A comprehensive review on the pancreatic lipase inhibitory peptides: A future anti-obesity strategy
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Analytical Biochemistry Research Centre (ABrC), Universiti Innovation Incubator Building, SAINS@USM Campus, Universiti Sains Malaysia, Lebuh Bukit Jambul 11900, Penang, MALAYSIA
College of Pharmacy, University of Hafr Al Batin, Hafr Al Batin, SAUDI ARABIA
Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, MALAYSIA
Center for Drug Research, Universiti Sains Malaysia, Penang, MALAYSIA
Department of Physiology, School of Medicine, University College of Cork, Cork, IRELAND
Online publication date: 2023-03-07
Publication date: 2023-05-01
Electron J Gen Med 2023;20(3):em470
Dysregulation of lipid homeostasis contributes to obesity and can directly lead to several critical public health concerns globally. This paper aimed to present a brief review of related properties and the use of pancreatic lipase inhibitors as the future weight loss drug discovery and development procured from a wide range of natural sources. A total of 176 pancreatic lipase inhibitory peptides were identified from recent publications and peptide databases. These peptides were classified into three categories according to their peptide length and further analyzed using bioinformatic approaches to identify their structural activity relationship. Molecular docking analyses were conducted for each amino acid at the terminal position of the peptides to predict the binding affinity between peptide-enzyme protein complexes based on intermolecular contact interactions. Overall, the observations revealed the features of the inhibitory peptides and their inhibitory mechanisms and interactions. These findings strived to benefit scientists whose research may be relevant to anti-obesity drug development and/or discovery thereby support effective translation of preclinical research for humans’ health being.
WHO. Overweight and obesity. World Health Organization; 2021. Available at: (Accessed: 1 December 2021).
Bray GA, Heisel WE, Afshin A, et al. The science of obesity management: An endocrine society scientific statement. Endocr Rev. 2018;39(2):79-132. PMid:29518206 PMCid:PMC5888222.
Liu T-T, Liu X-T, Chen Q-X, Shi Y. Lipase inhibitors for obesity: A review. Biomed Pharmacother. 2020;128:110314. PMid:32485574.
Avila C, Holloway AC, Hahn MK, et al. An overview of links between obesity and mental health. Curr Obes Rep. 2015; 4(3):303-10. PMid:26627487.
NIDDK. Treatment for overweight & obesity. NIDDK; 2021. Available at: (Accessed: 4 December 2021).
Krentz AJ, Fujioka K, Hompesch M. Evolution of pharmacological obesity treatments: Focus on adverse side‐effect profiles. Diabetes Obes Metab. 2016;18(6):558-70. PMid:26936802.
Złotek U, Jakubczyk A, Rybczyńska-Tkaczyk K, Ćwiek P, Baraniak B, Lewicki S. Characteristics of new peptides GQLGEHGGAGMG, GEHGGAGMGGGQFQPV, EQGFLPGPEESGR, RLARAGLAQ, YGNPVGGVGH, and GNPVGGVGHGTTGT as inhibitors of enzymes involved in metabolic syndrome and antimicrobial potential. Molecules. 2020;25(11):2492. PMid:32471271 PMCid:PMC7321301.
Ketprayoon T, Noitang S, Sangtanoo P, et al. An in vitro study of lipase inhibitory peptides obtained from de-oiled rice bran. RSC Adv. 2021;11(31):18915-29. PMid:35478653 PMCid:PMC9033478.
Esfandi R, Seidu I, Willmore W, Tsopmo A. Antioxidant, pancreatic lipase, and α‐amylase inhibitory properties of oat bran hydrolyzed proteins and peptides. J Food Biochem. 2021:46(4):e13762. PMid:33997997.
Coronado-Cáceres LJ, Hernández-Ledesma B, Mojica L, et al. Cocoa (theobroma cacao L.) seed-derived peptides reduce blood pressure by interacting with the catalytic site of the angiotensin-converting enzyme. Foods. 2021;10(10):2340. PMid:34681387 PMCid:PMC8534856.
