Alternative titles; symbols
HGNC Approved Gene Symbol: PENK
Cytogenetic location: 8q12.1 Genomic coordinates (GRCh38): 8:56,440,957-56,446,641 (from NCBI)
Met-enkephalin (tyr-gly-gly-phe-met) and leu-enkephalin (tyr-gly-gly-phe-leu) are pentapeptides that compete with and mimic the effects of opiate drugs. Although interest in enkephalins stems largely from their possible role in the brain, the richest source of these peptides is the adrenal gland. Pheochromocytomas have been used to prepare cDNA clones of the preproenkephalin gene (Legon et al., 1982). Comb et al. (1982) determined the complete nucleotide sequence of a cDNA copy of enkephalin precursor mRNA from human pheochromocytoma. The corresponding amino acid sequence shows that the precursor is 267 amino acids long and contains 6 interspersed Met-enkephalin sequences and 1 Leu-enkephalin sequence. The precursor does not contain the sequences of dynorphin, alpha-neo-endorphin or beta-endorphin. (Because of structural similarities it had been postulated that beta-endorphin is precursor of Met-enkephalin, and that dynorphin or alpha-neo-endorphin is precursor of Leu-enkephalin.) See 131340.
Noda et al. (1982) cloned a human genomic DNA segment containing the entire gene. They found that the general organization of the preproenkephalin gene is strikingly similar to that of the gene encoding preproopiomelanocortin (176830), another multihormone precursor. complete mRNA and amino acid sequence of human preproenkephalin were deduced from the gene sequence. Preproenkephalin has 267 amino acids, as does proopiomelanocortin. Both genes contain 2 introns. In both, all the repeated enkephalin or melanotropin sequences are encoded by a single large exon (exon 3). Preproenkephalin mRNA encodes 4 copies of met-enkephalin, 2 copies of met-enkephalin extended sequences, and 1 copy of leu-enkephalin. Each copy is flanked by paired basic amino acids which are presumably recognized by the processing protease.
Litt et al. (1987, 1988) used probes derived from rat and human proenkephalin to study DNA from rodent-human somatic cell hybrids and map PENK to chromosome 8. In situ hybridization confirmed this assignment and indicated the regional localization of 8q23-q24.
Konig et al. (1996) adopted a genetic approach to study the role of the mammalian opioid system in many physiologic functions, including pain perception and analgesia, responses to stress, aggression, and dominance. Using homologous recombination in ES cells, they disrupted the preproenkephalin gene to generate enkephalin-deficient mice. Homozygous mutant mice were healthy, fertile, and cared for their offspring but displayed significant behavioral abnormalities. Abnormal behaviors in homozygous-deficient pups and adolescent mice included hiding under the bedding, frantic running or jumping, and prolonged freezing in response to moderate noise. They were more anxious, and males displayed increased offensive aggressiveness. Mutant animals showed marked differences from controls in supraspinal, but not in spinal, responses to painful stimuli. Unexpectedly, homozygous-deficient mice exhibited normal stress-induced analgesia. The results showed that enkephalins modulate responses to painful stimuli. Thus, Konig et al. (1996) concluded that genetic factors may contribute significantly to the experience of pain. Studies in humans showed that opiates do not change nociceptive thresholds, but rather reduce the subjective feeling of pain.
Ragnauth et al. (2001) studied ovariectomized female transgenic preproenkephalin-knockout mice and their wildtype and heterozygous controls. They presented transgenic data strongly suggesting that opioids, and particularly enkephalin gene products, are acting naturally to inhibit fear and anxiety.
Comb, M., Seeburg, P. H., Adelman, J., Eiden, L., Herbert, E. Primary structure of the human Met- and Leu-enkephalin precursor and its mRNA. Nature 295: 663-666, 1982. [PubMed: 7057924] [Full Text: https://doi.org/10.1038/295663a0]
Konig, M., Zimmer, A. M., Steiner, H., Holmes, P. V., Crawley, J. N., Brownstein, M. J., Zimmer, A. Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature 383: 535-538, 1996. [PubMed: 8849726] [Full Text: https://doi.org/10.1038/383535a0]
Legon, S., Glover, D. M., Hughes, J., Lowry, P. J., Rigby, P. W. J., Watson, C. J. The structure and expression of the preproenkephalin gene. Nucleic Acids Res. 10: 7905-7918, 1982. [PubMed: 6761648] [Full Text: https://doi.org/10.1093/nar/10.24.7905]
Litt, M., Buroker, N. E., Kondoleon, S., Douglass, J., Liston, D., Sheehy, R., Magenis, R. E. Chromosomal localization of the human proenkephalin and prodynorphin genes. Am. J. Hum. Genet. 42: 327-334, 1988. [PubMed: 2893547]
Litt, M., Buroker, N. E., Kondoleon, S. K., Liston, D., Douglass, J., Sheehy, R., Magenis, R. E. Chromosomal localization of the human proenkephalin and prodynorphin genes. (Abstract) Cytogenet. Cell Genet. 46: 651 only, 1987.
Noda, M., Teranishi, Y., Takahashi, H., Toyosato, M., Notake, M., Nakanishi, S., Numa, S. Isolation and structural organization of the human preproenkephalin gene. Nature 297: 431-434, 1982. [PubMed: 6281660] [Full Text: https://doi.org/10.1038/297431a0]
Ragnauth, A., Schuller, A., Morgan, M., Chan, J., Ogawa, S., Pintar, J., Bodnar, R. J., Pfaff, D. W. Female preproenkephalin-knockout mice display altered emotional responses. Proc. Nat. Acad. Sci. 98: 1958-1963, 2001. [PubMed: 11172058] [Full Text: https://doi.org/10.1073/pnas.98.4.1958]
Terao, M., Watanabe, Y., Mishina, M., Numa, S. Sequence requirement for transcription in vivo of the human preproenkephalin A gene. EMBO J. 2: 2223-2228, 1983. [PubMed: 6321155] [Full Text: https://doi.org/10.1002/j.1460-2075.1983.tb01727.x]