domain of peptidylglycine alpha-amidating monooxygenase, is associated with endosomes. J Biol Chem. 1998;273:33524-32 pubmed
    The cytosolic domain of the peptide processing enzyme peptidylglycine alpha-amidating monooxygenase (PAM) contains signals that direct its trafficking in the secretory and endosomal pathways. Using the yeast two-hybrid system, Alam et al...
  9. Driscoll W, Mueller S, Eipper B, Mueller G. Differential regulation of peptide alpha-amidation by dexamethasone and disulfiram. Mol Pharmacol. 1999;55:1067-76 pubmed the hydroxylase and lyase activities of the bifunctional enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). The first step, catalyzed by peptidylglycine-alpha-hydroxylating monooxygenase (PHM; EC 1.14.17...

More Information


  1. Caldwell B, Darlington D, Penzes P, Johnson R, Eipper B, Mains R. The novel kinase peptidylglycine alpha-amidating monooxygenase cytosolic interactor protein 2 interacts with the cytosolic routing determinants of the peptide processing enzyme peptidylglycine alpha-amidating monooxygenase. J Biol Chem. 1999;274:34646-56 pubmed
    ..cytosolic domain of the peptide-processing integral membrane protein peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14. 17.3) contains multiple signals determining its subcellular localization...
  2. Stoffers D, Green C, Eipper B. Alternative mRNA splicing generates multiple forms of peptidyl-glycine alpha-amidating monooxygenase in rat atrium. Proc Natl Acad Sci U S A. 1989;86:735-9 pubmed
    Peptidyl-glycine alpha-amidating monooxygenase (PAM; EC 1.14.17...
  3. Glauder J, Ragg H, Rauch J, Engels J. Human peptidylglycine alpha-amidating monooxygenase: cDNA, cloning and functional expression of a truncated form in COS cells. Biochem Biophys Res Commun. 1990;169:551-8 pubmed
    We have identified a cDNA encoding human peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17...
  4. Pritchard L, Turnbull A, White A. Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity. J Endocrinol. 2002;172:411-21 pubmed
    ..We predict that further research into hypothalamic POMC processing, and the proteolytic enzymes involved, may yield important new clues on how flux through the MC4R pathway is regulated. ..
  5. Elizegi E, Pino I, Vicent S, Blanco D, Saffiotti U, Montuenga L. Hyperplasia of alveolar neuroendocrine cells in rat lung carcinogenesis by silica with selective expression of proadrenomedullin-derived peptides and amidating enzymes. Lab Invest. 2001;81:1627-38 pubmed
    ..during their processing by a well-characterized amidating enzyme, peptidylglycine alpha-amidating monooxygenase (PAM)...
  6. Yang Y, Chen H, Yu C, Zeng R, Cui D, Wu X, et al. In Vitro Amidating Processing of Products Expressed by Gene Engineering. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2000;32:312-315 pubmed
    ..This study provides a useful method for the amidation of recombinant products in vitro. ..
  7. Prigge S, Eipper B, Mains R, Amzel L. Dioxygen binds end-on to mononuclear copper in a precatalytic enzyme complex. Science. 2004;304:864-7 pubmed
    ..We trapped the copper-dioxygen complex in the enzyme peptidylglycine-alphahydroxylating monooxygenase (PHM) by freezing protein crystals that had been soaked with a slow substrate and ascorbate in the presence of oxygen...
  8. Xin X, Ferraro F, Bäck N, Eipper B, Mains R. Cdk5 and Trio modulate endocrine cell exocytosis. J Cell Sci. 2004;117:4739-48 pubmed
    ..Together, these data suggest that control of the cortical actin cytoskeleton, long known to modulate hormone exocytosis and subsequent endocytosis, involves Cdk5-mediated activation of Trio. ..
  9. Labrador V, Brun C, Konig S, Roatti A, Baertschi A. Peptidyl-glycine alpha-amidating monooxygenase targeting and shaping of atrial secretory vesicles: inhibition by mutated N-terminal ProANP and PBA. Circ Res. 2004;95:e98-109 pubmed
    ..1) aggregates of proANP and coexpressed proANP-EGFP recruited peptidylglycine alpha-amidating monooxygenase (PAM)-1, an abundant atrial integral vesicle membrane protein; (2) coexpressed N-terminal-mutated (Glu23,24-->Gln23,..