Siow H-L, Choi S-B, Gan C-Y. Structure–activity studies of protease activating, lipase inhibiting, bile acid binding and cholesterol-lowering effects of pre-screened cumin seed bioactive peptides. J Funct Foods. 2016;27:600-11.
Garzón AG, Cian RE, Aquino ME, Drago SR. Isolation and identification of cholesterol esterase and pancreatic lipase inhibitory peptides from brewer’s spent grain by consecutive chromatography and mass spectrometry. Food Funct. 2020;11(6):4994-5003. PMid:32515459.
Wang J, Zhou M, Wu T, Fang L, Liu C, Min W. Novel anti-obesity peptide (RLLPH) derived from hazelnut (corylus heterophylla fisch) protein hydrolysates inhibits adipogenesis in 3T3-L1 adipocytes by regulating adipogenic transcription factors and adenosine monophosphate-activated protein kinase (AMPK) activation. J Biosci Bioeng. 2020;129(3):259-68. PMid:31630942.
Martinez‐Villaluenga C, Rupasinghe SG, Schuler MA, de Mejia EG. Peptides from purified soybean β‐conglycinin inhibit fatty acid synthase by interaction with the thioesterase catalytic domain. FEBS J. 2010;277(6):1481-93. PMid:20148945.
Jakubczyk A, Karaś M, Złotek U, Szymanowska U. Identification of potential inhibitory peptides of enzymes involved in the metabolic syndrome obtained by simulated gastrointestinal digestion of fermented bean (phaseolus vulgaris L.) seeds. Int Food Res J. 2017;100(Pt 1):489-96. PMid:28873712.
Lee YG, Cho J-Y, Hwang EJ, Jeon T-I, Moon J-H. Glu–Phe from onion (allium cepa L.) attenuates lipogenesis in hepatocytes. Biosci Biotechnol Biochem. 2017;81(7):1409-16. PMid:28345482.
Zhang Y, He S, Rui X, Simpson BK. Interactions of C. frondosa-derived inhibitory peptides against angiotensin I-converting enzyme (ACE), α-amylase and lipase. Food Chem. 2022;367:130695. PMid:34365251.
Kim Y-M, Kim I-H, Choi J-W, Lee M-K, Nam T-J. The anti-obesity effects of a tuna peptide on 3T3-L1 adipocytes are mediated by the inhibition of the expression of lipogenic and adipogenic genes and by the activation of the Wnt/β-catenin signaling pathway. Int J Mol Med. 2015;36(2):327-34. PMid:26046125 PMCid:PMC4501660.
Abdelhedi O, Khemakhem H, Nasri R, et al. Assessment of cholesterol, glycemia control and short-and long-term antihypertensive effects of smooth hound viscera peptides in high-salt and fructose diet-fed wistar rats. Mar Drugs. 2019;17(4):194. PMid:30934709 PMCid:PMC6520678.
Wang Y-M, Pan X, He Y, Chi C-F, Wang B. Hypolipidemic activities of two pentapeptides (VIAPW and IRWWW) from miiuy croaker (miichthys miiuy) muscle on lipid accumulation in HepG2 cells through regulation of AMPK pathway. Appl Sci. 2020;10(3):817.
Fan X, Cui Y, Zhang R, Zhang X. Purification and identification of anti-obesity peptides derived from spirulina platensis. J Funct Foods. 2018;47:350-60.
Zielińska E, Karaś M, Baraniak B, Jakubczyk A. Evaluation of ACE, α-glucosidase, and lipase inhibitory activities of peptides obtained by in vitro digestion of selected species of edible insects. Eur Food Res Technol. 2020;246(7):1361-9.
Mudgil P, Baba WN, Kamal H, et al. A comparative investigation into novel cholesterol esterase and pancreatic lipase inhibitory peptides from cow and camel casein hydrolysates generated upon enzymatic hydrolysis and in-vitro digestion. Food Chem. 2022;367:130661. PMid:34348197.
Mudgil P, Kamal H, Yuen GC, Maqsood S. Characterization and identification of novel antidiabetic and anti-obesity peptides from camel milk protein hydrolysates. Food Chem. 2018;259:46-54. PMid:29680061.
