Structure–activity relationship of rubiscolins as δ opioid peptides

Yang, Shao Nian; Sonoda, Soushi; Chen, Liping; Yoshikawa, Masaaki

doi:10.1016/s0196-9781(03)00117-7

Cited by 25 publications

(21 citation statements)

References 21 publications

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“…The minimum effective dose for the orexigenic effect of rubiscolin‐6 (YPLDLF, 0.3 mg/kg p.o.) was approximately one‐third of rubiscolin‐5 (YPLDL, 1 mg/kg p.o., data not shown), which is a peptide truncated with the residue of rubiscolin‐6 at the C‐terminus, having lower affinity for the δ opioid receptor than rubiscolin‐6 . The orexigenic activity of rubiscolin‐6 after oral administration was inhibited by central administration of an antagonist for the δ opioid receptor, despite the fact that the antagonist did not affect food intake in the absence of rubiscolin‐6 (Fig.…”

Section: Discussionmentioning

confidence: 92%

Orally administered rubiscolin‐6, a δ opioid peptide derived from Rubisco, stimulates food intake via leptomeningeal lipocallin‐type prostaglandin D synthase in mice

Kikuchi

Lazarus

Miyamoto

et al. 2012

Molecular Nutrition Food Res

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Section: Discussionmentioning

confidence: 92%

Orally administered rubiscolin‐6, a δ opioid peptide derived from Rubisco, stimulates food intake via leptomeningeal lipocallin‐type prostaglandin D synthase in mice

Kikuchi

Lazarus

Miyamoto

et al. 2012

Molecular Nutrition Food Res

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“…Casomorphins (e.g., human -casomorphin-7, YPFVEPI), 2) hemorphin (YPWT) derived from hemoglobin, 7) and endomorphin-1 and 2 (YPWF-NH 2 and YPFF-NH 2 respectively) 5) containing the Tyr-Pro-aromatic amino acid sequence in these molecules, are also -selective opioid peptides, of animal origin. In contrast, opioid peptides of plant origin, such as gluten exorphin 4,8) and rubiscolin, 9,10) with the Tyr-Pro-non-aromatic amino acid sequence, are selective for the receptor. Soymorphins were the first -selective opioid peptides of plant origin to be identified.…”

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confidence: 99%

Soymorphins, Novel μ Opioid Peptides Derived from Soy β-Conglycinin β-Subunit, Have Anxiolytic Activities

Ohinata

Agui

Yoshikawa

2007

Bioscience, Biotechnology, and Biochemistry

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Based on the amino acid sequence YPFV found in the soy -conglycinin -subunit, which is common to an opioid peptide human -casomorphin-4, peptides YPF-VV, YPFVVN, and YPFVVNA were synthesized according to their primary structure. On guinea pig ileum (GPI) assay, they showed opioid activity (IC 50 = 6.0, 9.2 and 13 M respectively) more potent than humancasomorphins, and were named soymorphins-5, -6, and -7, respectively. Their opioid activities on mouse vas deferens (MVD) assay were less potent than on GPI assay, suggesting that they are selective for the opioid receptor. Human -casomorphin-4 and soymorphin-5 were released from the soy 7S fraction (-conglycinin) by the action of gastrointestinal proteases. Soymorphins-5, -6, and -7 had anxiolytic activities after oral administration at doses of 10-30 mg/kg in the elevated plus-maze test in mice.Key words: opioid peptide; opioid receptor; anxiolytic effect; soy protein; -conglycinin -subunitOpioid is a chemical substance that has morphine-like action. An opioid peptide, bovine -casomorphin-7 (YPFPGPI), isolated from casein peptone, was the first example of bioactive peptides released from food proteins.1) We have reported that human -casomorphin-4 (YPFV) and related peptides derived from human -casein also have opioid activities, though they are less potent than their bovine counterparts.2) Of three soyconglycinin subunits (, 0 , and ), 3) the -subunit has the human -casomorphin-4 sequence (YPFV). Longer peptides, YPFVV, YPFVVN, and YPFVVNA, were synthesized according to the primary structure of theconglycinin -subunit by the Fmoc strategy, and their opioid activities were tested by guinea pig ileum (GPI) and mouse vas deferens (MVD) assay, as previously described.4) All experiments were approved by the Kyoto University Ethics Committee for Animal Research Use.The peptides were found to have opioid activities on GPI assay. Figure 1 indicates the typical suppressive effect of YPFVV on electrically stimulated contractions on GPI assay. YPFVVN and YPFVVNA also dosedependently inhibited ileum contractions (data not shown). These results suggest that YPFVV, YPFVVN, and YPFVVNA have opioid activities; they were named soymorphins-5, -6, and -7 respectively. The opioid activities of synthetic peptides derived from the soyconglycinin -subunit are summarized in Table 1. The IC 50 values of soymorphins-5, -6, and -7 on GPI assay were 6.0, 9.2, and 13 mM respectively, and their opioid activities were more potent than those of humancasomorphin-4, -5, and -6 (IC 50 = 20, 14, and 25 mM, respectively). There are three types of opioid receptors: , , and . 5,6) The opioid activities of soymorphins were larger on GPI assay than those on MVD assay, suggesting that these peptides are selective for theopioid receptor. The affinities for the -opioid receptor were 17, 39, and 47 mM respectively, and the rank order of their affinities for the receptor was consistent with that of the opioid activities on GPI assay. Taking all this 1 µM 3 µM 10 µM 1 min Guinea Pig Ileum (GPI) Assay. Ileum-...