  10. Driscoll W, Hill D, Smalstig A, Mueller G. Murine atrial HL-1 cells express highly active peptidylglycine alpha-amidating enzyme. Peptides. 2006;27:1547-53 pubmed
    Peptidylglycine-alpha-hydroxylating monooxygenase (PHM; EC catalyzes the rate limiting step in peptide alpha-amidation, a posttranslational modification that is essential for receptor recognition and signal transduction...
  11. Maltese J, Eipper B. Developmental expression of peptidylglycine alpha-amidating monooxygenase (PAM) in primary cultures of neonatal rat cardiocytes: a model for studying regulation of PAM expression in the rat heart. Mol Endocrinol. 1992;6:1998-2008 pubmed
    ..cardiomyocytes were used to investigate the expression of peptidylglycine alpha-amidating monooxygenase (PAM), a bifunctional enzyme required for the production of alpha-amidated neuroendocrine peptides...
  12. Stoffers D, Ouafik L, Eipper B. Characterization of novel mRNAs encoding enzymes involved in peptide alpha-amidation. J Biol Chem. 1991;266:1701-7 pubmed two separable enzymatic activities both derived from the peptidylglycine alpha-amidating monooxygenase (PAM) precursor...
  13. Muth E, Driscoll W, Smalstig A, Goping G, Mueller G. Proteomic analysis of rat atrial secretory granules: a platform for testable hypotheses. Biochim Biophys Acta. 2004;1699:263-75 pubmed be membrane-associated with the most prominent proteins being peptidylglycine alpha-amidating monooxygenase (PAM) and pro-atrial natriuretic peptide (pro-ANP)...
  14. Husten E, Eipper B. The membrane-bound bifunctional peptidylglycine alpha-amidating monooxygenase protein. Exploration of its domain structure through limited proteolysis. J Biol Chem. 1991;266:17004-10 pubmed
    ..precursors is catalyzed by the sequential action of peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL)...
  15. Hwang I, Fung M, Liong E, Tipoe G, Tang F. Age-related changes in adrenomedullin expression and hypoxia-inducible factor-1 activity in the rat lung and their responses to hypoxia. J Gerontol A Biol Sci Med Sci. 2007;62:41-9 pubmed
    ..CRLR), receptor activity modifying protein (RAMP) mRNA, HIF-1 and peptidyl-glycine-amidating monooxygenase (PAM) mRNA levels were measured by reverse transcription-polymerase chain reaction...
  16. Alam M, Caldwell B, Johnson R, Darlington D, Mains R, Eipper B. Novel proteins that interact with the COOH-terminal cytosolic routing determinants of an integral membrane peptide-processing enzyme. J Biol Chem. 1996;271:28636-40 pubmed
    The steady state distribution of membrane forms of peptidylglycine alpha-amidating monooxygenase (PAM) in the secretory pathway of neurons and endocrine cells depends on signals in its cytosolic COOH-terminal domain (CD)...
  17. Bauer J, Sunman J, Foster M, Thompson J, Ogonowski A, Cutler S, et al. Anti-inflammatory effects of 4-phenyl-3-butenoic acid and 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester, potential inhibitors of neuropeptide bioactivation. J Pharmacol Exp Ther. 2007;320:1171-7 pubmed
    ..peptide, and this process is catalyzed by sequential action of the enzymes peptidylglycine alpha-monooxygenase (PAM) and peptidylamidoglycolate lyase...
