Peptidylglycine alpha-amidating monooxygenase: Difference between revisions

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{{Infobox_gene}}
'''Peptidyl-glycine alpha-amidating monooxygenase''' is an [[enzyme]] that is required for the biosynthesis of many signaling peptides.  This transformation is achieved by conversion of a prohormone to the corresponding amide (C(O)NH<sub>2</sub>).  This enzyme is the only known pathway for generating peptide amides, which renders the peptide more hydrophilic.<ref>{{cite journal | vauthors = Eipper BA, Milgram SL, Husten EJ, Yun HY, Mains RE | title = Peptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing, and routing domains. | journal = Protein Sci. | volume = 2 | issue = 4 | pages = 489–97 | year = 1993 | pmid = 8518727 | pmc = 2142366 | doi = 10.1002/pro.5560020401 }}</ref>  In humans, PAM is encoded by the ''[[PAM (gene)|PAM]]'' [[gene]].<ref name="pmid2357221">{{cite journal | vauthors = Glauder J, Ragg H, Rauch J, Engels JW | title = Human peptidylglycine alpha-amidating monooxygenase: cDNA, cloning and functional expression of a truncated form in COS cells | journal = Biochem Biophys Res Commun | volume = 169 | issue = 2 | pages = 551–8 | date = Jul 1990 | pmid = 2357221 | pmc =  | doi = 10.1016/0006-291X(90)90366-U }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PAM peptidylglycine alpha-amidating monooxygenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5066| accessdate = }}</ref>
'''Peptidyl-glycine alpha-amidating monooxygenase''' is an [[enzyme]] that catalyzes the [[biosynthesis]] of many [[signaling peptides]] and, in humans, is encoded by the ''[[PAM (gene)|PAM]]'' [[gene]].<ref name="pmid2357221">{{cite journal | vauthors = Glauder J, Ragg H, Rauch J, Engels JW | title = Human peptidylglycine alpha-amidating monooxygenase: cDNA, cloning and functional expression of a truncated form in COS cells | journal = Biochem Biophys Res Commun | volume = 169 | issue = 2 | pages = 551–8 | date = Jul 1990 | pmid = 2357221 | pmc =  | doi = 10.1016/0006-291X(90)90366-U }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PAM peptidylglycine alpha-amidating monooxygenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5066| accessdate = }}</ref> This transformation is achieved by conversion of a prohormone to the corresponding amide (C(O)NH<sub>2</sub>).  This enzyme is the only known pathway for generating peptide amides, which renders the peptide more hydrophilic.<ref>{{cite journal | vauthors = Eipper BA, Milgram SL, Husten EJ, Yun HY, Mains RE | title = Peptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing, and routing domains. | journal = Protein Sci. | volume = 2 | issue = 4 | pages = 489–97 | year = 1993 | pmid = 8518727 | pmc = 2142366 | doi = 10.1002/pro.5560020401 }}</ref>  The reaction pathway catalyzed by PAM is accessed via quantum tunneling and substrate preorganization.<ref>{{ cite journal | vauthors = McIntyre NR, Lowe EW, Belof JL, Ivkovic M, Shafer J, Space B, Merkler DJ | title = Evidence for Substrate Preorganization in the Peptidylglycine α-Amidating Monooxygenase Reaction Describing the Contribution of Ground State Structure to Hydrogen Tunneling. | journal = J. Am. Chem. Soc. | volume = 132 | issue = 46 | pages = 16393-16402 | year = 2010 | doi = 10.1021/ja1019194 | pmc = 2988104 }} </ref>


== Function ==
== Function ==

Latest revision as of 13:51, 23 December 2018

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Peptidyl-glycine alpha-amidating monooxygenase is an enzyme that catalyzes the biosynthesis of many signaling peptides and, in humans, is encoded by the PAM gene.[1][2] This transformation is achieved by conversion of a prohormone to the corresponding amide (C(O)NH2). This enzyme is the only known pathway for generating peptide amides, which renders the peptide more hydrophilic.[3] The reaction pathway catalyzed by PAM is accessed via quantum tunneling and substrate preorganization.[4]

