Abstract
Peptide alpha-amidation is a widespread, often essential posttranslational modification shared by many bioactive peptides and accomplished by the products of a single gene encoding a multifunctional protein, peptidylglycine alpha-amidating monooxygenase (PAM). PAM has two catalytic domains that work sequentially to produce the final alpha-amidated product peptide. Tissue-specific alternative splicing can generate forms of PAM retaining or lacking a domain required for the posttranslational separation of the two catalytic activities by endoproteases found in neuroendocrine tissue. Tissue-specific alternative splicing also governs the presence of a transmembrane domain and generation of integral membrane or soluble forms of PAM. The COOH-terminal domain of the integral membrane PAM proteins contains routing information essential for the retrieval of PAM from the surface of endocrine and nonendocrine cells. Tissue-specific endoproteolytic processing can generate soluble PAM proteins from integral membrane precursors. Soluble PAM proteins are rapidly secreted from stably transfected nonneuroendocrine cells but are stored in the regulated secretory granules characteristic of neurons and endocrine cells.
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- Barr P. J. Mammalian subtilisins: the long-sought dibasic processing endoproteases. Cell. 1991 Jul 12;66(1):1–3. doi: 10.1016/0092-8674(91)90129-m. [DOI] [PubMed] [Google Scholar]
- Bertelsen A. H., Beaudry G. A., Galella E. A., Jones B. N., Ray M. L., Mehta N. M. Cloning and characterization of two alternatively spliced rat alpha-amidating enzyme cDNAs from rat medullary thyroid carcinoma. Arch Biochem Biophys. 1990 May 15;279(1):87–96. doi: 10.1016/0003-9861(90)90466-c. [DOI] [PubMed] [Google Scholar]
- Bloomquist B. T., Eipper B. A., Mains R. E. Prohormone-converting enzymes: regulation and evaluation of function using antisense RNA. Mol Endocrinol. 1991 Dec;5(12):2014–2024. doi: 10.1210/mend-5-12-2014. [DOI] [PubMed] [Google Scholar]
- Bradbury A. F., Mistry J., Roos B. A., Smyth D. G. 4-Phenyl-3-butenoic acid, an in vivo inhibitor of peptidylglycine hydroxylase (peptide amidating enzyme). Eur J Biochem. 1990 Apr 30;189(2):363–368. doi: 10.1111/j.1432-1033.1990.tb15497.x. [DOI] [PubMed] [Google Scholar]
- Eipper B. A., Perkins S. N., Husten E. J., Johnson R. C., Keutmann H. T., Mains R. E. Peptidyl-alpha-hydroxyglycine alpha-amidating lyase. Purification, characterization, and expression. J Biol Chem. 1991 Apr 25;266(12):7827–7833. [PubMed] [Google Scholar]
- Eipper B. A., Stoffers D. A., Mains R. E. The biosynthesis of neuropeptides: peptide alpha-amidation. Annu Rev Neurosci. 1992;15:57–85. doi: 10.1146/annurev.ne.15.030192.000421. [DOI] [PubMed] [Google Scholar]
- Glauder J., Ragg H., Rauch J., Engels J. W. Human peptidylglycine alpha-amidating monooxygenase: cDNA, cloning and functional expression of a truncated form in COS cells. Biochem Biophys Res Commun. 1990 Jun 15;169(2):551–558. doi: 10.1016/0006-291x(90)90366-u. [DOI] [PubMed] [Google Scholar]
- Grino M., Guillaume V., Boudouresque F., Conte-Devolx B., Maltese J. Y., Oliver C. Glucocorticoids regulate peptidyl-glycine alpha-amidating monooxygenase gene expression in the rat hypothalamic paraventricular nucleus. Mol Endocrinol. 1990 Nov;4(11):1613–1619. doi: 10.1210/mend-4-11-1613. [DOI] [PubMed] [Google Scholar]
- Hilsted L. Alpha-amidation of gastrin is impaired by diethyldithiocarbamate. Regul Pept. 1990 Jul 30;29(2-3):179–187. doi: 10.1016/0167-0115(90)90081-7. [DOI] [PubMed] [Google Scholar]
