Met-enkephalin

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Met-enkephalin
Stereo, Kekulé, skeletal formula of Met-enkphalin
Identifiers
CAS number 58569-55-4 YesY
PubChem 6427062
ChemSpider 391597 YesY
EC number 261-335-8
KEGG C11684 N
MeSH Enkephalin,+Methionine
ChEMBL CHEMBL13786 YesY
Jmol-3D images Image 1
Image 2
Properties
Molecular formula C27H35N5O7S
Molar mass 573.66 g mol−1
log P 0.607
Acidity (pKa) 3.234
Basicity (pKb) 10.763
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Met-enkephalin, 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]

History[edit]

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

Chemistry[edit]

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]

Pharmacology[edit]

Distribution[edit]

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[edit]

Met-enkephalin is synthesized from proenkephalin via proteolyic 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[edit]

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.

Pharmacodynamics[edit]

Met-enkephalin is a potent agonist of the δ-opioid receptor, and to a lesser extent the of 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[edit]

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.

See also[edit]

References[edit]

  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. ^ a b c Christoph Stein (1999). = 4Rfr8cQayvgC&pg = PA22 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. ^ a b Thomas Carleton Moore (1993). = dJyJGevjkzQC&pg = PA179 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. ^ a b c Fleur L. Strand (1999). = PNPU0sknfCUC&pg = PA348 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 : Official Publication of the Federation of American Societies for Experimental Biology 1 (1): 16–21. PMID 3111927. 
  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. 
  8. ^ a b c 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. 
  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. 
  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.