Increased Tyrosine in the Brain and Serum of Mice by Orally Administering Dipeptide SY

Abstract

We examined the effect of orally administering L-Ser-L-Tyr (SY) dipeptide on the brain of a serine deficiency disease model mouse to attain the efficient delivery of L-Tyr and L-Ser into the mouse brain. Oral SY administration increased the L-Tyr level more efficiently than L-Tyr administration with the same intake dose, but did not significantly affect the L-Ser level when compared with L-Ser administration.Key words: brain; dipeptide; Phgdh; serine; tyrosine It is well established that dysregulation in neurotransmission systems have been thought to underlie psychiatric disorders including schizophrenia.1) L-Tyrosine (L-Tyr) and L-serine (L-Ser) play distinct roles in these neurotransmission systems. Catecholamines comprising dopamine, adrenaline, and noradrenaline are synthesized from L-Tyr, 2) while L-Ser serves as a precursor for the synthesis of D-Ser, an essential coagonist of the N-methyl-D-aspartate (NMDA)-selective glutamate receptors.3) Changes in the availability of L-Tyr and L-Ser in the brain are respectively likely to influence the catecholamine and D-Ser levels. 2)We have recently reported that brain-specific knockout mice (BKO) of D-3-phosphoglycerate dehydrogenase (Phgdh), which catalyzes the first step in the de novo biosynthesis of L-Ser, exhibited marked reductions in both the L-and D-Ser levels in the brain, this being accompanied by a diminished NMDA receptor function. 4) Our study highlighted the maintenance of an abundance of D-Ser by de novo synthesized L-Ser, whereby the NMDA receptor can be activated in the adult mouse brain. Since a reduction of the D-Ser level in the brain has been strongly implicated in the NMDA receptor hypofunction, which is thought to underlie the pathophysiology of schizophrenia, 5) the decreased abundance of L-Ser may contribute to increasing the vulnerability of aberrant glutamatergic transmission and schizophrenia-related phenotypes. A recent study has reported that a family with schizophrenia had a chromosomal translocation, which reduced the expression of PSAT1 encoding phosphoserine aminotransferase 1, the second enzyme involved in de novo L-Ser synthesis.6) Despite exhibiting such differing nervous symptoms as microcephaly, psychomotor retardation, and intractable seizures, patients with a genetic L-Ser deficiency have markedly decreased levels of L-and D-Ser in the cerebrospinal fluid and blood due to a mutation of PHGDH, PSAT1 or PSPH.7) Although oral supplementation of L-and/or D-Ser is a potent therapeutic treatment for these patients, it is known that L-and D-Ser diffuse poorly through the blood-brain barrier.8) There is therefore concern that a high-dose intake of these amino acids may cause an unfavorable side effect such as renal toxicity. 9)Dietary proteins are digested into amino acids or diand tripeptides in the intestines during gastrointestinal transit. The free amino acids are then absorbed by amino acid transporters in the brush border membrane of small intestinal cells, while both di-and tripeptides are absorbed in the peptide form by pe...

Soy peptide ingestion augments the synthesis and metabolism of noradrenaline in the mouse brain

“…Furthermore, we recently demonstrated that oral ingestion of the dipeptide Ser-Tyr (SY) increases the Tyr content in several brain regions of adult mice more efficiently than administration of Tyr alone at the same intake dose. 8) SY is the most prevalent Tyr-containing dipeptide moiety in several soy proteins. 9) Indeed, SY and other Tyr-containing dipeptides can be detected in their free dipeptide form in the soy peptides used in our in vivo study.…”

Orally administrated dipeptide Ser-Tyr efficiently stimulates noradrenergic turnover in the mouse brain

“…Our recent study also demonstrated that oral administration of a dipeptide Ser-Tyr (SY) efficiently increases the free Y content relative to the sole administration of Y alone at the same intake dose in several brain regions of adult mice. 7) This suggests that Y derived from soy proteins/peptides may affect catecholamine metabolism in the brain, since Y can be transported efficiently at the blood-brain barrier and serves as a precursor of catecholamines.…”

Quantitative mass spectrometric analysis of dipeptides in protein hydrolysate by a TNBS derivatization-aided standard addition method

“…Commercially available soybean hydrolysate (Hinute AM) was used in this study, as it is known to contain a number of bioactive dipeptides. These peptides exhibit properties such as in vitro angiotensin I-converting enzyme inhibitory activity (IC 50 : GY, 220 lmol L À1 ; IY, 3.7 lmol L À1 ) (Matsui & Matsumoto, 2006) and improved brain dysregulation effects (SY) (Esaki et al, 2013). Potential interfering effects from the simultaneous detection and quantification of the three targets (GY, IY, and SY) (e.g., overlapped elution and/or suppressed ionization of targets on LC-MS) were considered, and dipeptides with reversed sequences, i.e., YG, YS, and YI, together with LY and YL (having the same molecular weight as target IY), were selected for the study.…”