Met-enkephalin: Difference between revisions

| verifiedrevid = 458949133

| ImageFile = Met-enkephalin Structure.svg

| ImageFile1 = Met-enkephalin ball-and-stick.png

| ImageSize1 = 250px

| ImageName = Skeletal formula of Met-enkphalin

| IUPACName = (2''S'')-2-<nowiki>[[</nowiki>(2''S'')-2-<nowiki>[[</nowiki>2-<nowiki>[[</nowiki>2-<nowiki>[[</nowiki>(2''S'')-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylsulfanylbutanoic acid

| OtherNames = [Met]enkephalin; [Met⁵]enkephalin; <small>L</small>-Tyrosylglycylglycyl-<small>L</small>-phenylalanyl-<small>L</small>-methionine

|Section1={{Chembox Identifiers

| IUPHAR_ligand = 1614

| CASNo = 58569-55-4

| CASNo_Ref = {{cascite|correct|CAS}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 9JEZ9OD3AS

| PubChem = 443363

| ChemSpiderID = 391597

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| EINECS = 261-335-8

| KEGG = C11684

| KEGG_Ref = {{keggcite|changed|kegg}}

| MeSHName = Enkephalin,+Methionine

| ChEBI = 6618

| ChEMBL = 13786

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| SMILES = CSCCC(NC(=O)C(Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)C(N)Cc1ccc(O)cc1)C(O)=O

| SMILES1 = 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

| StdInChI = 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)

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = YFGBQHOOROIVKG-UHFFFAOYSA-N

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

|Section2={{Chembox Properties

| C=27 | H=35 | N=5 | S=1 | O=7

| LogP = 0.607

| pKa = 3.234

| pKb = 10.763

'''Met-enkephalin''', also known as '''metenkefalin''' ([[International Nonproprietary Name|INN]]), sometimes referred to as '''opioid growth factor''' ('''OGF'''),<ref name="pmid8164525">{{cite journal |vauthors=Zagon IS, Isayama T, McLaughlin PJ | title = Preproenkephalin mRNA expression in the developing and adult rat brain | journal = Brain Research. Molecular Brain Research | volume = 21 | issue = 1–2 | pages = 85–98 |date=January 1994 | pmid = 8164525 | doi = 10.1016/0169-328x(94)90381-6}}</ref> is a [[natural product|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 [[delta-opioid receptor|δ-opioid receptor]], due to their high [[potency (pharmacology)|potency]] and [[binding selectivity|selectivity]] for the site over the other [[endogenous opioid]]s.<ref name="Stein1999">{{cite book | author = Christoph Stein | title = Opioids in pain control: basic and clinical aspects | url = https://books.google.com/books?id=4Rfr8cQayvgC&pg=PA22 | access-date = 25 November 2011 | year = 1999 | publisher = Cambridge University Press | isbn = 978-0-521-62269-1 | pages = 22–23}}</ref>

== History ==

Met-enkephalin was discovered and characterized by [[John Hughes (neuroscientist)|John Hughes]], [[Hans Kosterlitz]], ''et al''. in 1975 after a search for endogenous ligands of the opioid receptors.<ref name="Moore1993">{{cite book | author = Thomas Carleton Moore | title = Neurovascular immunology: vasoactive neurotransmitters and modulators in cellular immunity and memory | url = https://books.google.com/books?id=dJyJGevjkzQC&pg=PA179 | access-date = 25 November 2011 | year = 1993 | publisher = CRC Press | isbn = 978-0-8493-6894-3 | page = 179}}</ref>

== Chemistry ==

Met-enkephalin is a [[pentapeptide (oligopeptide)|pentapeptide]] with the [[amino acid sequence]] tyr-gly-gly-phe-met. The [[tyrosine]] [[residue (chemistry)|residue]] at position 1 is thought to be [[structural analog|analogous]] to the 3-[[hydroxyl]] [[functional group|group]] on [[morphine]].{{Citation needed|date=November 2011}}

== 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 [[Posterior horn of spinal cord|dorsal horn]] of the [[spinal cord]].<ref name="Stein1999" /> It is also present in the periphery, notably in some [[Type Ia sensory fiber|primary afferent fiber]]s that [[innervate]] the [[pelvic viscera]].<ref name="Stein1999" />

