Met-enkephalin

Last updated
Met-enkephalin
Met-enkephalin Structure.svg
Met-enkephalin ball-and-stick.png
Names
IUPAC name
(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylsulfanylbutanoic acid
Other names
[Met]enkephalin; [Met5]enkephalin; L-Tyrosylglycylglycyl-L-phenylalanyl-L-methionine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.055.741 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 261-335-8
KEGG
MeSH Enkephalin,+Methionine
PubChem CID
UNII
  • InChI=1S/C27H35N5O7S/c1-40-12-11-21(27(38)39)32-26(37)22(14-17-5-3-2-4-6-17)31-24(35)16-29-23(34)15-30-25(36)20(28)13-18-7-9-19(33)10-8-18/h2-10,20-22,33H,11-16,28H2,1H3,(H,29,34)(H,30,36)(H,31,35)(H,32,37)(H,38,39) X mark.svgN
    Key: YFGBQHOOROIVKG-UHFFFAOYSA-N X mark.svgN
  • CSCCC(NC(=O)C(Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)C(N)Cc1ccc(O)cc1)C(O)=O
  • CSCCC(NC(=O)C(CC1=CC=CC=C1)NC(=O)CNC(=O)CNC(=O)C(N)CC1=CC=C(O)C=C1)C(O)=O
Properties
C27H35N5O7S
Molar mass 573.67 g·mol−1
log P 0.607
Acidity (pKa)3.234
Basicity (pKb)10.763
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Met-enkephalin, also known as metenkefalin (INN), sometimes referred to as opioid growth factor (OGF), [1] is a naturally occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkephalin, the other being leu-enkephalin. The enkephalins are considered to be the primary endogenous ligands of the δ-opioid receptor, due to their high potency and selectivity for the site over the other endogenous opioids. [2]

Contents

History

Met-enkephalin was discovered and characterized by John Hughes, Hans Kosterlitz, et al. in 1975 after a search for endogenous ligands of the opioid receptors. [3]

Chemistry

Met-enkephalin is a pentapeptide with the amino acid sequence tyr-gly-gly-phe-met. The tyrosine residue at position 1 is thought to be analogous to the 3-hydroxyl group on morphine.[ citation needed ]

Biochemistry

Distribution

Met-enkephalin is found mainly in the adrenal medulla and throughout the central nervous system (CNS), including in the striatum, cerebral cortex, olfactory tubercle, hippocampus, septum, thalamus, and periaqueductal gray, as well as the dorsal horn of the spinal cord. [2] It is also present in the periphery, notably in some primary afferent fibers that innervate the pelvic viscera. [2]

Biosynthesis

Met-enkephalin is synthesized from proenkephalin via proteolytic cleavage [4] in two metabolic steps. Proenkephalin A is first reduced by either one of two trypsin-like endopeptidase enzymes, prohormone convertase 1 (PC1) or prohormone convertase 2 (PC2); then, the resulting intermediates are further reduced by the enzyme carboxypeptidase E (CPE; previously known as enkephalin convertase (EC)). [5] [6] Proenkephalin A contains four sequences of met-enkephalin (at the following positions: 100–104; 107–111; 136–140; 210–214), and as a result, its cleavage generates four copies of met-enkephalin peptides at once. [4] In addition, anabolism of proenkephalin A results in the production of one copy each of two C-terminal-extended met-enkephalin derivatives, the heptapeptide met-enkephalin-arg-phe (261–267), and the octapeptide met-enkephalin-arg-gly-leu (186–193), [4] though whether they affect the opioid receptors in a similar manner as met-enkephalin is not entirely clear. [7]

Clearance

Met- and leu-enkephalin are metabolized by a variety of different enzymes, including aminopeptidase N (APN), [8] neutral endopeptidase (NEP), [8] dipeptidyl peptidase 3 (DPP3), [8] carboxypeptidase A6 (CPA6), [9] and angiotensin-converting enzyme (ACE). [10] These enzymes are sometimes referred to as enkephalinases.

Biological activity

Met-enkephalin is a potent agonist of the δ-opioid receptor, and to a lesser extent the μ-opioid receptor, with little to no effect on the κ-opioid receptor. It is through these receptors that met-enkephalin produces its opioid effects, such as analgesia and antidepressant-like effects.

