Proenkephalin peptides

Proenkephalin peptides Leu-Enkephalin (3) Met-Ehkephalin (4) Met-enkephalin-Arg6-Phe ... 

Fig. 1. Schematic drawing of precursors for selected brain oligopeptides. Shaded areas represent the location of sequences of active peptide products which are normally cleaved by trypsin-like enzymes acting on double-basic amino acid residues. Precursors are not necessarily drawn to scale, (a) CRF precursor (b) proopiomelanocortin (POMC) (c) P-protachykinin (d) proenkephalin A (e) CGRP precursor (f) preprodynorphin, ie, preproenkephalin B. Terms are...

Delta receptors are relatively selective for two related penta-peptides, methionine enkephalin and leucine enkephalin (met- and leu-enkephalin), which were isolated from porcine brain (Hughes 1975). Both met- and leu-enkephalin inhibit electrically induced contractions of guinea pig ileum, an effect that mimics those effects seen with opioid drugs, and is naloxone reversible. The enkephalins are processed posttranslational ly from proenkephalin, and secreted from central and peripheral neurons and endocrine cells in the adrenal medulla. 

Endogenous opioids are peptides that are cleaved from the precursors proenkephalin, pro-opiomelanocortin, and prodynorphin. All contain the amino acid sequence of the pentapeptides [Met]- or [Leuj-enkephalin (A). The effects of the opioids can be abolished by antagonists (e.g., naloxone A), with the exception of buprenorphine. 

Both Met-enkephalin and Leu-enkephalin have their own pro- and prepro forms.29 Bovine preproenkephalin A is a 268-residue protein containing a 20-residue signal sequence and four sequences of Met-enkephalin and one of Leu-enkephalin, each flanked by pairs of basic residues. There are also Met-enkephalin-Arg-Gly-Leu (YGGFMRGL) and Met-enkephalin-Arg-Phe sequences. Not all of these are cut out cleanly, and other peptides such as Met-enkephalin-Arg-Arg-Val-NH2 are also found in brain. Proenkephalin B contains three copies of Leu-enkephalin contained within longer peptides. One of these, P-dynorphin (Table 30-4), is also a potent opioid compound. The enkephalins are thought to act as neurotransmitters, which are rapidly degraded after their release by two or three membrane-bound... 

Opiates act on a variety of receptors. The three most important subtypes are the mu, delta, and kappa opiate receptors (Fig. 13—25). The brain makes its own endogenous opiate-like substances, sometimes referred to as the brain s own morphine. They are peptides derived from precursor proteins called pro-opiomelanocortin (POMC), proenkephalin, and prodynorphin. Parts of these precursor proteins are cleaved off to form endorphins or enkephalins, stored in opiate neurons, and presumably released during neurotransmission to mediate endogenous opiate-like actions (Fig. 13-25). However, the precise number and function of endogenous opiates and their receptors and their role in pain relief and other central nervous system (CNS) actions remain largely unknown. 

Note Three distinct families of peptides have been identified the enkephalins, the endorphins, and the dynorphins. Each family is derived from a distinct precursor polypeptide and has a characteristic anatomical distribution. These precursors are now designated as proenkephalin (also proenkephalin A), proopiomelanocortin (POMP), and prodynorphin (also proenkephalin). 

The endogenous opioid peptides have a range of affinities for the different types of opioid receptor. Some met-enkephalin derivatives, for example, show affinity for mu and delta receptors, whereas other peptides, derived from proenkephalin, show a preference for the delta sites. All peptides from prodynorphin act predominantly on kappa sites, while beta-endorphin behaves like the enkephalins and shows selectivity for the mu and delta sites. 

Seizinger, B. R., Grimm, C., Hollt, V., and Herz, A. (1984). Evidence for a selective processing of proenkephalin B into different opioid peptide forms in particular regions of rat brain and pituitary. 

The relatively large number of opioid peptides isolated in recent years is a reflection of the complexity of the endogenous opioid system. The major opioid peptides are cleavage products of three distinct proteins, which are the primary products of three genes. These precursor proteins are proenkephalin... 

Davis TP, Porreca F, Burks TF, Dray A (1985) The proenkephalin A fragment, peptide E central processing and CNS activity in vivo. Eur J Pharmacol 777 177-183. 

Merchenthaler I, Maderdrut JL, Altschuler RA, Petrusz P (1986b) Immunocytochemical localization of proenkephalin-derived peptides in the central nervous system of the rat. Neuroscience 17 325-348. 

Figure 2 Proneuropeptides structural features for proteolytic processing. Neuropeptides are synthesized as proneuropeptide precursors, also known as prohormones, that require proteolytic processing to liberate the active neuropeptide. Proteolytic processing occurs at dibasic and monobasic sites, as well as at multibasic sites. The precursor proteins may contain one copy of the active neuropeptide, such as the proneuropeptides for NPY, galanin, CRF, and vasopressin. Some proneuropeptides such as proenkephalin contain multiple copies of the active neuropeptide proenkephalin contains four copies of (Met)enkephalin (ME), one copy of (Leu)enkephalin (LE), and the related opioid peptides ME-Arg-Phe (H) and ME-Arg-Cly-Leu (O).

Two of the most abundant endogenous opioid peptides, methionine-enkephalin (Met-enk Tyr-Gly-Gly-Phe-Met) and leucine-enkephalin (Leu-enk Tyr-Gly-Gly-Phe-Leu) are derived from the precursor protein, proenkephalin (PENK). PENK is a 267 amino acid precursor that contains 6 copies of Met-enk, two of which are extended forms (Tyr-Gly-Gly-Phe-Met-Arg-Phe and Tyr-Gly-Gly-Phe-Met-Arg-Gly-Leu) and one copy of Leu-enk. This ratio is essentially the same as the ratio of these peptides found in brain and adrenal chromaffin cells. The fact that there are two distinct peptides closely related in stmcture and function proved to be a major obstacle that slowed their discovery (Kosterlitz and Hughes, 1977). 

Gubler U, Seeburg P, Hoffman BJ, Gage LP, Udenfiiend S (1982) Molecular cloning establishes proenkephalin as precursor of enkephalin-containing peptides. Nature 295 206—208. 

Hiddinga HJ, Isaak DD, Lewis RV (1994a) Enkephalin-containing peptides processed fiom proenkephalin significantly enhance the... 

ENDORPHINS. Each of these families derives from different precursors, proenkephalin, prodynoiphin, and PROOPIOMELANOCORTIN, respectively. There are also at least three classes of OPIOID RECEPTORS, but the peptide families do not map to the receptors in a simple w ay. 

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