Abstract

Two food-derived opioid peptides with high δ-opioid receptor affinity and selectivity, rubiscolin-5 and rubiscolin-6, were isolated from spinach leaves in 2001. Ribulose 1,5-bisphosphate carboxylase/oxygenase [EC 4.1.1.39 (RuBisCO)], digested by pepsin, is known as a precursor for them. The most important advantage of rubiscolins is their oral bioavailability. Both peptides produced analgesia not only after intracerebroventricular administration, but also orally. Moreover, rubiscolin-6 enhanced memory consolidation, influenced the processes of learning and memory, and reduced anxiety. In an animal model of acute stress, rubiscolin-6 induced an antidepressive-like effect. Moreover, this peptide regulated food intake, stimulated appetite in mice fed a balanced diet and suppressed food intake in case of high-fat diet. This review summarizes various biological activities of rubiscolins and recent developments on the structure-activity relationship of rubiscolin analogs, aimed at improving their pharmacological properties. Naturally occurring opioids, such as rubiscolins, can serve as the basis of new therapeutics or functional foods.

References

• 1. Bartoszewski R., Łaczmańska I., Króliczewski J., SzczepaniakA.: The characteristic of ribulose-1,5-biphosphate carboxylase/oxygenase(rubisco). Directions of studies. Postepy Biochem., 2003;49: 116–124
  Google Scholar
• 2. Caballero J., Saavedra M., Fernández M., González-Nilo F.D.: Quantitativestructure-activity relationship of rubiscolin analogues as δopioid peptides using comparative molecular field analysis (CoMFA)and comparative molecular similarity indices analysis (CoMSIA). J.Agric. Food Chem., 2007; 55: 8101–8104
  Google Scholar
• 3. Cassell R.J., Mores K.L., Zerfas B.L., Mahmoud A.H., Lill M.A.,Trader D.J., van Rijn R.M.: Rubiscolins are naturally occurring Gprotein-biased delta opioid receptor peptides. Eur. Neuropsychopharmacol.,2019; 29: 450–456
  Google Scholar
• 4. Chajra H., Amstutz B., Schweikert K., Auriol D., Redziniak G.,Lefèvre F.: Opioid receptor delta as a global modulator of skin differentiationand barrier function repair. Int. J. Cosmet. Sci., 2015;37: 386–394
  Google Scholar
• 5. Hirata H., Sonoda S., Agui S., Yoshida M., Ohinata K., YoshikawaM.: Rubiscolin-6, a δ opioid peptide derived from spinach Rubisco,has anxiolytic effect via activating σ1 and dopamine D1 receptors.Peptides, 2007; 28: 1998–2003
  Google Scholar
• 6. Janecka A., Fichna J., Janecki T.: Opioid receptors and their ligands.Curr. Top. Med. Chem., 2004; 4: 1–17
  Google Scholar
• 7. Janecka A., Perlikowska R., Gach K., Wyrebska A., Fichna J.: Developmentof opioid peptide analogs for pain relief. Curr. Pharm.Des., 2010; 16: 1126–1135
  Google Scholar
• 8. Janecka A., Staniszewska R., Fichna J.: Endomorphin analogs.Curr. Med. Chem., 2007; 14: 3201–3208
  Google Scholar
• 9. Kairupan T.S., Cheng K.C., Asakawa A., Amitani H., Yagi T., AtakaK., Rokot N.T., Kapantow N.H., Kato I., Inui A.: Rubiscolin-6 activatesopioid receptors to enhance glucose uptake in skeletal muscle. J.Food Drug Anal., 2019; 27: 266–274
  Google Scholar
• 10. Kaneko K., Lazarus M., Miyamoto C., Oishi Y., Nagata N., YangS., Yoshikawa M., Aritake K., Furuyashiki T., Narumiya S., UradeY., Ohinata K.: Orally administered rubiscolin-6, a δ opioid peptidederived from Rubisco, stimulates food intake via leptomeningeallipocallin-type prostaglandin D synthase in mice. Mol. Nutr. FoodRes., 2012; 56: 1315–1323
  Google Scholar
• 11. Kaneko K., Mizushige T., Miyazaki Y., Lazarus M., Urade Y., YoshikawaM., Kanamoto R., Ohinata K.: δ-Opioid receptor activationstimulates normal diet intake but conversely suppresses high-fatdiet intake in mice. Am. J. Physiol. Regul. Integr. Comp.Physiol.,2014; 306: R265–R272
  Google Scholar
• 12. Kaneko K., Yoshikawa M., Ohinata K.: Novel orexigenic pathwayprostaglandin D2-NPY system – involvement in orally active orexigenicδ opioid peptide. Neuropeptides, 2012; 46: 353–357
  Google Scholar
• 13. Kastin A.J.: Handbook of Biologically Active Peptides. 2nd ed.Academic Press, 2013
  Google Scholar
• 14. Mitsumoto Y., Sato R., Tagawa N., Kato I.: Rubiscolin-6, a δ-opioidpeptide from spinach RuBisCO, exerts antidepressant-like effect inrestraint-stressed mice. J. Nutr. Sci. Vitaminol., 2019; 65: 202–204
  Google Scholar
• 15. Miyazaki Y., Kaneko K., Iguchi S., Mizushige T., KanamotoR., Yoshikawa M., Shimizu T., Ohinata K.: Orally administeredδ opioid agonist peptide rubiscolin-6 stimulates food intake inaged mice with ghrelin resistance. Mol. Nutr. Food Res., 2014;58: 2046–2052
  Google Scholar
• 16. Nasehi M., Kafi F., Zarrindast M.R.: Differential mechanisms ofopioidergic and dopaminergic systems of the ventral hippocampus(CA3) in anxiolytic-like behaviors induced by cholestasis in mice.Eur. J. Pharmacol., 2013; 714: 352–358
  Google Scholar
• 17. Ohinata K., Takagi K., Biyajima K., Fujiwara Y., Fukumoto S.,Eguchi N., Urade Y., Asakawa A., Fujimiya M., Inui A., Yoshikawa M.:Central prostaglandin D2 stimulates food intake via the neuropeptideY system in mice. FEBS Lett., 2008; 582: 679–684
  Google Scholar
• 18. Perlikowska R., Janecka A.: Rubiscolins – highly potent peptidesderived from plant proteins. Mini Rev. Med. Chem., 2018;18: 104–112
  Google Scholar
• 19. Raehal K.M., Walker J.K., Bohn L.M.: Morphine side effects inβ-arrestin 2 knockout mice. J. Pharmacol. Exp. Ther., 2005; 314:1195–1201
  Google Scholar
• 20. Yang S., Kawamura Y., Yoshikawa M.: Effect of rubiscolin, a δopioid peptide derived from Rubisco, on memory consolidation.Peptides, 2003; 24: 325–328
  Google Scholar
• 21. Yang S., Yunden J., Sonoda S., Doyama N., Lipkowski A.W.,Kawamura Y., Yoshikawa M.: Rubiscolin, a δ-selective opioid peptidederived from plant Rubisco. FEBS Lett., 2001; 509: 213–217
  Google Scholar
• 22. Yoshikawa M.: Bioactive peptides derived from natural proteinswith respect to diversity of their receptors and physiological effects.Peptides, 2015; 72: 208–225
  Google Scholar

Full text