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]
Met-enkephalin is synthesized from proenkephalin via proteolyticcleavage[4] in two metabolic steps. Proenkephalin A is first reduced by either one of two trypsin-like endopeptidaseenzymes, 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]
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]
^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. PMID20040394.
^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. PMID19716174. S2CID19181608.
^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. PMID20487892. S2CID23138078.