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
Ensembl
UniProt
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

<span class="mw-page-title-main">Proopiomelanocortin</span> Mammalian protein found in Homo sapiens

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

<span class="mw-page-title-main">Thyrotropin-releasing hormone</span> Hormone

Thyrotropin-releasing hormone (TRH) is a hypophysiotropic hormone produced by neurons in the hypothalamus that stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary.

<span class="mw-page-title-main">Amylin</span> Peptide hormone that plays a role in glycemic regulation

Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

<span class="mw-page-title-main">Aldosterone synthase</span> Protein-coding gene in the species Homo sapiens

Aldosterone synthase, also called steroid 18-hydroxylase, corticosterone 18-monooxygenase or P450C18, is a steroid hydroxylase cytochrome P450 enzyme involved in the biosynthesis of the mineralocorticoid aldosterone and other steroids. The enzyme catalyzes sequential hydroxylations of the steroid angular methyl group at C18 after initial 11β-hydroxylation. It is encoded by the CYP11B2 gene in humans.

<span class="mw-page-title-main">21-Hydroxylase</span> Human enzyme that hydroxylates steroids

Steroid 21-hydroxylase is a protein that in humans is encoded by the CYP21A2 gene. The protein is an enzyme that hydroxylates steroids at the C21 position on the molecule. Naming conventions for enzymes are based on the substrate acted upon and the chemical process performed. Biochemically, this enzyme is involved in the biosynthesis of the adrenal gland hormones aldosterone and cortisol, which are important in blood pressure regulation, sodium homeostasis and blood sugar control. The enzyme converts progesterone and 17α-hydroxyprogesterone into 11-deoxycorticosterone and 11-deoxycortisol, respectively, within metabolic pathways which in humans ultimately lead to aldosterone and cortisol creation—deficiency in the enzyme may cause congenital adrenal hyperplasia.

<span class="mw-page-title-main">ACTH receptor</span> Mammalian protein found in Homo sapiens

The adrenocorticotropic hormone receptor or ACTH receptor also known as the melanocortin receptor 2 or MC2 receptor is a type of melanocortin receptor (type 2) which is specific for ACTH. A G protein–coupled receptor located on the external cell plasma membrane, it is coupled to Gαs and upregulates levels of cAMP by activating adenylyl cyclase. The ACTH receptor plays a role in immune function and glucose metabolism.

<span class="mw-page-title-main">Dopamine beta-hydroxylase</span> Mammalian protein found in Homo sapiens

Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine.

In enzymology, a peptidylglycine monooxygenase (EC 1.14.17.3) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Corticotropin-releasing hormone receptor 2</span> Protein found in humans

Corticotropin-releasing hormone receptor 2 (CRHR2) is a protein, also known by the IUPHAR-recommended name CRF2, that is encoded by the CRHR2 gene and occurs on the surfaces of some mammalian cells. CRF2 receptors are type 2 G protein-coupled receptors for corticotropin-releasing hormone (CRH) that are resident in the plasma membranes of hormone-sensitive cells. CRH, a peptide of 41 amino acids synthesized in the hypothalamus, is the principal neuroregulator of the hypothalamic-pituitary-adrenal axis, signaling via guanine nucleotide-binding proteins (G proteins) and downstream effectors such as adenylate cyclase. The CRF2 receptor is a multi-pass membrane protein with a transmembrane domain composed of seven helices arranged in a V-shape. CRF2 receptors are activated by two structurally similar peptides, urocortin II, and urocortin III, as well as CRH.

<span class="mw-page-title-main">Somatostatin receptor 3</span> Protein-coding gene in the species Homo sapiens

Shekel Somatostatin receptor type 3 is a protein that in humans is encoded by the SSTR3 gene.

<span class="mw-page-title-main">PRKAR1A</span> Protein-coding gene in the species Homo sapiens

cAMP-dependent protein kinase type I-alpha regulatory subunit is an enzyme that in humans is encoded by the PRKAR1A gene.

<span class="mw-page-title-main">Amidase</span>

In enzymology, an amidase (EC 3.5.1.4, acylamidase, acylase (misleading), amidohydrolase (ambiguous), deaminase (ambiguous), fatty acylamidase, N-acetylaminohydrolase (ambiguous)) is an enzyme that catalyzes the hydrolysis of an amide. In this way, the two substrates of this enzyme are an amide and H2O, whereas its two products are monocarboxylate and NH3.

<span class="mw-page-title-main">Kalirin</span> Protein-coding gene in the species Homo sapiens

Kalirin, also known as Huntingtin-associated protein-interacting protein (HAPIP), protein duo (DUO), or serine/threonine-protein kinase with Dbl- and pleckstrin homology domain, is a protein that in humans is encoded by the KALRN gene. Kalirin was first identified in 1997 as a protein interacting with huntingtin-associated protein 1. Is also known to play an important role in nerve growth and axonal development.

<span class="mw-page-title-main">Luteinizing hormone beta polypeptide</span> Protein-coding gene in the species Homo sapiens

Luteinizing hormone subunit beta also known as lutropin subunit beta or LHβ is a polypeptide that in association with an alpha subunit common to all gonadotropin hormones forms the reproductive signaling molecule luteinizing hormone. In humans it is encoded by the LHB gene.

<span class="mw-page-title-main">UHMK1</span> Protein-coding gene in the species Homo sapiens

U2AF homology motif (UHM) kinase 1, also known as UHMK1, is a protein which in humans is encoded by the UHMK1 gene.

<span class="mw-page-title-main">Maltase-glucoamylase</span> Enzyme

Maltase-glucoamylase, intestinal is an enzyme that in humans is encoded by the MGAM gene.

<span class="mw-page-title-main">Amidorphin</span> Chemical compound

Amidorphin is an endogenous, C-terminally amidated, opioid peptide generated as a cleavage product of proenkephalin A in some mammalian species; in humans and most other species, the peptide is 1 residue longer and is not amidated. Amidorphin is widely distributed in the mammalian brain, with particularly high concentrations found in the striatum, and outside of the brain in adrenal medulla and posterior pituitary. The 26-residue peptide named amidorphin is found in several species including bovine, sheep, and pig. Humans and commonly studied lab animals produce a 27-residue peptide that does not have an amidated C-terminal residue; this is due to the absence of a Gly in the precursor sequence and replacement with Ala, which is not a substrate for the amidating enzyme. The properties of the 27-residue peptide are presumably similar to those of amidorphin, although this has not been adequately tested.

<span class="mw-page-title-main">Monooxygenase DBH-like 1</span> Protein-coding gene in the species Homo sapiens

DBH-like monooxygenase protein 1, also known as monooxygenase X, is an enzyme that in humans is encoded by the MOXD1 gene.

<span class="mw-page-title-main">RASSF9</span> Protein-coding gene in the species Homo sapiens

Ras association domain-containing protein 9 (RASSF9), also known as PAM COOH-terminal interactor protein 1 (PCIP1) or peptidylglycine alpha-amidating monooxygenase COOH-terminal interactor (PAMCI) is a protein that in humans is encoded by the RASSF9 gene.

<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.

Further reading