Study on the Inhibitory Effect of Bioactive Peptides Derived from Yak Milk Cheese on Cholesterol Esterase

Overview

Journal Foods

Specialty Biotechnology

Date 2024 Sep 28

PMID 39335898

Authors

Peng Wang

Xuemei Song

Qi Liang

Affiliations

Soon will be listed here.

Abstract

The bioactive peptides derived from yak milk cheese exhibited cholesterol-lowering properties. However, there was limited research on their inhibitory effects on cholesterol esterase (CE) and elucidation of their potential inhibitory mechanisms. In this study, we identified CE-inhibiting peptides through virtual screening and in vitro assays. Additionally, molecular docking and molecular dynamics studies were conducted to explore the mechanisms. The results indicated that peptides RK7 (RPKHPIK), KQ7 (KVLPVPQ), QP13 (QEPVLGPVRGPFP), TL9 (TPVVVPPFL), VN10 (VYPFPGPIPN), LQ10 (LPPTVMFPPQ), and SN12 (SLVYPFPGPIPN) possessed molecular weights of less than 1.5 kDa and a high proportion of hydrophobic amino acids, demonstrating notable inhibitory effects on CE. Molecular docking and dynamics revealed that peptides RK7, KQ7, QP13, and VN10 bound to key amino acid residues Arg423, His435, and Ser422 of CE through hydrogen bonds, hydrophobic interactions, salt bridges, and π-π stacking, occupying the substrate-binding site and exerting inhibitory effects on CE. The four peptides were further synthesized to verify their CE-inhibitory effects in vitro. RK7, KQ7, QP13, and VN10 exhibited inhibitory activity on CE with IC values of 8.16 × 10 mol/L, 8.10 × 10 mol/L, 4.63 × 10 mol/L, and 7.97 × 10 mol/L; RK7, KQ7, QP13, and VN10 were effective in inhibiting CE after simulated gastrointestinal digestion, especially with a significant increase in the inhibitory activity of KQ7 and RK7, respectively. Our findings suggested that bioactive peptides from yak milk cheese represented a novel class of potential CE inhibitors.

Citing Articles

Assessment of hypolipidemic potential of cholesteryl esterase inhibitory peptides in different probiotic fermented milk through in vitro, , and molecular docking studies.

Ajayi F, AlShebli F, Yap P, Gan C, Maqsood S, Mudgil P Food Chem X. 2024; 24:101998.

PMID: 39634518 PMC: 11616526. DOI: 10.1016/j.fochx.2024.101998.

References

Lopez-Martinez C, Flores-Morales P, Cruz M, Gonzalez T, Feliz M, Diez A . Proline cis-trans isomerization and its implications for the dimerization of analogues of cyclopeptide stylostatin 1: a combined computational and experimental study. Phys Chem Chem Phys. 2016; 18(18):12755-67. DOI: 10.1039/c5cp05937b. View

Pagadala N, Syed K, Tuszynski J . Software for molecular docking: a review. Biophys Rev. 2017; 9(2):91-102. PMC: 5425816. DOI: 10.1007/s12551-016-0247-1. View

Khiari Z, Ndagijimana M, Betti M . Low molecular weight bioactive peptides derived from the enzymatic hydrolysis of collagen after isoelectric solubilization/precipitation process of turkey by-products. Poult Sci. 2014; 93(9):2347-62. DOI: 10.3382/ps.2014-03953. View

Mascoli V, Liguori N, Cupellini L, Elias E, Mennucci B, Croce R . Uncovering the interactions driving carotenoid binding in light-harvesting complexes. Chem Sci. 2021; 12(14):5113-5122. PMC: 8179543. DOI: 10.1039/d1sc00071c. View

Hui D, Brockman H, Schroeder F . Cholesterol esterase: a cholesterol transfer protein. Biochemistry. 1995; 34(12):3942-7. DOI: 10.1021/bi00012a011. View