It is also the endogenous ligand of the opioid growth factor receptor (OGFR; formerly known as the ζ-opioid receptor), which plays a role in the regulation of tissue growth and regeneration; hence why met-enkephalin is sometimes called OGF instead.

Pharmacokinetics

Met-enkephalin has low bioavailability, is rapidly metabolized, and has a very short half-life (minutes). [3] [11] These properties are considered undesirable in pharmaceuticals as large doses would need to be administered multiple times an hour to maintain a therapeutically relevant effect, making it unlikely that met-enkephalin will ever be used as a medicine.

[D-Ala2]-Met-enkephalinamide (DALA), is a synthetic enkephalin analog which is not susceptible to degradation by brain enzymes and at low doses (5 to 10 micrograms) caused profound, long-lasting, morphine-like analgesia when microinjected into a rat’s brain. [12]

See also

Related Research Articles

Endorphins are peptides produced in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in the pituitary gland of the brain. Endorphins are endogenous painkillers often produced in the brain and adrenal medulla during physical exercise or orgasm and inhibit pain, muscle cramps, and relieve stress.

<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">Enkephalin</span> Pentapeptide

An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin have been found, one containing leucine ("leu"), and the other containing methionine ("met"). Both are products of the proenkephalin gene.

β-Endorphin Peptide hormone in humans

β-Endorphin (beta-endorphin) is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin.

<span class="mw-page-title-main">Opioid peptide</span> Class of peptides that bind to opioid receptors

Opioid peptides or opiate peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble those of opiates. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, control of food intake, and the rewarding effects of alcohol and nicotine.

<span class="mw-page-title-main">Opiorphin</span> Endogenous chemical compound first isolated from human saliva

Opiorphin is an endogenous chemical compound first isolated from human saliva. Initial research with mice shows the compound has a painkilling effect greater than that of morphine. It works by stopping the normal breakup of enkephalins, natural pain-killing opioids in the spinal cord. It is a relatively simple molecule consisting of a five-amino acid polypeptide, Gln-Arg-Phe-Ser-Arg (QRFSR).

<span class="mw-page-title-main">Carboxypeptidase E</span> Enzyme found in humans

Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) and enkephalin convertase, is an enzyme that in humans is encoded by the CPE gene. This enzyme catalyzes the release of C-terminal arginine or lysine residues from polypeptides.

Leu-enkephalin is an endogenous opioid peptide neurotransmitter with the amino acid sequence Tyr-Gly-Gly-Phe-Leu that is found naturally in the brains of many animals, including humans. It is one of the two forms of enkephalin; the other is met-enkephalin. The tyrosine residue at position 1 is thought to be analogous to the 3-hydroxyl group on morphine. Leu-enkephalin has agonistic actions at both the μ- and δ-opioid receptors, with significantly greater preference for the latter. It has little to no effect on the κ-opioid receptor.

Big dynorphin is an endogenous opioid peptide of the dynorphin family that is composed of both dynorphin A and dynorphin B. Big dynorphin has the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-Lys-Arg-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr. It has nociceptive and anxiolytic-like properties, as well as effects on memory in mice.

<span class="mw-page-title-main">RB-101</span> Chemical compound

RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research.

Enkephalinases are enzymes that degrade endogenous enkephalin opioid peptides. They include:

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

Adrenorphin, also sometimes referred to as metorphamide, is an endogenous, C-terminally amidated, opioid octapeptide (Tyr-Gly-Gly-Phe-Met-Arg-Arg-Val-NH2, YGGFMRRV-NH2) that is produced from proteolytic cleavage of proenkephalin A and is widely distributed throughout the mammalian brain. It was named based on the fact that it was originally detected in human phaeochromocytoma tumour derived from the adrenal medulla, and was subsequently found in normal human and bovine adrenal medulla as well. Adrenorphin exhibits potent opioid activity, acting as a balanced μ- and κ-opioid receptor agonist while having no effects on δ-opioid receptors. It possesses analgesic and respiratory depressive properties.

<span class="mw-page-title-main">Oligopeptidase</span> Enzymes that cleaves peptides but not proteins

An Oligopeptidase is an enzyme that cleaves peptides but not proteins. This property is due to its structure: the active site of this enzyme is located at the end of a narrow cavity which can only be reached by peptides.