- Iwasaki Y., Kawahara T., Shimoi H., Suzuki K., Ghisalba O., Kangawa K., Matsuo H., Nishikawa Y. Purification and cDNA cloning of Xenopus laevis skin peptidylhydroxyglycine N-C lyase, catalyzing the second reaction of C-terminal alpha-amidation. Eur J Biochem. 1991 Nov 1;201(3):551–559. doi: 10.1111/j.1432-1033.1991.tb16314.x. [DOI] [PubMed] [Google Scholar]
- Johansen T. E., O'Hare M. M., Wulff B. S., Schwartz T. W. CHO cells synthesize amidated neuropeptide Y from a C-peptide deleted form of the precursor. Endocrinology. 1991 Jul;129(1):553–555. doi: 10.1210/endo-129-1-553. [DOI] [PubMed] [Google Scholar]
- Johnson-Flanagan A. M., Huiwen Z., Thiagarajah M. R., Saini H. S. Role of Abscisic Acid in the Induction of Freezing Tolerance in Brassica napus Suspension-Cultured Cells. Plant Physiol. 1991 Apr;95(4):1044–1048. doi: 10.1104/pp.95.4.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jung L. J., Scheller R. H. Peptide processing and targeting in the neuronal secretory pathway. Science. 1991 Mar 15;251(4999):1330–1335. doi: 10.1126/science.2003219. [DOI] [PubMed] [Google Scholar]
- 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 Oct 15;172(1):197–203. doi: 10.1016/s0006-291x(05)80193-7. [DOI] [PubMed] [Google Scholar]
- 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 Sep 3;269(2):319–323. doi: 10.1016/0014-5793(90)81184-p. [DOI] [PubMed] [Google Scholar]
- Katopodis A. G., Ping D. S., Smith C. E., May S. W. Functional and structural characterization of peptidylamidoglycolate lyase, the enzyme catalyzing the second step in peptide amidation. Biochemistry. 1991 Jun 25;30(25):6189–6194. doi: 10.1021/bi00239a016. [DOI] [PubMed] [Google Scholar]
- Katopodis A. G., Ping D., May S. W. A novel enzyme from bovine neurointermediate pituitary catalyzes dealkylation of alpha-hydroxyglycine derivatives, thereby functioning sequentially with peptidylglycine alpha-amidating monooxygenase in peptide amidation. Biochemistry. 1990 Jul 3;29(26):6115–6120. doi: 10.1021/bi00478a001. [DOI] [PubMed] [Google Scholar]
- Klein R. S., Fricker L. D. Cultured astrocytes express mRNA for peptidylglycine-alpha-amidating monooxygenase, a neuropeptide processing enzyme. Brain Res. 1992 Nov 20;596(1-2):202–208. doi: 10.1016/0006-8993(92)91548-s. [DOI] [PubMed] [Google Scholar]
- Kobayashi K., Kurosawa Y., Fujita K., Nagatsu T. Human dopamine beta-hydroxylase gene: two mRNA types having different 3'-terminal regions are produced through alternative polyadenylation. Nucleic Acids Res. 1989 Feb 11;17(3):1089–1102. doi: 10.1093/nar/17.3.1089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lackey D. B. Isolation and structural determination of a novel TRH-like tripeptide, pyroGlu-Tyr-Pro amide, from alfalfa. J Biol Chem. 1992 Sep 5;267(25):17508–17511. [PubMed] [Google Scholar]
- Lindberg I. The new eukaryotic precursor processing proteinases. Mol Endocrinol. 1991 Oct;5(10):1361–1365. doi: 10.1210/mend-5-10-1361. [DOI] [PubMed] [Google Scholar]
- Mains R. E., Bloomquist B. T., Eipper B. A. Manipulation of neuropeptide biosynthesis through the expression of antisense RNA for peptidylglycine alpha-amidating monooxygenase. Mol Endocrinol. 1991 Feb;5(2):187–193. doi: 10.1210/mend-5-2-187. [DOI] [PubMed] [Google Scholar]
- Maltese J. Y., Eipper B. A. 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 Dec;6(12):1998–2008. doi: 10.1210/mend.6.12.1491686. [DOI] [PubMed] [Google Scholar]
- Marchand J. E., Hershman K., Kumar M. S., Thompson M. L., Kream R. M. Disulfiram administration affects substance P-like immunoreactive and monoaminergic neural systems in rodent brain. J Biol Chem. 1990 Jan 5;265(1):264–273. [PubMed] [Google Scholar]
