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]
In humans, the enzyme is encoded by the PAMgene.[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
neuroendocrinepeptides 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:
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:
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]
^Wilcox BJ, Ritenour-Rodgers KJ, Asser AS, Baumgart LE, Baumgart MA, Boger DL, et al. (March 1999). "N-acylglycine amidation: implications for the biosynthesis of fatty acid primary amides". Biochemistry. 38 (11): 3235–3245.
doi:
10.1021/bi982255j.
PMID10079066.
^Glauder J, Ragg H, Rauch J, Engels JW (June 1990). "Human peptidylglycine alpha-amidating monooxygenase: cDNA, cloning and functional expression of a truncated form in COS cells". Biochemical and Biophysical Research Communications. 169 (2): 551–558.
doi:
10.1016/0006-291X(90)90366-U.
PMID2357221.
Braas KM, Harakall SA, Ouafik L, Eipper BA, May V (May 1992). "Expression of peptidylglycine alpha-amidating monooxygenase: an in situ hybridization and immunocytochemical study". Endocrinology. 130 (5): 2778–2788.
doi:
10.1210/endo.130.5.1572293.
PMID1572293.
Tateishi K, Arakawa F, Misumi Y, Treston AM, Vos M, Matsuoka Y (November 1994). "Isolation and functional expression of human pancreatic peptidylglycine alpha-amidating monooxygenase". Biochemical and Biophysical Research Communications. 205 (1): 282–290.
doi:
10.1006/bbrc.1994.2662.
PMID7999037.
Kapuscinski M, Green M, Sinha SN, Shepherd JJ, Shulkes A (July 1993). "Peptide alpha-amidation activity in human plasma: relationship to gastrin processing". Clinical Endocrinology. 39 (1): 51–58.
doi:
10.1111/j.1365-2265.1993.tb01750.x.
PMID8102327.
S2CID72764842.