Neoendorphins are a group of endogenous opioid peptides derived from the proteolytic cleavage of prodynorphin. They include α-neoendorphin and β-neoendorphin. The α-neoendorphin is present in greater amounts in the brain than β-neoendorphin. Both are products of the dynorphin gene, which also expresses dynorphin A, dynorphin A-(1-8), and dynorphin B. These opioid neurotransmitters are especially active in Central Nervous System receptors, whose primary function is pain sensation. These peptides all have the consensus amino acid sequence of Try-Gly-Gly-Phe-Met (met-enkephalin) or Tyr-Gly-Gly-Phe-Leu ( leu-enkephalin). Binding of neoendorphins to opioid receptors (OPR), in the dorsal root ganglion (DRG) neurons results in the reduction of time of calcium-dependent action potential. The α-neoendorphins bind OPRD1(delta), OPRK1(kappa), and OPRM1 (mu) and β-neoendorphin bind OPRK1.

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

Kelatorphan is a drug which acts as a powerful and complete inhibitor of nearly all of the enzymes responsible for catabolism of the endogenous enkephalins, including neutral endopeptidase (NEP), dipeptidyl peptidase III (DPP3), aminopeptidase N (APN), and angiotensin-converting enzyme (ACE). In mice, with the intracerebroventricular co-administration of a 50 µg dose of kelatorphan (this route is necessary because kelatorphan is incapable of crossing the blood-brain-barrier) hence alongside exogenous [Met]enkephalin (ED50 approximately 10 ng), it potentiated the analgesic effects of the latter by 50,000 times. Kelatorphan also displays potent antinociceptive effects alone, and does not depress respiration, although at high doses it actually increases it.

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

Spinorphin is an endogenous, non-classical opioid peptide of the hemorphin family first isolated from the bovine spinal cord (hence the prefix spin-) and acts as a regulator of the enkephalinases, a class of enzymes that break down endogenous the enkephalin peptides. It does so by inhibiting the enzymes aminopeptidase N (APN), dipeptidyl peptidase III (DPP3), angiotensin-converting enzyme (ACE), and neutral endopeptidase (NEP). Spinorphin is a heptapeptide and has the amino acid sequence Leu-Val-Val-Tyr-Pro-Trp-Thr (LVVYPWT). It has been observed to possess antinociceptive, antiallodynic, and anti-inflammatory properties. The mechanism of action of spinorphin has not been fully elucidated (i.e., how it acts to inhibit the enkephalinases), but it has been found to act as an antagonist of the P2X3 receptor, and as a weak partial agonist/antagonist of the FP1 receptor.

<span class="mw-page-title-main">Tynorphin</span> Synthetic opioid chemical compound

Tynorphin is a synthetic opioid peptide which is a potent and competitive inhibitor of the enkephalinase class of enzymes which break down the endogenous enkephalin peptides. It specifically inactivates dipeptidyl aminopeptidase III (DPP3) with very high efficacy, but also inhibits neutral endopeptidase (NEP), aminopeptidase N (APN), and angiotensin-converting enzyme (ACE) to a lesser extent. It has a pentapeptide structure with the amino acid sequence Val-Val-Tyr-Pro-Trp (VVYPW).

<span class="mw-page-title-main">Hemorphin-4</span> Endogenous opioid peptide

Hemorphin-4 is an endogenous opioid peptide of the hemorphin family which possesses antinociceptive properties and is derived from the β-chain of hemoglobin in the bloodstream. It is a tetrapeptide with the amino acid sequence Tyr-Pro-Trp-Thr. Hemorphin-4 has affinities for the μ-, δ-, and κ-opioid receptors that are in the same range as the structurally related β-casomorphins, although affinity to the κ-opioid receptor is markedly higher in comparison. It acts as an agonist at these sites. Hemorphin-4 also has inhibitory effects on angiotensin-converting enzyme (ACE), and as a result, may play a role in the regulation of blood pressure. Notably, inhibition of ACE also reduces enkephalin catabolism.

Hemorphins are a class of naturally occurring, endogenous opioid peptides which are found in the bloodstream, and are derived from the β-chain of hemoglobin. They have antinociceptive effects via activation of the opioid receptors, and some may also play a role in blood pressure through inhibition of the angiotensin-converting enzyme (ACE), as well as cause an elevation of endogenous enkephalin levels. Some examples of hemorphins include hemorphin-4, spinorphin, and valorphin.

