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Gene Review

PAM  -  peptidylglycine alpha-amidating monooxygenase

Homo sapiens

Synonyms: PAL, PHM, Peptidyl-glycine alpha-amidating monooxygenase
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Disease relevance of PAM

  • Long-term follow-up of these patients for new second primary lung cancers may help to determine the potential predictive value of PAM detected in the BAL fluid [1].
  • However, classic small cell lines demonstrated high levels of expression of both PAM and AADC genes, as did the carcinoid subset of the NSCLC lines [2].
  • The high expression of peptidylglycine alpha-amidating monooxygenase mRNA in glioblastoma and glioma cell lines points to the involvement of alpha-amidated peptides in tumorigenic growth processes in the brain [3].
  • PAM mRNA levels were found to be 3-fold higher in prostate adenocarcinomas compared with that of human benign prostate hyperplasia (BPH) as demonstrated by real-time quantitative reverse transcription-PCR [4].
  • However in contradistinction to patients with medullary thyroid carcinoma, PAM activity does not appear to be a useful tumour marker of gastrinoma [5].

Psychiatry related information on PAM

  • Of the cerebral cortical regions examined, only the temporal pole showed reduced PAM activity in patients with Alzheimer's disease (AD) compared with controls [6].
  • Levels of alpha-amidating activity, peptidyl-glycine alpha-amidating monooxygenase (PAM), were reduced in the CSF of patients with dementia of the Alzheimer type (DAT) compared with healthy, age-matched controls [6].
  • We describe a method for enhancing this post-auricular muscle response (PAMR) using lateral eye movement, which increases both the tonic EMG activity in the PAM and the magnitude of the PAMR, and decreases response latency [7].

High impact information on PAM

  • Treponemicidal levels of penicillin in the CSF were not obtained following intramuscular (IM) injections of 600,000 IU of penicillin G procaine along with 2% aluminum monostearate (PAM) [8].
  • To characterize the trafficking of integral membrane PAM proteins in neuroendocrine cells, we have generated stable AtT-20 cell lines expressing full length and COOH-terminally truncated integral membrane PAM proteins [9].
  • Endoproteolytic processing of full length PAM-1 and PAM-2 resulted in the secretion of soluble PAM proteins; the secretion of these soluble PAM proteins was stimulus dependent [9].
  • Thus the punctate juxtanuclear staining of full length PAM represents PAM in endosomes [9].
  • Although some of the truncated PAM protein was also processed and stored in AtT-20 cells, much of the expressed protein was redistributed to the plasma membrane [9].

Chemical compound and disease context of PAM


Biological context of PAM

  • Reporter assays using a chimeric mRNA that combined luciferase and the 3' UTR of PAM mRNA demonstrated a decrease of the reporter activity due to an increase in the nuclear localization of reporter mRNAs, while the deletion of the 15-nt La binding site led to their clear-cut cytoplasmic relocalization [15].
  • We have previously reported a putative regulatory RNA binding protein (PAM mRNA-BP) that binds specifically to the 3' untranslated region (UTR) of PAM-mRNA [15].
  • Furthermore, La protein overexpression caused a nuclear retention of PAM mRNAs and resulted in the down-regulation of endogenous PAM activity [15].
  • There was no simple correlation apparent between AADC and PAM gene expression in the lung cancer cell lines [2].
  • Although the yeast genome encodes no PHM-like enzyme, PHMcc expressed in yeast is at least as active as PHMcc produced by mammalian cells [16].

Anatomical context of PAM

  • Treatment of cultured ciliary epithelial cells with veratridine and phorbol ester up-regulates CPE and PAM [17].
  • A comparison of PAM activity and DDC levels in 30 lung cancer cell lines indicated that peptide amidating activity may be an indicator of NE status [1].
  • In contrast to previous reports, PAM IR was found in B-cells of human and rat [18].
  • Most of the B/D-cells were PAM immunoreactive, although with variable intensity, whereas less than half of A-cells displayed IR [18].
  • Similarly, production of active PHM in mouse fibroblasts is impaired in the presence of a mutant ATP7A gene [16].

