Enkephalins Met-Enkephalin

Leu-enkephalin, Met-enkephalin [59141-40-11 polypeptide multiple tissues endogenous opiates... 

In the anterior pituitary gland (see Hormones, anteriorpituitaryhormones), both adrenocorticotropic hormones (ACTH) and the endogenous opiate hormone, P-endorphin, are synthesized from a common prohormone (2) (see Opioids,endogenous). In the adrenal medulla, five to seven copies of another opiate hormone, methionine—enkephalin (Met-enkephalin), and one copy of leucine—enkephalin (Leu-enkephalin) are synthesized from each precursor molecule (3). 

Three families of endogenous opioid peptides have been described in detail the endorphins, the pentapeptide enkephalins methionine-enkephalin (met-enkephalin) and leucine-enkephalin (leu-enkephalin), and the dynorphins. The three families of opioid receptors have overlapping affinities for these endogenous peptides (Table 31-1). 

Tang F, Man WSY (1991) The regional distribution of thyrotropin releasing hormone, leu-enkephalin, met-enkephalin, substance P, somatostatin and cholecystokinin in the rat brain and pituitary. Neuropeptides 79 287-292. 

Aminopeptidase B (EC 3.4.11.6 aminopeptidase Ml) is thought to be a chloride-activated-thiolproteinase. Substrates of interest include leu-enkephalin, met-enkephalin and bradykinin. Inhibitors include arphamenine A and arphamenine B. 

The endogenous opiates include -endorphin, the enkephalins (met-enkephalin and leu-enkephalin), the dynorphins, and the neoendorphins. All are peptides, varying in size from 5 to 31 amino acid residues. All have in common an amino terminus consisting of either of two pentapeptide sequences Try-Gly-Gly-Phe-Met (the met-enkephalin sequence) or Tyr-Gly-Gly-Phe-Leu (the leu-enkephalin sequence). The fundamental endogenous opioid peptides are the pentapeptides, met-enkephalin and leu-enkephalin which function as neurotransmitters in the CNS. 

Leu-enkephalin Met-enkephalin Analgesia Regulation of analgesia and behavior antidepressant endocrine function... 

Several peptides are related in different ways to these classical opioid peptides. FMREamide (Phe-Met-Arg-Phe-NH2) contains the first four amino acids of enkephalin and is active in various invertebrates (58) FMREamide-related peptides also have been located in the mammalian brain. Although these... 

Biosynthesis. Three separate genes encode the opioid peptides (see Fig. 1). Enkephalin is derived from preproenkephalin A, which contains six copies of Met-enkephalin and extended peptides, and one copy of Leu-enkephalin (62—66). ( -Endorphin is one of the many products of POMC, and represents the N-terminal 31 amino acids of P-Hpotropin (67,68). Three different dynorphin peptides are derived from the third opioid gene, preproenkephalin B, or preprodynorphin (69). The dynorphin peptides include dynorphin A, dynorphin B, and a-neo-endorphin. 

Evidence soon emerged that the endogenous opioids were peptides rather than simple morphine-like molecules (9). The first direct evidence for endogenous opioids in brain extracts was provided in 1975 when two pentapeptides were purified that differed only in the carboxyl terminal amino acids (10) (Table 1). These peptides were called methionine- (Met-) and leucine- (Leu-) enkephalin, from the Greek term meaning "in the head."... 

At the time of the discovery of Met-enkephalin, its sequence was observed to be identical to that of residues 61—65 contained in the C-fragment of the pituitary hormone p-Hpotropin [12584-99-5] (p-LPH) (see Hormones), first isolated in 1964 (11). In 1976, the isolation of a larger peptide fragment, P-endorphin [60617-12-1] that also displayed opiate-like activity was reported (12). This peptide s 31-amino-acid sequence comprised residues 61—91 of P-LPH. Subsequentiy, another potent opioid peptide, dynorphin [72957-38-17, was isolated from pituitary (13). The first five amino acids (qv) of this 17-amino-acid peptide are identical to the Leu-enkephalin sequence (see Table 1). 

Group II consists of the enkephalins which come from the 267-aniino acid piecuisoi pro-enkephalin A [88402-54-4] (Fig. 2). This proteia contains four copies of Met-enkephalin, one copy of Leu-enkephalin, and the extended peptides Met-enkephalin-Arg -Phe (the last Met-enkephalin sequence ia Fig. 2) and Met-enkephalin-Arg -Gly -Leu (the fourth Met-enkephalin sequence ia Fig. 2) (25,26). AH of these products ate formed by trypsin-like cleavage between pairs of basic residues. The extended enkephalin peptides are further cleaved by carboxypeptidase E (27) to form authentic Met-enkephalin. 

The opioid peptides vary in their binding affinities for the multiple opioid receptor types. Leu- and Met-enkephalin have a higher affinity for 5-receptors than for the other opioid receptor types (68), whereas the dynorphin peptides have a higher affinity for K-sites (69). P-Endorphin binds with equal affinity to both p- and 5-receptors, but binds with lower affinity to K-sites (70). The existence of a P-endorphin-selective receptor, the S-receptor, has been postulated whether this site is actually a separate P-endorphin-selective receptor or is a subtype of a classical opioid receptor is a matter of controversy (71,72). The existence of opioid receptor subtypes in general is quite controversial although there is some evidence for subtypes of p- (73), 5-(74), and K-receptors (72,75), confirmation of which may be obtained by future molecular cloning studies. 

Several enzymes, none of which are completely specific for the enkephalins, are known to cleave Leu- and Met-enkephalin at various peptide bonds. The main enzymes that degrade enkephalin are 2inc metaHopeptidases. The first enkephalin-degrading enzyme to be identified, an aminopeptidase which cleaves the amino terminal Tyr-Gly bond (179), has been shown to be aminopeptidase-N (APN) (180). It is a cytoplasmic enzyme which is uniformly distributed throughout the brain. The increased analgesic activity of synthetic enkephalins substituted by D-amino acids at position 2, eg,... 

Prototypic ligands Morphine Met/leu-enkephalin Ethylketocyclacozine Nociceptin/OFQ... 

Figure 4. Enzymatic hydrolysis of met-enkephalin (2.5 nmol) showing the sequential release of amino acids and the final mixture. The amino acids were identified from the retention times of the standard amino acid mixture 9, Gly 12, Tyr 14, Met 17, Phe. (Reprinted from reference 5. Copyright 1987 American Chemical Society.)...

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