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)[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 Bgee Human Mouse (ortholog) Top expressed in right ventricle corpus epididymis parotid gland vena cava glomerulus metanephric glomerulus ascending aorta tibia synovial joint visceral pleura Top expressed in aortic valve ascending aorta superior frontal gyrus atrioventricular valve lip atrium esophagus knee joint myocardium of ventricle endocardial cushion 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 [3] [4]
Wikidata
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Peptidyl-glycine alpha-amidating monooxygenase, or PAM, is an enzyme that catalyzes the conversion of an n+1 residue long peptide with a C-terminal glycine into an n-residue peptide with a terminal amide group. In the process, one molecule of O2 is consumed and the glycine residue is removed from the peptide and converted to glyoxylic acid.^[5]

The enzyme is involved in the biosynthesis of many signaling peptides and some fatty acid amides.^[6]

In humans, the enzyme is encoded by the PAM gene.^[7][8] 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. Replacing the carboxylic acid group with an amide group makes the peptide more hydrophobic and more likely to be neutrally charged at physiologic pH, and it is believed that these neutrally charged peptide amides can more easily bind to receptors.^[5]

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. The reaction pathway catalyzed by PAM is accessed via quantum tunneling and substrate preorganization.^[9] 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.^[8]

The PHM subunit effects hydroxylation of a C-terminal glycine residue:

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

This process shown above is the hydroxylation of a methylene group (-CH₂-) by O₂, and this process relies on a copper ion cofactor. Dopamine beta-hydroxylase, also a copper-containing enzyme, effects a similar transformation.^[10]

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⁻.

In insects

Insect PαAMs are responsive to O₂ concentrations and depends upon Cu²⁺. Simpson et al 2015 finds insect PαAMs to respond to hypoxia by regulating the activity of several peptide hormones. They find PαAM to probably be an important part of neuroendocrine responses to hypoxia.^[11]

References

Further reading

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