Processing of Opioid Peptide Precursors

All these opioid peptides are generated by processing longer precursor proteins, which have been subsequently cloned. There are three distinct genes responsible for generating these peptides (Fig. 2).

1. Pre-Proenkephalin

The pre-proenkephalin gene contains four copies of Met-enkephalin and one copy each of Leu-enkephalin, the heptapeptide Met-enkephalin-Arg-Phe, and the octapeptide Met-Enkephalin-Arg-Gly-Leu (Fig. 2A). No dynorphin sequences are present within this precursor. However, the sequence of the gene predicts many additional putative peptides that also contain the sequence of met-enkephalin as the N terminus and thus might have opioid activity and be physiologically important. For example, peptide F contains [Met5]en-kephalin sequences at both its N terminus and its C terminus. The carboxy-terminally amidated peptide

Preproenkephalin Sequence Amino Acids
Figure 2 Structures of the precursors of the opioid peptides. Schematics of the precursor proteins for (A) the enkephalins, (B) the dynorphins, (C) b-endorphin, and (D) orphanin FQ/nociceptin.

comprising the first 26 amino acids of peptide F is named amidorphin. Peptide E has a [Met5]enkephalin sequence at its N terminus and that of [Leu5]enkepha-lin at its C terminus. Several peptides in which peptide

E has been truncated at the C terminus have also been isolated: BAM 22, BAM 20, BAM 18, BAM 12, as well as an amidated octapeptide corresponding to the first 8 amino acids of peptide E termed metorphamide or adrenorphin. The physiological significance of these additional peptides remains unclear. They may represent distinct neuropeptides with their own actions. However, the presence of dibasic amino acids following the enkephalin sequence in most of them raises the possibility that they might simply be further processed to the enkephalins. Although they were described many years ago, little work has been reported on these compounds for many years.

2. Pre-Prodynorphin

The pre-prodynorphin gene encodes a larger precursor that has many additional putative opioid peptides (Fig. 2B). The dynorphin precursor is quite distinct from the enkephalin precursor. It contains three [Leu5]enkephalin sequences, each flanked by pairs of basic amino acids. If Lys-Arg pairs were the only processing signals, pre-prodynorphin would be cleaved into three larger opioid peptides: b-neoendor-phin, dynorphin A, and leumorphine. However, several other peptides derived from pre-prodynorphin have been identified. Thus, the formation of dynorphin B results from the cleavage of leumorphin, whereas dynorphin A (1-8) is generated from dynorphin A. In addition, several larger peptides have been identified as putative processing products: a peptide containing dynorphin A at the N terminus and dynorphin B at the C-terminal end have been isolated. Dynorphin 24 contains dynorphin A with a C-terminal extension of Lys-Arg and the sequence of Leu-Enk. There is also evidence for a peptide comprising dynorphin A and leumorphin. In addition to dynorphin A (1-17), the truncated dynorphin A (1-8), and dynorphin B, this precursor also generates a-neoendorphin and b-neoen-dorphin. Again, the significance of these different peptides remains uncertain. Pharmacologically, they have opiate-like actions, but their physiologically relevance has not been proven.

3. Pre-Opiomelanocortin b-Endorphin has the most interesting precursor peptide, pre-opiomelanocortin (Fig. 2C). Unlike the other opioid precursor peptides, the b-endorphin precursor makes many important, biologically active peptides that are not related to the opioid family. The precursor for b-endorphin also generates ACTH, an important stress hormone, a-melanocyte-stimulating hormone (MSH), and b-MSH. The association of b-endorphin with stress hormones is intriguing in view of the many associations between stress and a diminished percep tion of pain. In the pituitary, stimuli that release ACTH also release b-endorphin.

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