Production of an antihypertensive peptide from milk by the brown rot fungus Neolentinus lepideus
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ORIGINAL PAPER
Production of an antihypertensive peptide from milk by the brown rot fungus Neolentinus lepideus Kenji Okamoto1 · Sayo Kawamura1 · Mizuki Tagawa1 · Toshifumi Mizuta1 · Hasan M. Zahid2 · Toru Nabika2 Received: 10 April 2020 / Revised: 23 May 2020 / Accepted: 31 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Fermented milk has been shown to have beneficial effects on human health exerted through its bioactive peptides. The lactose-fermenting brown rot fungus Neolentinus lepideus has been shown to ferment milk; however, its ability to produce bioactive peptides has not been explored. This study, therefore, aimed to investigate the ability N. lepideus for the production of antihypertensive peptides in fermented milk and to characterize the peptides. Here we have used 9% skim milk as the substrate and fermented it with the mycelia of N. lepideus. The fermented milk exhibited higher angiotensin I-converting enzyme (ACE) inhibitory activity as compared to the commercially available sour milk containing Ile-Pro-Pro and Val-ProPro. As a result of isolation and purification by reverse-phase high-performance liquid chromatography, followed by peptide sequencing and MS analysis, the dipeptide Tyr-Pro (YP) was identified as an active peptide. The concentration of YP in the fermented milk reached up to 450 μg/ml, which was > twofold higher than the IC50 for ACE inhibition. Subsequently, the antihypertensive effect of YP was validated through intravenous injection of the peptide, which exhibited a significant lowering of blood pressure in a rat model of genetic hypertension. In addition, the transcriptomic analysis revealed the probable role of the carboxypeptidases for the increased yield of YP. These results together indicated that the fermentation with basidiomycete fungus could be a viable approach to produce bioactive peptides, and may, therefore, be applicable in the development of a cost-effective mass production system for functional peptides. Keywords Angiotensin I-converting enzyme · ACE inhibition · Peptide · Milk fermentation · Brown rot fungus · Antihypertensive effect Abbreviations ACE Angiotensin I-converting enzyme RP-HPLC Reverse-phase high-performance liquid chromatography HPLC High-performance liquid chromatography ESI–MS Electrospray ionization mass spectrometry YP Dipeptide Tyr-Pro RAAS Renin-angiotensin aldosterone system TFA Trifluoroacetic acid IPP Ile-Pro-Pro VPP Val-Pro-Pro
* Kenji Okamoto okamoto@tottori‑u.ac.jp 1
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4‑101 Koyama, Tottori 680‑8552, Japan
Department of Functional Pathology, Shimane University School of Medicine, Izumo 693‑8501, Japan
2
FPKM Fragments per kilobase of transcript per million mapped reads SHR Spontaneously hypertensive rat SHRSP Stroke-prone spontaneously hypertensive rat MAP Mean arterial pressure
Introduction Hypertension, also known as high blood pressure, is defined by systolic blood pressure ≥ 130 mmHg
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