  18. Satani M, Takahashi K, Sakamoto H, Harada S, Kaida Y, Noguchi M. Expression and characterization of human bifunctional peptidylglycine alpha-amidating monooxygenase. Protein Expr Purif. 2003;28:293-302 pubmed
    ..PAM possesses two catalytic domains in a single polypeptide, peptidylglycine alpha-hydroxylating monooxygenase (PHM, EC and peptidylamidoglycolate lyase (PAL, EC
  19. Bell Parikh L, Eipper B, Mains R. Response of an integral granule membrane protein to changes in pH. J Biol Chem. 2001;276:29854-63 pubmed
    ..Because peptidylglycine alpha-amidating monooxygenase (PAM) is one of the few membrane-spanning proteins concentrated in secretory granules and is a known effector of ..
  20. Prohaska J, Gybina A, Broderius M, Brokate B. Peptidylglycine-alpha-amidating monooxygenase activity and protein are lower in copper-deficient rats and suckling copper-deficient mice. Arch Biochem Biophys. 2005;434:212-20 pubmed
    Peptidylglycine-alpha-amidating monooxygenase (PAM) is a copper-dependent enzyme involved in peptide posttranslational activation...
  21. Chew G, Galloway L, McIntyre N, Schroder L, Richards K, Miller S, et al. Ubiquitin and ubiquitin-derived peptides as substrates for peptidylglycine alpha-amidating monooxygenase. FEBS Lett. 2005;579:4678-84 pubmed
    ..The enzyme catalyzing this reaction is peptidylglycine alpha-amidating monooxygenase (PAM)...
  22. Bauman A, Ralle M, Blackburn N. Large scale production of the copper enzyme peptidylglycine monooxygenase using an automated bioreactor. Protein Expr Purif. 2007;51:34-8 pubmed
    Rat PHM (peptidylglycine alpha-hydroxylating monooxygenase; EC expressed in CHO DG44 cells as a recombinant protein (rat PHMcc, residues 42-356 cloned in the pCIS vector, A.S. Kolhekar, H.T. Keutman, R. E. Mains, A.S.W...
  23. Yun H, Johnson R, Mains R, Eipper B. Topological switching of the COOH-terminal domain of peptidylglycine alpha-amidating monooxygenase by alternative RNA splicing. Arch Biochem Biophys. 1993;301:77-84 pubmed
    ..Four alternatively spliced forms of PAM RNA (PAM-1, -2, -3, and -4) were transcribed in vitro and used to synthesize PAM proteins in a cell-free ..
  24. Merkler D, Merkler K, Stern W, Fleming F. Fatty acid amide biosynthesis: a possible new role for peptidylglycine alpha-amidating enzyme and acyl-coenzyme A: glycine N-acyltransferase. Arch Biochem Biophys. 1996;330:430-4 pubmed
    ..The sequential actions of acyl-CoA:glycine N-acyltransferase and peptidyl-glycine alpha-amidating enzyme would lead to the biosynthesis of fatty acid amides. ..
  25. McIntyre N, Lowe E, Chew G, Owen T, Merkler D. Thiorphan, tiopronin, and related analogs as substrates and inhibitors of peptidylglycine alpha-amidating monooxygenase (PAM). FEBS Lett. 2006;580:521-32 pubmed
    ..We report here that thiorphan and tiopronin are substrates for PAM, exhibiting relatively low K(M,app) and V(MAX,app) values...
  26. Bonnemaison M, Bäck N, Duffy M, Ralle M, Mains R, Eipper B. Adaptor Protein-1 Complex Affects the Endocytic Trafficking and Function of Peptidylglycine α-Amidating Monooxygenase, a Luminal Cuproenzyme. J Biol Chem. 2015;290:21264-79 pubmed publisher the trafficking of Atp7a, a copper-transporting P-type ATPase, and peptidylglycine α-amidating monooxygenase (PAM), a copper-dependent membrane enzyme...
  27. Ferraro F, Eipper B, Mains R. Retrieval and reuse of pituitary secretory granule proteins. J Biol Chem. 2005;280:25424-35 pubmed
    ..We examined the turnover of peptidylglycine alpha-amidating monooxygenase (PAM), a membrane enzyme involved in the final maturation of many peptides, and VAMP2, a vesicle soluble N-..