Function

This gene encodes a multifunctional protein. It has two enzymatically active domains with catalytic activities - peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL). These catalytic domains work sequentially to catalyze neuroendocrine peptides to active alpha-amidated products. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene, but some of their full-length sequences are not yet known.[2]

The PHM subunit effects hydroxylation of an O-terminal glycine residue:

peptide-C(O)NHCH2CO2− + O2 + 2 [H] → peptide-C(O)NHCH(OH)CO2− + H2O

Involving hydroxylation of a hydrocarbon by O2, this process relies on a copper cofactor. Dopamine beta-hydroxylase, also a copper-containing enzyme, effects a similar transformation.

The PAL subunit then completes the conversion, by catalyzing elimination from the hydroxylated glycine:

peptide-C(O)NHCH(OH)CO2− → peptide-C(O)NH2 + CH(O)CO2−

The eliminated coproduct is glyoxylate, written above as CH(O)CO2−.

References

  1. ↑ Glauder J, Ragg H, Rauch J, Engels JW (Jul 1990). "Human peptidylglycine alpha-amidating monooxygenase: cDNA, cloning and functional expression of a truncated form in COS cells". Biochem Biophys Res Commun. 169 (2): 551–8. doi:10.1016/0006-291X(90)90366-U. PMID 2357221.
  2. ↑ 2.0 2.1 "Entrez Gene: PAM peptidylglycine alpha-amidating monooxygenase".
  3. ↑ Eipper BA, Milgram SL, Husten EJ, Yun HY, Mains RE (1993). "Peptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing, and routing domains". Protein Sci. 2 (4): 489–97. doi:10.1002/pro.5560020401. PMC 2142366. PMID 8518727.
  4. ↑ McIntyre NR, Lowe EW, Belof JL, Ivkovic M, Shafer J, Space B, Merkler DJ (2010). "Evidence for Substrate Preorganization in the Peptidylglycine α-Amidating Monooxygenase Reaction Describing the Contribution of Ground State Structure to Hydrogen Tunneling". J. Am. Chem. Soc. 132 (46): 16393–16402. doi:10.1021/ja1019194. PMC 2988104.