=== Biosynthesis ===

Met-enkephalin is [[synthesis (chemistry)|synthesized]] from [[proenkephalin]] via [[Proteolysis|proteolytic]] [[bond cleavage|cleavage]]<ref name="Strand1999">{{cite book | author = Fleur L. Strand | title = Neuropeptides: regulators of physiological processes | url = https://archive.org/details/neuropeptidesreg0000stra | url-access = registration | access-date = 25 November 2011 | year = 1999 | publisher = MIT Press | isbn = 978-0-262-19407-5 | page = [https://archive.org/details/neuropeptidesreg0000stra/page/348 348]}}</ref> in two [[metabolism|metabolic]] steps. Proenkephalin A is first reduced by either one of two [[trypsin]]-like [[endopeptidase]] [[enzyme]]s, [[prohormone convertase 1]] (PC1) or [[prohormone convertase 2]] (PC2); then, the resulting [[reaction intermediate|intermediate]]s are further reduced by the enzyme [[carboxypeptidase E]] (CPE; previously known as enkephalin convertase (EC)).<ref name="pmid3111927">{{cite journal |vauthors=Costa E, Mocchetti I, Supattapone S, Snyder SH | title = Opioid peptide biosynthesis: enzymatic selectivity and regulatory mechanisms | journal = The FASEB Journal | volume = 1 | issue = 1 | pages = 16–21 |date=July 1987 | pmid = 3111927 | doi = 10.1096/fasebj.1.1.3111927 | doi-access = free | s2cid = 23334563 | url = http://www.fasebj.org/cgi/pmidlookup?view=long&pmid=3111927}}</ref><ref name="pmid20040394">{{cite journal |vauthors=Krajnik M, Schäfer M, Sobanski P, etal | title = Enkephalin, its precursor, processing enzymes, and receptor as part of a local opioid network throughout the respiratory system of lung cancer patients | journal = Human Pathology | volume = 41 | issue = 5 | pages = 632–42 |date=May 2010 | pmid = 20040394 | doi = 10.1016/j.humpath.2009.08.025 }}</ref> 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.<ref name="Strand1999" /> In addition, anabolism of proenkephalin A results in the production of one copy each of two [[C-terminus|C-terminal]]-extended met-enkephalin [[derivative (chemistry)|derivatives]], the [[heptapeptide]] met-enkephalin-arg-phe (261–267), and the [[octapeptide]] met-enkephalin-arg-gly-leu (186–193),<ref name="Strand1999" /> though whether they affect the opioid receptors in a similar manner as met-enkephalin is not entirely clear.<ref name="pmid19716174">{{cite journal |vauthors=Vats ID, Chaudhary S, Karar J, Nath M, Pasha Q, Pasha S | title = Endogenous peptide: Met-enkephalin-Arg-Phe, differently regulate expression of opioid receptors on chronic treatment | journal = Neuropeptides | volume = 43 | issue = 5 | pages = 355–62 |date=October 2009 | pmid = 19716174 | doi = 10.1016/j.npep.2009.07.003 | s2cid = 19181608 }}</ref>

=== Clearance ===

Met- and leu-enkephalin are metabolized by a variety of different enzymes, including [[aminopeptidase N]] (APN),<ref name="pmid18855623">{{cite journal | vauthors = Thanawala V, Kadam VJ, Ghosh R | title = Enkephalinase inhibitors: potential agents for the management of pain | journal = Current Drug Targets | volume = 9 | issue = 10 | pages = 887–94 | date = October 2008 | pmid = 18855623 | doi = 10.2174/138945008785909356 | url = http://www.bentham-direct.org/pages/content.php?CDT/2008/00000009/00000010/0009J.SGM | archive-url = https://archive.today/20130414094722/http://www.bentham-direct.org/pages/content.php?CDT/2008/00000009/00000010/0009J.SGM | url-status = dead | archive-date = 2013-04-14 }}</ref> [[neutral endopeptidase]] (NEP),<ref name="pmid18855623"/> [[dipeptidyl peptidase 3]] (DPP3),<ref name="pmid18855623"/> [[carboxypeptidase A6]] (CPA6),<ref name="pmid18178555">{{cite journal |vauthors=Lyons PJ, Callaway MB, Fricker LD | title = Characterization of carboxypeptidase A6, an extracellular matrix peptidase | journal = The Journal of Biological Chemistry | volume = 283 | issue = 11 | pages = 7054–63 |date=March 2008 | pmid = 18178555 | doi = 10.1074/jbc.M707680200 | doi-access = free }}</ref> and [[angiotensin-converting enzyme]] (ACE).<ref name="pmid20487892">{{cite journal |vauthors=Benuck M, Berg MJ, Marks N | title = Separate metabolic pathways for Leu-enkephalin and Met-enkephalin-Arg(6)-Phe(7) degradation by rat striatal synaptosomal membranes | journal = Neurochemistry International | volume = 4 | issue = 5 | pages = 389–96 | year = 1982 | pmid = 20487892 | doi = 10.1016/0197-0186(82)90081-X| s2cid = 23138078 }}</ref> These enzymes are sometimes referred to as [[enkephalinase]]s.

=== Biological activity ===

Met-enkephalin is a [[potency (pharmacology)|potent]] [[agonist]] of the [[delta-opioid receptor|δ-opioid receptor]], and to a lesser extent the [[mu-opioid receptor|μ-opioid receptor]], with little to no effect on the [[kappa-opioid receptor|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 (biochemistry)|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).<ref name="Moore1993"/><ref name="KraemerRogol2005">{{cite book | author1 = William J. Kraemer | author2 = Alan David Rogol | title = The endocrine system in sports and exercise | url = https://books.google.com/books?id=TlC5Hfl04sMC&pg=PA203 | access-date = 25 November 2011 | date = 29 August 2005 | publisher = John Wiley & Sons | isbn = 978-1-4051-3017-2 | pages = 203–}}</ref> 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.<ref>{{Cite journal|last1=Pert|first1=C. B.|last2=Pert|first2=A.|last3=Chang|first3=J. K.|last4=Fong|first4=B. T.|date=1976-10-15|title=(D-Ala2)-Met-enkephalinamide: a potent, long-lasting synthetic pentapeptide analgesic|pmid=968485|journal=Science |volume=194|issue=4262|pages=330–332|issn=0036-8075|doi=10.1126/science.968485|bibcode=1976Sci...194..330P}}</ref>

== See also ==

* [[Leu-enkephalin]]

== References ==

{{Reflist|30em}}

{{Opioid receptor modulators}}

{{DEFAULTSORT:Met-enkephalin}}

[[Category:Opioid peptides]]

[[Category:Delta-opioid receptor agonists]]

[[Category:Pentapeptides]]