  28. Kato I, Yonekura H, Tajima M, Yanagi M, Yamamoto H, Okamoto H. Two enzymes concerned in peptide hormone alpha-amidation are synthesized from a single mRNA. Biochem Biophys Res Commun. 1990;172:197-203 pubmed
    ..These results indicated that two enzymes concerned in peptide hormone alpha-amidation are generated from a common precursor protein encoded by a single mRNA. ..
  29. Sharma S, Raghuraman G, Lee M, Prabhakar N, Kumar G. Intermittent hypoxia activates peptidylglycine alpha-amidating monooxygenase in rat brain stem via reactive oxygen species-mediated proteolytic processing. J Appl Physiol (1985). 2009;106:12-9 pubmed publisher
    ..Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17...
  30. Vishwanatha K, Bäck N, Mains R, Eipper B. A histidine-rich linker region in peptidylglycine ?-amidating monooxygenase has the properties of a pH sensor. J Biol Chem. 2014;289:12404-20 pubmed publisher
    ..The two catalytic domains of peptidylglycine ?-amidating monooxygenase (PAM), a type I integral membrane protein, catalyze the sequential reactions that convert peptidyl-Gly substrates into ..
  31. Milgram S, Mains R, Eipper B. Identification of routing determinants in the cytosolic domain of a secretory granule-associated integral membrane protein. J Biol Chem. 1996;271:17526-35 pubmed
    We have investigated the trafficking of integral membrane peptidylglycine alpha-amidating monooxygenase (PAM) in the neuroendocrine AtT-20 cell line...
  32. Fraboulet S, Boudouresque F, Delfino C, Fina F, Oliver C, Ouafik L. Effect of thyroid hormones on peptidylglycine alpha-amidating monooxygenase gene expression in anterior pituitary gland: transcriptional studies and messenger ribonucleic acid stability. Endocrinology. 1996;137:5493-501 pubmed
    Peptidylglycine alpha-amidating monooxygenase (PAM; EC is a multifunctional protein containing two enzymes that act sequentially to catalyze the alpha-amidation of neuroendocrine peptides...
  33. Hand T, Mains R, Eipper B. Identification of the promoter for the gene encoding the bifunctional enzyme, peptidylglycine alpha-amidating monooxygenase. DNA Cell Biol. 1996;15:1093-104 pubmed
    The gene encoding rat peptidylglycine alpha-amidating monooxygenase (PAM) contains 26 protein-coding exons. We identified two non-overlapping genomic clones encoding the 5' untranslated region (UTR) of the PAM gene...
  34. Rudzka K, Moreno D, Eipper B, Mains R, Estrin D, Amzel L. Coordination of peroxide to the Cu(M) center of peptidylglycine ?-hydroxylating monooxygenase (PHM): structural and computational study. J Biol Inorg Chem. 2013;18:223-32 pubmed publisher
    ..Peptidylglycine ?-hydroxylating monooxygenase (PHM) performs the first step of the amidation reaction-the hydroxylation of peptidylglycine substrates at the C? ..
  35. Sobota J, Mohler W, Cowan A, Eipper B, Mains R. Dynamics of peptidergic secretory granule transport are regulated by neuronal stimulation. BMC Neurosci. 2010;11:32 pubmed publisher
    ..Data from antibody uptake, quantification of enzyme secretion and appearance of pHluorin fluorescence demonstrate distributed release of peptides all along the axon, not just at terminals. ..
  36. Zhang J, Zheng M, Eipper B, Pintar J. Embryonic and uterine expression patterns of peptidylglycine alpha-amidating monooxygenase transcripts suggest a widespread role for amidated peptides in development. Dev Biol. 1997;192:375-91 pubmed
    ..includes COOH-terminal amidation by the bifunctional enzyme peptidylglycine alpha-amidating monooxygenase (PAM)...
  37. Eipper B, Green C, Campbell T, Stoffers D, Keutmann H, Mains R, et al. Alternative splicing and endoproteolytic processing generate tissue-specific forms of pituitary peptidylglycine alpha-amidating monooxygenase (PAM). J Biol Chem. 1992;267:4008-15 pubmed
    ..This bifunctional protein contains peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) catalytic domains necessary for the two-step ..