Leumorphin, also known as dynorphin B1–29, is a naturally occurring endogenous opioid peptide. Derived as a proteolytic cleavage product of residues 226-254 of prodynorphin, leumorphin is a nonacosapeptide and has the sequence Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr-Arg-Ser-Gln-Glu-Asp-Pro-Asn-Ala-Tyr-Ser-Gly-Glu-Leu-Phe-Asp-Ala. It can be further reduced to dynorphin B and dynorphin B-14 by pitrilysin metallopeptidase 1, an enzyme of the endopeptidase family. Leumorphin behaves as a potent and selective κ-opioid receptor agonist, similarly to other endogenous opioid peptide derivatives of prodynorphin.

References

  1. ↑ Zagon IS, Isayama T, McLaughlin PJ (January 1994). "Preproenkephalin mRNA expression in the developing and adult rat brain". Brain Research. Molecular Brain Research. 21 (1–2): 85–98. doi:10.1016/0169-328x(94)90381-6. PMID   8164525.
  2. 1 2 3 Christoph Stein (1999). Opioids in pain control: basic and clinical aspects. Cambridge University Press. pp. 22–23. ISBN   978-0-521-62269-1 . Retrieved 25 November 2011.
  3. 1 2 Thomas Carleton Moore (1993). Neurovascular immunology: vasoactive neurotransmitters and modulators in cellular immunity and memory. CRC Press. p. 179. ISBN   978-0-8493-6894-3 . Retrieved 25 November 2011.
  4. 1 2 3 Fleur L. Strand (1999). Neuropeptides: regulators of physiological processes . MIT Press. p.  348. ISBN   978-0-262-19407-5 . Retrieved 25 November 2011.
  5. ↑ Costa E, Mocchetti I, Supattapone S, Snyder SH (July 1987). "Opioid peptide biosynthesis: enzymatic selectivity and regulatory mechanisms". The FASEB Journal. 1 (1): 16–21. doi: 10.1096/fasebj.1.1.3111927 . PMID   3111927. S2CID   23334563.
  6. ↑ Krajnik M, Schäfer M, Sobanski P, et al. (May 2010). "Enkephalin, its precursor, processing enzymes, and receptor as part of a local opioid network throughout the respiratory system of lung cancer patients". Human Pathology. 41 (5): 632–42. doi:10.1016/j.humpath.2009.08.025. PMID   20040394.
  7. ↑ Vats ID, Chaudhary S, Karar J, Nath M, Pasha Q, Pasha S (October 2009). "Endogenous peptide: Met-enkephalin-Arg-Phe, differently regulate expression of opioid receptors on chronic treatment". Neuropeptides. 43 (5): 355–62. doi:10.1016/j.npep.2009.07.003. PMID   19716174. S2CID   19181608.
  8. 1 2 3 Thanawala V, Kadam VJ, Ghosh R (October 2008). "Enkephalinase inhibitors: potential agents for the management of pain". Current Drug Targets. 9 (10): 887–94. doi:10.2174/138945008785909356. PMID   18855623. Archived from the original on 2013-04-14.
  9. ↑ Lyons PJ, Callaway MB, Fricker LD (March 2008). "Characterization of carboxypeptidase A6, an extracellular matrix peptidase". The Journal of Biological Chemistry. 283 (11): 7054–63. doi: 10.1074/jbc.M707680200 . PMID   18178555.
  10. ↑ Benuck M, Berg MJ, Marks N (1982). "Separate metabolic pathways for Leu-enkephalin and Met-enkephalin-Arg(6)-Phe(7) degradation by rat striatal synaptosomal membranes". Neurochemistry International. 4 (5): 389–96. doi:10.1016/0197-0186(82)90081-X. PMID   20487892. S2CID   23138078.
  11. ↑ William J. Kraemer; Alan David Rogol (29 August 2005). The endocrine system in sports and exercise. John Wiley & Sons. pp. 203–. ISBN   978-1-4051-3017-2 . Retrieved 25 November 2011.
  12. ↑ Pert, C. B.; Pert, A.; Chang, J. K.; Fong, B. T. (1976-10-15). "(D-Ala2)-Met-enkephalinamide: a potent, long-lasting synthetic pentapeptide analgesic". Science. 194 (4262): 330–332. Bibcode:1976Sci...194..330P. doi:10.1126/science.968485. ISSN   0036-8075. PMID   968485.
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