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)
End	103,031,105 bp
Gene location (Mouse)
Chr.	Chromosome 1 (mouse)
End	98,095,646 bp
RNA expression pattern
	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
	; ; ; ;
	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; soma; 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
	5066
	18484
	ENSG00000145730
	ENSMUSG00000026335
	P19021
	P97467
NM_000919; NM_001177306; NM_138766; NM_138821; NM_138822;
	NM_001319943
	NM_013626; NM_001357127
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
	Wikidata
View/Edit Human	View/Edit Mouse

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]