Peptidylglycine alpha-amidating monooxygenase

PAM
Identifiers
Aliases	PAM, PAL, PHM, Peptidylglycine alpha-amidating monooxygenase
External IDs	OMIM: 170270; MGI: 97475; HomoloGene: 37369; GeneCards: PAM; OMA:PAM - orthologs
Gene location (Human) Chr. Chromosome 5 (human) Band 5q21.1 Start 102,753,981 bp End 103,031,105 bp
Gene location (Mouse) Chr. Chromosome 1 (mouse) Band 1 D|1 47.76 cM Start 97,795,114 bp End 98,095,646 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in cardiac muscle tissue of right atrium right ventricle right auricle corpus epididymis parotid gland beta cell vena cava Descending thoracic aorta glomerulus metanephric glomerulus Top expressed in aortic valve ascending aorta decidua dentate gyrus of hippocampal formation granule cell gastrula superior frontal gyrus primary visual cortex atrioventricular valve lip neural layer of retina More reference expression data BioGPS 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 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 plasma membrane secretory granule membrane secretory granule perikaryon membrane extracellular space 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 by RNA polymerase II 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 long-chain fatty acid metabolic process peptide metabolic process 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
Wikidata
View/Edit Human View/Edit Mouse

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

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

In humans, the enzyme is encoded by the PAM gene. 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.

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.

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⁻.

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.