Peptidylglycine alpha-amidating monooxygenase explained

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.

The enzyme is involved in the biosynthesis of many signaling peptides and some fatty acid amides.[1]

In humans, the enzyme is encoded by the PAM gene.[2] [3] 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.[4]

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.[5] 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.[3]

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

peptide-C(O)NHCH2CO2− + O2 + 2 [H] → peptide-C(O)NHCH(OH)CO2− + H2OThis 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.[6]

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 O concentrations and depends upon Cu. 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.[7]

Further reading

Notes and References

  1. Wilcox BJ, Ritenour-Rodgers KJ, Asser AS, Baumgart LE, Baumgart MA, Boger DL, DeBlassio JL, deLong MA, Glufke U, Henz ME, King L, Merkler KA, Patterson JE, Robleski JJ, Vederas JC, Merkler DJ . 6 . N-acylglycine amidation: implications for the biosynthesis of fatty acid primary amides . Biochemistry . 38 . 11 . 3235–3245 . March 1999 . 10079066 . 10.1021/bi982255j .
  2. Glauder J, Ragg H, Rauch J, Engels JW . 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 . June 1990 . 2357221 . 10.1016/0006-291X(90)90366-U .
  3. Web site: Entrez Gene: PAM peptidylglycine alpha-amidating monooxygenase.
  4. Eipper BA, Milgram SL, Husten EJ, Yun HY, Mains RE . Peptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing, and routing domains . Protein Science . 2 . 4 . 489–497 . April 1993 . 8518727 . 2142366 . 10.1002/pro.5560020401 .
  5. McIntyre NR, Lowe EW, Belof JL, Ivkovic M, Shafer J, Space B, Merkler DJ . Evidence for substrate preorganization in the peptidylglycine α-amidating monooxygenase reaction describing the contribution of ground state structure to hydrogen tunneling . Journal of the American Chemical Society . 132 . 46 . 16393–16402 . November 2010 . 21043511 . 2988104 . 10.1021/ja1019194 .
  6. Abad E, Rommel JB, Kästner J . Reaction mechanism of the bicopper enzyme peptidylglycine α-hydroxylating monooxygenase . The Journal of Biological Chemistry . 289 . 20 . 13726–13738 . May 2014 . 24668808 . 4022847 . 10.1074/jbc.M114.558494 . free .
  7. Harrison JF, Greenlee KJ, Verberk WC . Functional Hypoxia in Insects: Definition, Assessment, and Consequences for Physiology, Ecology, and Evolution . Annual Review of Entomology . 63 . 1 . 303–325 . January 2018 . 28992421 . 10.1146/annurev-ento-020117-043145 . . free . 2066/193219 . free .

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