Associations of PAM with chemical compounds


Physical interactions of PAM

  • Moreover, we identified the La autoantigen as a protein that specifically binds the 3' UTR of PAM mRNA in vivo and in vitro [15].
  • Internalized PAM complexed with PAM antibody was found in a subcellular compartment which overlapped with internalized transferrin and with structures binding WGA [9].
  • The plasminogen binding domain of PAM is highly variable, and this variation has been linked to host selective immune pressure [23].

Enzymatic interactions of PAM

  • Casein kinase II phosphorylates Ser(949) and Thr(946) of PAM, generating a short, cytosolic acidic cluster [24].

Regulatory relationships of PAM


Other interactions of PAM


Analytical, diagnostic and therapeutic context of PAM


  1. Peptide amidating activity in human bronchoalveolar lavage fluid. Scott, F.M., Treston, A.M., Shaw, G.L., Avis, I., Sorenson, J., Kelly, K., Dempsey, E.C., Cantor, A.B., Tockman, M., Mulshine, J.L. Lung Cancer (1996) [Pubmed]
  2. Expression in human lung cancer cell lines of genes of prohormone processing and the neuroendocrine phenotype. Vos, M.D., Scott, F.M., Iwai, N., Treston, A.M. J. Cell. Biochem. Suppl. (1996) [Pubmed]
  3. Neutralization of adrenomedullin inhibits the growth of human glioblastoma cell lines in vitro and suppresses tumor xenograft growth in vivo. Ouafik, L., Sauze, S., Boudouresque, F., Chinot, O., Delfino, C., Fina, F., Vuaroqueaux, V., Dussert, C., Palmari, J., Dufour, H., Grisoli, F., Casellas, P., Brünner, N., Martin, P.M. Am. J. Pathol. (2002) [Pubmed]
  4. Expression of adrenomedullin and peptide amidation activity in human prostate cancer and in human prostate cancer cell lines. Rocchi, P., Boudouresque, F., Zamora, A.J., Muracciole, X., Lechevallier, E., Martin, P.M., Ouafik, L. Cancer Res. (2001) [Pubmed]
  5. Peptide alpha-amidation activity in human plasma: relationship to gastrin processing. Kapuscinski, M., Green, M., Sinha, S.N., Shepherd, J.J., Shulkes, A. Clin. Endocrinol. (Oxf) (1993) [Pubmed]
  6. Alzheimer's disease: low levels of peptide alpha-amidation activity in brain and CSF. Wand, G.S., May, C., May, V., Whitehouse, P.J., Rapoport, S.I., Eipper, B.A. Neurology (1987) [Pubmed]
  7. Effects of eye rotation on the sound-evoked post-auricular muscle response (PAMR). Patuzzi, R.B., O'Beirne, G.A. Hear. Res. (1999) [Pubmed]
  8. Penicillin levels in blood and CSF achieved by treatment of syphilis. Dunlop, E.M., Al-Egaily, S.S., Houang, E.T. JAMA (1979) [Pubmed]
  9. COOH-terminal signals mediate the trafficking of a peptide processing enzyme in endocrine cells. Milgram, S.L., Mains, R.E., Eipper, B.A. J. Cell Biol. (1993) [Pubmed]
  10. Reversal of the transformed phenotype and inhibition of peptidylglycine alpha-monooxygenase in Ras-transformed cells by 4-phenyl-3-butenoic acid. Sunman, J.A., Foster, M.S., Folse, S.L., May, S.W., Matesic, D.F. Mol. Carcinog. (2004) [Pubmed]
  11. Acid-base status in dietary treatment of phenylketonuria. Manz, F., Schmidt, H., Schärer, K., Bickel, H. Pediatr. Res. (1977) [Pubmed]
  12. The combination of cisplatin, doxorubicin, and mitomycin (PAM) compared with the FAM regimen in treating advanced gastric carcinoma. A phase II randomized trial of the Italian Oncology Group for Clinical Research. De Lisi, V., Cocconi, G., Angelini, F., Cavicchi, F., Di Costanzo, F., Gilli, G., Rodinò, C., Soldani, M., Tonato, M., Finardi, C. Cancer (1996) [Pubmed]
