Peptidylglycine alpha-amidating monooxygenase

Last updated
PAM
Protein PAM PDB 1opm.png
Identifiers
Aliases PAM , PAL, PHM, Peptidylglycine alpha-amidating monooxygenase
External IDs OMIM: 170270; MGI: 97475; HomoloGene: 37369; GeneCards: PAM; OMA:PAM - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5066

18484

Ensembl

ENSG00000145730

ENSMUSG00000026335

UniProt

P19021

P97467

RefSeq (mRNA)

NM_013626
NM_001357127

RefSeq (protein)

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
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]

Related Research Articles

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<span class="mw-page-title-main">Copper type II ascorbate-dependent monooxygenase</span> Class of enzymes

In molecular biology, the copper type II ascorbate-dependent monooxygenases are a class of enzymes that require copper as a cofactor and which use ascorbate as an electron donor. This family contains two related enzymes, dopamine beta-monooxygenase EC 1.14.17.1 and peptidylglycine alpha-amidating monooxygenase EC 1.14.17.3. There are a few regions of sequence similarities between these two enzymes, two of these regions contain clusters of conserved histidine residues which are most probably involved in binding copper.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000145730 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026335 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Eipper BA, Milgram SL, Husten EJ, Yun HY, Mains RE (April 1993). "Peptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing, and routing domains". Protein Science. 2 (4): 489–497. doi:10.1002/pro.5560020401. PMC   2142366 . PMID   8518727.
  6. ↑ 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. PMID   10079066.
  7. ↑ 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. PMID   2357221.
  8. 1 2 "Entrez Gene: PAM peptidylglycine alpha-amidating monooxygenase".
  9. ↑ McIntyre NR, Lowe EW, Belof JL, Ivkovic M, Shafer J, Space B, Merkler DJ (November 2010). "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. doi:10.1021/ja1019194. PMC   2988104 . PMID   21043511.
  10. ↑ Abad E, Rommel JB, Kästner J (May 2014). "Reaction mechanism of the bicopper enzyme peptidylglycine α-hydroxylating monooxygenase". The Journal of Biological Chemistry. 289 (20): 13726–13738. doi: 10.1074/jbc.M114.558494 . PMC   4022847 . PMID   24668808.
  11. ↑ Harrison JF, Greenlee KJ, Verberk WC (January 2018). "Functional Hypoxia in Insects: Definition, Assessment, and Consequences for Physiology, Ecology, and Evolution". Annual Review of Entomology. 63 (1). Annual Reviews: 303–325. doi: 10.1146/annurev-ento-020117-043145 . hdl: 2066/193219 . PMID   28992421.

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