Peptidylglycine alpha-amidating monooxygenase

Peptidyl-glycine alpha-amidating monooxygenase is an enzyme that catalyzes the conversion of glycine amides to amides and glyoxylate.

PAM
Identifiers
Aliases	PAM, PAL, PHM, Peptidylglycine alpha-amidating monooxygenase
External IDs	OMIM: 170270 MGI: 97475 HomoloGene: 37369 GeneCards: PAM
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q21.1 Start 102,753,981 bp[1] End 103,031,105 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 D|1 47.76 cM Start 97,795,114 bp[2] End 98,095,646 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • metal ion binding • calcium ion binding • copper ion binding • lyase activity • protein kinase binding • monooxygenase activity • catalytic activity • oxidoreductase activity • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced ascorbate as one donor, and incorporation of one atom of oxygen • L-ascorbic acid binding • GO:0001948 protein binding • zinc ion binding • peptidylglycine monooxygenase activity • peptidylamidoglycolate lyase activity Cellular component • extracellular exosome • extracellular region • integral component of membrane • trans-Golgi network • neuron projection • cell surface • neuronal cell body • perinuclear region of cytoplasm • cell membrane • secretory granule membrane • secretory granule • perikaryon • membrane • extracellular • transport vesicle membrane • cytoplasmic vesicle Biological process • response to hypoxia • limb development • ovulation cycle process • odontogenesis • regulation of protein secretion • response to estradiol • regulation of actin cytoskeleton organization • maternal process involved in female pregnancy • regulation of transcription from RNA polymerase II promoter • metabolism • protein homooligomerization • response to copper ion • heart development • central nervous system development • toxin metabolic process • response to pH • response to glucocorticoid • protein amidation • protein metabolic process • oxidation-reduction process • long-chain fatty acid metabolic process • peptide metabolic process • response to drug • lactation • peptide amidation • fatty acid primary amide biosynthetic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5066	18484
Ensembl	ENSG00000145730	ENSMUSG00000026335
UniProt	P19021	P97467
RefSeq (mRNA)	NM_000919 NM_001177306 NM_138766 NM_138821 NM_138822 NM_001319943	NM_013626 NM_001357127
RefSeq (protein)	NP_000910 NP_001170777 NP_001306872 NP_620121 NP_620176 NP_620177 NP_001351511 NP_001351512 NP_001351513 NP_001351514 NP_001351515 NP_001351516 NP_001351517 NP_001351518 NP_001351519 NP_001351520 NP_001351521 NP_001351522 NP_001351523	NP_038654 NP_001344056
Location (UCSC)	Chr 5: 102.75 – 103.03 Mb	Chr 1: 97.8 – 98.1 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

The enzyme is involved in the biosynthesis of many signaling peptides and some fatty acid amides.[5]

In humans, the enzyme is encoded by the PAM gene.[6][7] 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.[8]

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.[7]

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.[9]

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. GRCh38: Ensembl release 89: ENSG00000145730 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026335 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. . doi:10.1021/bi982255j. Cite journal requires |journal= (help); Missing or empty |title= (help)
6. 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.
7. "Entrez Gene: PAM peptidylglycine alpha-amidating monooxygenase".
8. 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.
9. . doi:10.1074/jbc.M114.558494. Cite journal requires |journal= (help); Missing or empty |title= (help)

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.