  13. Neoadjuvant chemotherapy with cisplatin, aclacinomycin A, and mitomycin C for cervical adenocarcinoma--a preliminary study. Saito, T., Takehara, M., Lee, R., Fujimoto, T., Nishimura, M., Tanaka, R., Ito, E., Adachi, K., Kudo, R. Int. J. Gynecol. Cancer (2004) [Pubmed]
  14. Photo-cross-linked hydrogels with polysaccharide-poly(amino acid) structure: new biomaterials for pharmaceutical applications. Pitarresi, G., Pierro, P., Palumbo, F.S., Tripodo, G., Giammona, G. Biomacromolecules (2006) [Pubmed]
  15. Mammalian peptidylglycine alpha-amidating monooxygenase mRNA expression can be modulated by the La autoantigen. Brenet, F., Dussault, N., Borch, J., Ferracci, G., Delfino, C., Roepstorff, P., Miquelis, R., Ouafik, L. Mol. Cell. Biol. (2005) [Pubmed]
  16. Supplying copper to the cuproenzyme peptidylglycine alpha-amidating monooxygenase. El Meskini, R., Culotta, V.C., Mains, R.E., Eipper, B.A. J. Biol. Chem. (2003) [Pubmed]
  17. Identification of a neuropeptide and neuropeptide-processing enzymes in aqueous humor confers neuroendocrine features to the human ocular ciliary epithelium. Ortego, J., Escribano, J., Crabb, J., Coca-Prados, M. J. Neurochem. (1996) [Pubmed]
  18. Immunocytochemical finding of the amidating enzymes in mouse pancreatic A-, B-, and D-cells: a comparison with human and rat. Garmendia, O., Rodríguez, M.P., Burrell, M.A., Villaro, A.C. J. Histochem. Cytochem. (2002) [Pubmed]
  19. Androgen-independent expression of adrenomedullin and peptidylglycine alpha-amidating monooxygenase in human prostatic carcinoma. Jiménez, N., Abasolo, I., Jongsma, J., Calvo, A., Garayoa, M., van der Kwast, T.H., van Steenbrugge, G.J., Montuenga, L.M. Mol. Carcinog. (2003) [Pubmed]
  20. Isolation and functional expression of human pancreatic peptidylglycine alpha-amidating monooxygenase. Tateishi, K., Arakawa, F., Misumi, Y., Treston, A.M., Vos, M., Matsuoka, Y. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
  21. Mononuclear copper active-oxygen complexes. Itoh, S. Current opinion in chemical biology. (2006) [Pubmed]
  22. Alternative splicing governs sulfation of tyrosine or oligosaccharide on peptidylglycine alpha-amidating monooxygenase. Yun, H.Y., Keutmann, H.T., Eipper, B.A. J. Biol. Chem. (1994) [Pubmed]
  23. The maintenance of high affinity plasminogen binding by group A streptococcal plasminogen-binding M-like protein is mediated by arginine and histidine residues within the a1 and a2 repeat domains. Sanderson-Smith, M.L., Walker, M.J., Ranson, M. J. Biol. Chem. (2006) [Pubmed]
  24. Access of a membrane protein to secretory granules is facilitated by phosphorylation. Steveson, T.C., Zhao, G.C., Keutmann, H.T., Mains, R.E., Eipper, B.A. J. Biol. Chem. (2001) [Pubmed]
  25. Signaling mediated by the cytosolic domain of peptidylglycine alpha-amidating monooxygenase. Alam, M.R., Steveson, T.C., Johnson, R.C., Bäck, N., Abraham, B., Mains, R.E., Eipper, B.A. Mol. Biol. Cell (2001) [Pubmed]
  26. Increased neuropeptide Y-immunoreactive innervation of aganglionic bowel in Hirschsprung's disease. Hamada, Y., Bishop, A.E., Federici, G., Rivosecchi, M., Talbot, I.C., Polak, J.M. Virchows Archiv. A, Pathological anatomy and histopathology. (1987) [Pubmed]
  27. Localization of integral membrane peptidylglycine alpha-amidating monooxygenase in neuroendocrine cells. Milgram, S.L., Kho, S.T., Martin, G.V., Mains, R.E., Eipper, B.A. J. Cell. Sci. (1997) [Pubmed]
  28. 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. Caldwell, B.D., Darlington, D.N., Penzes, P., Johnson, R.C., Eipper, B.A., Mains, R.E. J. Biol. Chem. (1999) [Pubmed]
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