Peptides Derived from Proenkephalin

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. 

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. 

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). 

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). 

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. 

BAM-18P (bovine adrenal medulla octadecapeptide) is a 18 amino acid residue peptide isolated from the bovine adrenal medulla, a derivative of proenkephalin A. It is a (p) opioid receptor agonist. 

The classical mammalian opioid peptides are derived from three distinct precursor proteins (Fig. 7.10) (see Refs. 75,266 for reviews). Processing of the precursor proteins occurs at pairs of basic residues. jS-Endorphin is derived from proopiomelanocortin (POMC), along with ACTH, a-MSH, and j3-lipotropin (see Ref 267 for a review). The enkephalins are derived from proenkephalin A (see Ref 268 for a review). This protein contains four copies of Met-enkephalin flanked by pairs of basic resi-... 

At least 15 endogenous peptides have now been discovered, varying in length from 5 to 33 amino acids (the enkephalins and the endorphins). These compounds are thought to be neurotransmitters or neurohormones in the brain and operate as the body s natural painkillers as well as having a number of other roles. They are derived from three inactive precursor proteins—proenkephalin, prodynorphin, or proopiomelanocortin (Fig. 12.38). 

Opium, derived from poppies, relieves pain and induces euphoria by binding to "opiate receptors" in the brain. These opioid drugs mimic the actions of three peptide families in the brain known as the endorphins, the enkephalins, and the dynorphins. These peptides, along with several nonopioid peptides (MSH, ACTH, lipotropin) are cleaved from the protein precursors pro-opiomelanocortin (POMC), proenkephalin, and prodynorphin (Fig. 3.5). 

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