Ghosh D, Wawrzak Z, Pletnev V, Li N, Kaiser R, Pangborn W . Structure of uncomplexed and linoleate-bound Candida cylindracea cholesterol esterase. Structure. 1995; 3(3):279-88. DOI: 10.1016/s0969-2126(01)00158-7. View

Gurung D, Danielson J, Tasnim A, Zhang J, Zou Y, Liu J . Proline Isomerization: From the Chemistry and Biology to Therapeutic Opportunities. Biology (Basel). 2023; 12(7). PMC: 10376262. DOI: 10.3390/biology12071008. View

Ohlsson L . Dairy products and plasma cholesterol levels. Food Nutr Res. 2010; 54. PMC: 2926059. DOI: 10.3402/fnr.v54i0.5124. View

Nagaoka S, Futamura Y, Miwa K, Awano T, Yamauchi K, Kanamaru Y . Identification of novel hypocholesterolemic peptides derived from bovine milk beta-lactoglobulin. Biochem Biophys Res Commun. 2001; 281(1):11-7. DOI: 10.1006/bbrc.2001.4298. View

10.

van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark A, Berendsen H . GROMACS: fast, flexible, and free. J Comput Chem. 2005; 26(16):1701-18. DOI: 10.1002/jcc.20291. View

11.

Santos L, Ferreira R, Caffarena E . Integrating Molecular Docking and Molecular Dynamics Simulations. Methods Mol Biol. 2019; 2053:13-34. DOI: 10.1007/978-1-4939-9752-7_2. View

12.

Berman H, Westbrook J, Feng Z, Gilliland G, Bhat T, Weissig H . The Protein Data Bank. Nucleic Acids Res. 1999; 28(1):235-42. PMC: 102472. DOI: 10.1093/nar/28.1.235. View

13.

Qin X, Zhong J, Wang Y . A mutant T1 lipase homology modeling, and its molecular docking and molecular dynamics simulation with fatty acids. J Biotechnol. 2021; 337:24-34. DOI: 10.1016/j.jbiotec.2021.06.024. View

14.

Pecorari D, Mazzanti A, Mancinelli M . Atropostatin: Design and Total Synthesis of an Atropisomeric Lactone-Atorvastatin Prodrug. Molecules. 2023; 28(7). PMC: 10095771. DOI: 10.3390/molecules28073176. View

15.

Luo H, Shen J, Chen C, Ma X, Lin C, Ouyang Q . Lipid-lowering effects of oleanolic acid in hyperlipidemic patients. Chin J Nat Med. 2018; 16(5):339-346. DOI: 10.1016/S1875-5364(18)30065-7. View

16.

Sabe V, Tolufashe G, Ibeji C, Maseko S, Govender T, Maguire G . Identification of potent L,D-transpeptidase 5 inhibitors for Mycobacterium tuberculosis as potential anti-TB leads: virtual screening and molecular dynamics simulations. J Mol Model. 2019; 25(11):328. DOI: 10.1007/s00894-019-4196-z. View

17.

Chen F, Sun H, Wang J, Zhu F, Liu H, Wang Z . Assessing the performance of MM/PBSA and MM/GBSA methods. 8. Predicting binding free energies and poses of protein-RNA complexes. RNA. 2018; 24(9):1183-1194. PMC: 6097651. DOI: 10.1261/rna.065896.118. View

18.

Gonzalez-Ortega O, Lopez-Limon A, Morales-Dominguez J, Soria-Guerra R . Production and purification of recombinant hypocholesterolemic peptides. Biotechnol Lett. 2014; 37(1):41-54. DOI: 10.1007/s10529-014-1657-4. View

19.

Liu F, Wang T, Dong X, Sun Y . Rational design of affinity peptide ligand by flexible docking simulation. J Chromatogr A. 2007; 1146(1):41-50. DOI: 10.1016/j.chroma.2007.01.130. View

20.

Genheden S, Ryde U . The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov. 2015; 10(5):449-61. PMC: 4487606. DOI: 10.1517/17460441.2015.1032936. View