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“…It is possible that this proline residue in rubiscolins induces a certain conformation that the more flexible enkephalin and deltorphin II circumvent. With our finding that rubiscolin peptides are G-protein-selective -OR agonists, it may be of interest to dock rubiscolin-6, or YPLDLV a more potent and -OR-selective synthetic analog (Yang et al, 2003b) to potentially obtain insight into which regions of the -OR are being engaged or spared to confer G-protein selectivity onto rubiscolin when compared with deltorphin II or leu-enkephalin.…”

Section: Discussionmentioning

confidence: 99%

Rubsicolins are naturally occurring G-protein-biased delta opioid receptor peptides

Cassell

Zerfas

et al. 2018

Preprint

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187 Total word count: 2299 Figures: 2 Tables: 2 References: 26 2 AbstractThe impact that β-arrestin proteins have on G-protein-coupled receptor trafficking, signaling and physiological behavior has gained much appreciation over the past decade. A number of studies have attributed the side effects associated with the use of naturally occurring and synthetic opioids, such as respiratory depression and constipation, to excessive recruitment of β-arrestin. These findings have led to the development of biased opioid small molecule agonists that do not recruit β-arrestin, activating only the canonical G-protein pathway. Similar Gprotein biased small molecule opioids have been found to occur in nature, particularly within kratom, and opioids within salvia have served as a template for the synthesis of other G-proteinbiased opioids. Here, we present the first report of naturally occurring peptides that selectively activate G-protein signaling pathways with minimal β-arrestin recruitment. We find that rubiscolin peptides, which are produced as cleavage products of the plant protein rubisco, bind to and activate G-protein signaling at  opioid receptors. However, unlike the naturally occurring  opioid peptides leu-enkephalin and deltorphin II, the rubiscolin peptides only very weakly recruit β-arrestin 2 and have undectable recruitment of β-arrestin 1 at the  opioid receptor.

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Structure–activity relationship of rubiscolins as δ opioid peptides

Cited by 25 publications

References 21 publications

Orally administered rubiscolin‐6, a δ opioid peptide derived from Rubisco, stimulates food intake via leptomeningeal lipocallin‐type prostaglandin D synthase in mice

Orally administered rubiscolin‐6, a δ opioid peptide derived from Rubisco, stimulates food intake via leptomeningeal lipocallin‐type prostaglandin D synthase in mice

Soymorphins, Novel μ Opioid Peptides Derived from Soy β-Conglycinin β-Subunit, Have Anxiolytic Activities

Rubsicolins are naturally occurring G-protein-biased delta opioid receptor peptides

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