  38. Braas K, Harakall S, Ouafik L, Eipper B, May V. Expression of peptidylglycine alpha-amidating monooxygenase: an in situ hybridization and immunocytochemical study. Endocrinology. 1992;130:2778-88 pubmed
    ..confers bioactivity to many neuroendocrine peptides, is catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM; EC
  39. Liu Z, Yang G, Li B, Chi C, Wu X. Cloning, co-expression with an amidating enzyme, and activity of the scorpion toxin BmK ITa1 cDNA in insect cells. Mol Biotechnol. 2003;24:21-6 pubmed
    ..cells of BmK ITa1 cDNA with an amidating enzyme expressed by the rat peptidylglycine alpha-amidating monooxygenase (PAM) gene...
  40. Rocchi P, Boudouresque F, Zamora A, Muracciole X, Lechevallier E, Martin P, et al. Expression of adrenomedullin and peptide amidation activity in human prostate cancer and in human prostate cancer cell lines. Cancer Res. 2001;61:1196-206 pubmed
    ..Peptidylglycine alpha-amidating monooxygenase (PAM) is the enzyme producing alpha-amidated bioactive peptides from their inactive glycine-extended precursors...
  41. Alam M, Steveson T, Johnson R, Back N, Abraham B, Mains R, et al. Signaling mediated by the cytosolic domain of peptidylglycine alpha-amidating monooxygenase. Mol Biol Cell. 2001;12:629-44 pubmed
    The luminal domains of membrane peptidylglycine alpha-amidating monooxygenase (PAM) are essential for peptide alpha-amidation, and the cytosolic domain (CD) is essential for trafficking...
  42. Kato I, Yonekura H, Yamamoto H, Okamoto H. Isolation and functional expression of pituitary peptidylglycine alpha-amidating enzyme mRNA. A variant lacking the transmembrane domain. FEBS Lett. 1990;269:319-23 pubmed
    ..When the cDNAs were expressed in COS-7 cells, the variant was the most efficient in producing a secretory form (37 kDA) of the enzyme. ..
  43. Prigge S, Kolhekar A, Eipper B, Mains R, Amzel L. Amidation of bioactive peptides: the structure of peptidylglycine alpha-hydroxylating monooxygenase. Science. 1997;278:1300-5 pubmed
    ..The amino-terminal domain of the bifunctional PAM protein is a peptidylglycine alpha-hydroxylating monooxygenase (PHM) with two coppers that cycle through cupric and cuprous oxidation states...
  44. Chufan E, De M, Eipper B, Mains R, Amzel L. Amidation of bioactive peptides: the structure of the lyase domain of the amidating enzyme. Structure. 2009;17:965-73 pubmed publisher
    ..A reaction mechanism is proposed based on this structural data and validated by biochemical analysis of site-directed PALcc mutants. ..
  45. Francone V, Ifrim M, Rajagopal C, Leddy C, Wang Y, Carson J, et al. Signaling from the secretory granule to the nucleus: Uhmk1 and PAM. Mol Endocrinol. 2010;24:1543-58 pubmed publisher
    ..Studies of peptidylglycine alpha-amidating monooxygenase (PAM), an essential secretory granule membrane enzyme, revealed a pathway that can relay information from secretory ..
  46. Bertelsen A, Beaudry G, Galella E, Jones B, Ray M, Mehta N. Cloning and characterization of two alternatively spliced rat alpha-amidating enzyme cDNAs from rat medullary thyroid carcinoma. Arch Biochem Biophys. 1990;279:87-96 pubmed
    ..In addition, data are presented which demonstrate that type B mRNA is also functional. The implications of the internal and carboxyl-end heterogeneity are discussed. ..
  47. El Meskini R, Culotta V, Mains R, Eipper B. Supplying copper to the cuproenzyme peptidylglycine alpha-amidating monooxygenase. J Biol Chem. 2003;278:12278-84 pubmed
    ..Similarly, production of active PHM in mouse fibroblasts is impaired in the presence of a mutant ATP7A gene. Although delivery of copper to lumenal cuproproteins like PAM involves ATP7A, lumenal chaperones may not be required.