Further reading

  • Pittner RA, Albrandt K, Beaumont K, Gaeta LS, Koda JE, Moore CX, Rittenhouse J, Rink TJ (1994). "Molecular physiology of amylin". J. Cell. Biochem. 55 Suppl (S1994A): 19–28. doi:10.1002/jcb.240550004. PMID 7929615.
  • Ouafik LH, Stoffers DA, Campbell TA, Johnson RC, Bloomquist BT, Mains RE, Eipper BA (1992). "The multifunctional peptidylglycine alpha-amidating monooxygenase gene: exon/intron organization of catalytic, processing, and routing domains". Mol. Endocrinol. 6 (10): 1571–84. doi:10.1210/me.6.10.1571. PMID 1448112.
  • Maltese JY, Eipper BA (1993). "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. 6 (12): 1998–2008. doi:10.1210/me.6.12.1998. PMID 1491686.
  • Braas KM, Harakall SA, Ouafik L, Eipper BA, May V (1992). "Expression of peptidylglycine alpha-amidating monooxygenase: an in situ hybridization and immunocytochemical study". Endocrinology. 130 (5): 2778–88. doi:10.1210/en.130.5.2778. PMID 1572293.
  • Roberts AN, Leighton B, Todd JA, Cockburn D, Schofield PN, Sutton R, Holt S, Boyd Y, Day AJ, Foot EA (1990). "Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus". Proc. Natl. Acad. Sci. U.S.A. 86 (24): 9662–6. doi:10.1073/pnas.86.24.9662. PMC 298561. PMID 2690069.
  • Vos MD, Jones JE, Treston AM (1995). "Human peptidylglycine alpha-amidating monooxygenase transcripts derived by alternative mRNA splicing of an unreported exon". Gene. 163 (2): 307–11. doi:10.1016/0378-1119(95)00364-C. PMID 7590286.
  • Tsukamoto T, Noguchi M, Kayama H, Watanabe T, Asoh T, Yamamoto T (1995). "Increased peptidylglycine alpha-amidating monooxygenase activity in cerebrospinal fluid of patients with multiple sclerosis". Intern. Med. 34 (4): 229–32. doi:10.2169/internalmedicine.34.229. PMID 7606087.
  • Yun HY, Johnson RC, Mains RE, Eipper BA (1993). "Topological switching of the COOH-terminal domain of peptidylglycine alpha-amidating monooxygenase by alternative RNA splicing". Arch. Biochem. Biophys. 301 (1): 77–84. doi:10.1006/abbi.1993.1117. PMID 7680192.
  • Mains RE, Milgram SL, Keutmann HT, Eipper BA (1995). "The NH2-terminal proregion of peptidylglycine alpha-amidating monooxygenase facilitates the secretion of soluble proteins". Mol. Endocrinol. 9 (1): 3–13. doi:10.1210/me.9.1.3. PMID 7760848.
  • Tateishi K, Arakawa F, Misumi Y, Treston AM, Vos M, Matsuoka Y (1995). "Isolation and functional expression of human pancreatic peptidylglycine alpha-amidating monooxygenase". Biochem. Biophys. Res. Commun. 205 (1): 282–90. doi:10.1006/bbrc.1994.2662. PMID 7999037.
  • Martínez A, Montuenga LM, Springall DR, Treston A, Cuttitta F, Polak JM (1993). "Immunocytochemical localization of peptidylglycine alpha-amidating monooxygenase enzymes (PAM) in human endocrine pancreas". J. Histochem. Cytochem. 41 (3): 375–80. doi:10.1177/41.3.8094086. PMID 8094086.
  • Kapuscinski M, Green M, Sinha SN, Shepherd JJ, Shulkes A (1993). "Peptide alpha-amidation activity in human plasma: relationship to gastrin processing". Clin. Endocrinol. 39 (1): 51–8. doi:10.1111/j.1365-2265.1993.tb01750.x. PMID 8102327.
  • Yun HY, Keutmann HT, Eipper BA (1994). "Alternative splicing governs sulfation of tyrosine or oligosaccharide on peptidylglycine alpha-amidating monooxygenase". J. Biol. Chem. 269 (14): 10946–55. PMID 8144680.
  • Ouafik LH, Mattei MG, Giraud P, Oliver C, Eipper BA, Mains RE (1994). "Localization of the gene encoding peptidylglycine alpha-amidating monooxygenase (PAM) to human chromosome 5q14-5q21". Genomics. 18 (2): 319–21. doi:10.1006/geno.1993.1471. PMID 8288234.
  • Husten EJ, Tausk FA, Keutmann HT, Eipper BA (1993). "Use of endoproteases to identify catalytic domains, linker regions, and functional interactions in soluble peptidylglycine alpha-amidating monooxygenase". J. Biol. Chem. 268 (13): 9709–17. PMID 8486658.
  • Yun HY, Milgram SL, Keutmann HT, Eipper BA (1996). "Phosphorylation of the cytosolic domain of peptidylglycine alpha-amidating monooxygenase". J. Biol. Chem. 270 (50): 30075–83. doi:10.1074/jbc.270.50.30075. PMID 8530412.
  • Morris KM, Cao F, Onagi H, Altamore TM, Gamble AB, Easton CJ (1 December 2012). "Prohormone-substrate peptide sequence recognition by peptidylglycine α-amidating monooxygenase and its reflection in increased glycolate inhibitor potency". Bioorganic & Medicinal Chemistry Letters. 22 (23): 7015–7018. doi:10.1016/j.bmcl.2012.10.004. PMID 23084901.


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