Met-enkephalin, also known as metenkefalin (INN), sometimes referred to as opioid growth factor ( OGF),
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.
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 functional group on
morphine.
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.
It is also present in the periphery, notably in some primary afferent fibers that
innervate the
pelvic viscera.
Biosynthesis
Met-enkephalin is synthesized from
proenkephalin via
Proteolysis bond cleavage in two
metabolism steps. Proenkephalin A is first reduced by either one of two
trypsin-like
endopeptidase , 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)).
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.
In addition, anabolism of proenkephalin A results in the production of one copy each of two
C-terminus-extended met-enkephalin derivatives, the
heptapeptide met-enkephalin-arg-phe (261–267), and the
octapeptide met-enkephalin-arg-gly-leu (186–193),
though whether they affect the opioid receptors in a similar manner as met-enkephalin is not entirely clear.
Clearance
Met- and leu-enkephalin are metabolized by a variety of different enzymes, including
aminopeptidase N (APN),
neutral endopeptidase (NEP),
dipeptidyl peptidase 3 (DPP3),
carboxypeptidase A6 (CPA6),
and angiotensin-converting enzyme (ACE).
These enzymes are sometimes referred to as
.
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).
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.
See also