Baba WN, Mudgil P, Baby B, Vijayan R, Gan C-Y, Maqsood S. New insights into the cholesterol esterase-and lipase-inhibiting potential of bioactive peptides from camel whey hydrolysates: Identification, characterization, and molecular interaction. J Dairy Sci. 2021;104(7):7393-405. PMid:33934858.
Lamiable A, Thévenet P, Rey J, Vavrusa M, Derreumaux P, Tufféry P. PEP-FOLD3: Faster de novo structure prediction for linear peptides in solution and in complex. Nucleic Acids Res. 2016;44(W1):W449-54. PMid:27131374 PMCid:PMC4987898.
van Zundert GCP, Rodrigues JPGLM, Trellet M, et al. The HADDOCK2.2 web server: User-friendly integrative modeling of biomolecular complexes. J Mol Biol. 2016;428(4):720-5. PMid:26410586.
Kangueane P, Nilofer C. Protein-protein docking: Methods and tools. In: Protein-protein and domain-domain interactions. Berlin: Springer; 2018. p. 161-8.
Medina-Franco JL, Méndez-Lucio O, Martinez-Mayorga K. The interplay between molecular modeling and chemoinformatics to characterize protein–ligand and protein–protein interactions landscapes for drug discovery. Adv Protein Chem Struct Biol. 2014;96:1-37. PMid:25443953.
Lowe ME. Structure and function of pancreatic lipase and colipase. Annu Rev Nutr. 1997;17(1):141-58. PMid:9240923.
Winkler FK, D’Arcy A, Hunziker W. Structure of human pancreatic lipase. Nature. 1990;343(6260):771-4. PMid:2106079.
Ayvazian L, Kerfelec B, Granon S, et al. The lipase C-terminal domain: A novel unusual inhibitor of pancreatic lipase activity. J Biol Chem. 2001;276(17):14014-8. PMid:11154696.
Lowe ME. The catalytic site residues and interfacial binding of human pancreatic lipase. J Biol Chem. 1992;267(24):17069-73. PMid:1512245.
Lowe ME. Molecular mechanisms of rat and human pancreatic triglyceride lipases. J Nutr. 1997;127(4):549-57. PMid:9109604.
Thayumanavan P, Nallaiyan S, Loganathan C, Sakayanathan P, Kandasamy S, Isa MA. Inhibition of glutathione and s-allyl glutathione on pancreatic lipase: Analysis through in vitro kinetics, fluorescence spectroscopy and in silico docking. Int J Biol Macromol. 2020;160:623-31. PMid:32473219.
Brockman HL. Kinetic behavior of the pancreatic lipase-colipase-lipid system. Biochimie. 2000;82(11):987-95. PMid:11099795.
Henderson GC. Plasma free fatty acid concentration as a modifiable risk factor for metabolic disease. Nutrients. 2021;13(8):2590. PMid:34444750 PMCid:PMC8402049.
Mancini MC, Halpern A. Pharmacological treatment of obesity. Arq Bras Endocrinol Metabol. 2006;50:377-89. PMid:16767304.
Thomas A, Allouche M, Basyn F, Brasseur R, Kerfelec B. Role of the lid hydrophobicity pattern in pancreatic lipase activity. J Biol Chem. 2005;280(48):40074-83. PMid:16179352.
Skoczinski P, Cangahuala MKE, Maniar D, Loos K. Enzymatic transesterification of urethane-bond containing ester. Colloid Polym Sci. 2021;299(3):561-73.
Brandl M, Weiss MS, Jabs A, Sühnel J, Hilgenfeld R. CH⋯ π-interactions in proteins. J Mol Biol. 2001;307(1):357-77. PMid:11243825.
Ding L, Wang L, Yu Z, et al. Importance of terminal amino acid residues to the transport of oligopeptides across the caco-2 cell monolayer. J Agric Food Chem. 2017; 65(35):7705-12. PMid:28812357.