- Milgram S. L., Johnson R. C., Mains R. E. Expression of individual forms of peptidylglycine alpha-amidating monooxygenase in AtT-20 cells: endoproteolytic processing and routing to secretory granules. J Cell Biol. 1992 May;117(4):717–728. doi: 10.1083/jcb.117.4.717. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murthy A. S., Keutmann H. T., Eipper B. A. Further characterization of peptidylglycine alpha-amidating monooxygenase from bovine neurointermediate pituitary. Mol Endocrinol. 1987 Apr;1(4):290–299. doi: 10.1210/mend-1-4-290. [DOI] [PubMed] [Google Scholar]
- Nakayama K., Hosaka M., Hatsuzawa K., Murakami K. Cloning and functional expression of a novel endoprotease involved in prohormone processing at dibasic sites. J Biochem. 1991 Jun;109(6):803–806. doi: 10.1093/oxfordjournals.jbchem.a123461. [DOI] [PubMed] [Google Scholar]
- Noguchi M., Seino H., Kochi H., Okamoto H., Tanaka T., Hirama M. The source of the oxygen atom in the alpha-hydroxyglycine intermediate of the peptidylglycine alpha-amidating reaction. Biochem J. 1992 May 1;283(Pt 3):883–888. doi: 10.1042/bj2830883. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ouafik L. H., Stoffers D. A., Campbell T. A., Johnson R. C., Bloomquist B. T., Mains R. E., Eipper B. A. The multifunctional peptidylglycine alpha-amidating monooxygenase gene: exon/intron organization of catalytic, processing, and routing domains. Mol Endocrinol. 1992 Oct;6(10):1571–1584. doi: 10.1210/mend.6.10.1448112. [DOI] [PubMed] [Google Scholar]
- Perkins S. N., Husten E. J., Eipper B. A. The 108-kDA peptidylglycine alpha-amidating monooxygenase precursor contains two separable enzymatic activities involved in peptide amidation. Biochem Biophys Res Commun. 1990 Sep 28;171(3):926–932. doi: 10.1016/0006-291x(90)90772-f. [DOI] [PubMed] [Google Scholar]
- Rhodes C. H., Xu R. Y., Angeletti R. H. Peptidylglycine alpha-amidating monooxygenase (PAM) in Schwann cells and glia as well as neurons. J Histochem Cytochem. 1990 Sep;38(9):1301–1311. doi: 10.1177/38.9.2387985. [DOI] [PubMed] [Google Scholar]
- Schafer M. K., Stoffers D. A., Eipper B. A., Watson S. J. Expression of peptidylglycine alpha-amidating monooxygenase (EC 1.14.17.3) in the rat central nervous system. J Neurosci. 1992 Jan;12(1):222–234. doi: 10.1523/JNEUROSCI.12-01-00222.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Southan C., Kruse L. I. Sequence similarity between dopamine beta-hydroxylase and peptide alpha-amidating enzyme: evidence for a conserved catalytic domain. FEBS Lett. 1989 Sep 11;255(1):116–120. doi: 10.1016/0014-5793(89)81072-5. [DOI] [PubMed] [Google Scholar]
- Stewart L. C., Klinman J. P. Cooperativity in the dopamine beta-monooxygenase reaction. Evidence for ascorbate regulation of enzyme activity. J Biol Chem. 1991 Jun 25;266(18):11537–11543. [PubMed] [Google Scholar]
- Suzuki K., Shimoi H., Iwasaki Y., Kawahara T., Matsuura Y., Nishikawa Y. Elucidation of amidating reaction mechanism by frog amidating enzyme, peptidylglycine alpha-hydroxylating monooxygenase, expressed in insect cell culture. EMBO J. 1990 Dec;9(13):4259–4265. doi: 10.1002/j.1460-2075.1990.tb07874.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takahashi K., Okamoto H., Seino H., Noguchi M. Peptidylglycine alpha-amidating reaction: evidence for a two-step mechanism involving a stable intermediate at neutral pH. Biochem Biophys Res Commun. 1990 Jun 15;169(2):524–530. doi: 10.1016/0006-291x(90)90362-q. [DOI] [PubMed] [Google Scholar]
- Takamatsu K., Tatemoto K. Isolation and characterization of two novel peptide amides originating from myelin basic protein in bovine brain. Neurochem Res. 1992 Mar;17(3):239–246. doi: 10.1007/BF00966665. [DOI] [PubMed] [Google Scholar]
- Tausk F. A., Milgram S. L., Mains R. E., Eipper B. A. Expression of a peptide processing enzyme in cultured cells: truncation mutants reveal a routing domain. Mol Endocrinol. 1992 Dec;6(12):2185–2196. doi: 10.1210/mend.6.12.1491698. [DOI] [PubMed] [Google Scholar]