Laughlin MJ, Chantler SE, Okita TW. N‐and c‐terminal peptide sequences are essential for enzyme assembly, allosteric, and/or catalytic properties of ADP‐glucose pyrophosphorylase. Plant J. 1998;14(2):159-68. PMid:9628013.
Latip W, Raja Abd Rahman RNZ, Leow ATC, Mohd Shariff F, Kamarudin NHA, Mohamad Ali MS. The effect of N-terminal domain removal towards the biochemical and structural features of a thermotolerant lipase from an antarctic pseudomonas sp. strain AMS3. Int J Mol Sci. 2018;19(2):560. PMid:29438291 PMCid:PMC5855782.
Weber DS, Warren JJ. The interaction between methionine and two aromatic amino acids is an abundant and multifunctional motif in proteins. Arch Biochem Biophys. 2019;672:108053. PMid:31351863.
Giese B, Wang M, Gao J, Stoltz M, Müller P, Graber M. Electron relay race in peptides. J Org Chem. 2009;74(10):3621-5. PMid:19344128.
Valley CC, Cembran A, Perlmutter JD, et al. The methionine-aromatic motif plays a unique role in stabilizing protein structure. J Biol Chem. 2012;287(42):34979-91. PMid:22859300 PMCid:PMC3471747.
Zauhar R, Colbert C, Morgan R, Welsh W. Evidence for a strong sulfur–aromatic interaction derived from crystallographic data. Biopolymers. 2000;53(3):233-48.<233::AID-BIP3>3.0.CO;2-4.
Ma B, Nussinov R. Trp/Met/Phe hot spots in protein-protein interactions: Potential targets in drug design. Curr Top Med Chem. 2007;7(10):999-1005. PMid:17508933.
Suresh CH, Mohan N, Vijayalakshmi KP, George R, Mathew JM. Typical aromatic noncovalent interactions in proteins: A theoretical study using phenylalanine. J Comput Chem. 2009;30(9):1392-404. PMid:19037862.
Betts MJ, Russell RB. Amino acid properties and consequences of substitutions. Bioinformatics Genetic. 2003;317:289.
London N, Movshovitz-Attias D, Schueler-Furman O. The structural basis of peptide-protein binding strategies. Structure. 2010;18(2):188-99. PMid:20159464.
Lu X, Hansen JC. Revisiting the structure and functions of the linker histone C-terminal tail domain. Biochem Cell Biol. 2003;81(3):173-6. PMid:12897851.
Sun A-Q, Luo Y, Backos DS, et al. Identification of functionally relevant lysine residues that modulate human farnesoid X receptor activation. Mol Pharmacol. 2013; 83(5):1078-86. PMid:23462506 PMCid:PMC3920091.
Uhlig T, Kyprianou T, Martinelli FG, et al. The emergence of peptides in the pharmaceutical business: From exploration to exploitation. EuPA Open Proteomics. 2014;4:58-69.
Anigboro AA, Avwioroko OJ, Akeghware O, Tonukari NJ. Anti-obesity, antioxidant and in silico evaluation of justicia carnea bioactive compounds as potential inhibitors of an enzyme linked with obesity: Insights from kinetics, semi-empirical quantum mechanics and molecular docking analysis. Biophys Chem. 2021;274:106607. PMid:33957576.
Hu B, Cui F, Yin F, Zeng X, Sun Y, Li Y. Caffeoylquinic acids competitively inhibit pancreatic lipase through binding to the catalytic triad. Int J Biol Macromol. 2015;80:529-35. PMid:26193679.
van Tilbeurgh H, Egloff M-P, Martinez C, Rugani N, Verger R, Cambillau C. Interfacial activation of the lipase–procolipase complex by mixed micelles revealed by X-ray crystallography. Nature. 1993;362(6423):814-20. PMid:8479519.
Yang Y, Lowe ME. The open lid mediates pancreatic lipase function. J Lipid Res. 2000;41(1):48-57. PMid:10627501.
Secundo F, Carrea G, Tarabiono C, et al. The lid is a structural and functional determinant of lipase activity and selectivity. J Mol Cat B: Enzym. 2006;39(1-4):166-70.
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