A Glycosaminoglycan Extract from Portunus pelagicus Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease
Abstract
:1. Introduction
2. Results
2.1. Isolation and Characterisation of a Glycosaminoglycan Extract from the Crab Portunus Pelagicus
2.2. P. pelagicus F5 Inhibits the Alzheimer’s Disease-Relevant β-Secretase 1
2.3. Heparin Binding Induces a Conformational Change in the Alzheimer’s Disease β-Secretase, BACE1
2.4. Heparin and P. pelagicus F5 Destabilise the Alzheimer’s Disease β-Secretase, BACE1
2.5. Attenuated Anticoagulant Activities of the P. pelagicus Glycosaminoglycan Extract
3. Discussion
4. Materials and Methods
4.1. Extraction of Glycosaminoglycans from Portunus pelagicus
4.2. Agarose Gel Electrophoresis
4.3. Attenuated FTIR Spectral Analysis of Marine-Derived Glycosaminoglycans
4.4. Nuclear Magnetic Resonance (NMR)
4.5. Constituent Δ-Disaccharide Analysis of Hp/HS-Like, Marine-Derived Carbohydrates
4.6. Determination of Human BACE1 Inhibitory Activity Using Förster Resonance Energy Transfer
4.7. Secondary Structure Determination of Human BACE1 by Circular Dichroism Spectroscopy
4.8. Investigating the Thermal Stability of Human BACE1 with Differential Scanning Fluorimetry
4.9. Activated Partial Thromboplastin Time (aPTT)
4.10. Prothrombin Time (PT)
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Lane, C.; Hardy, J.; Schott, J.M. Alzheimer’s disease. Eur. J. Neurol. 2017, 25, 59–70. [Google Scholar] [CrossRef]
- Cruts, M.; Theuns, J.; Van Broeckhoven, C. Locus-specific mutation databases for neurodegenerative brain diseases. Hum. Mutat. 2012, 33, 1340–1344. [Google Scholar] [CrossRef] [PubMed]
- Carreiras, M.; Mendes, E.; Perry, M.; Francisco, A.; Marco-Contelles, J. The Multifactorial Nature of Alzheimer’s Disease for Developing Potential Therapeutics. Curr. Top. Med. Chem. 2014, 13, 1745–1770. [Google Scholar] [CrossRef]
- Ibrahim, M.M.; Gabr, M.T. Multitarget therapeutic strategies for Alzheimer’s disease. Neural Regen. Res. 2019, 14, 437–440. [Google Scholar]
- Cai, H.; Wang, Y.; McCarthy, D.; Wen, H.; Borchelt, D.R.; Price, D.L.; Wong, P.C. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat. Neurosci. 2001, 4, 233–234. [Google Scholar] [CrossRef] [PubMed]
- Querfurth, H.W.; LaFerla, F.M. Alzheimer’s Disease. N. Engl. J. Med. 2010, 362, 329–344. [Google Scholar] [CrossRef]
- Lichtenthaler, S.F.; Haass, C.; Steiner, H. Regulated intramembrane proteolysis—Lessons from amyloid precursor protein processing. J. Neurochem. 2011, 117, 779–796. [Google Scholar] [CrossRef] [PubMed]
- Walsh, D.M.; Selkoe, D.J. Aβ Oligomers—A decade of discovery. J. Neurochem. 2007, 101, 1172–1184. [Google Scholar] [CrossRef]
- Thinakaran, G.; Koo, E.H. Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 2008, 283, 29615–29619. [Google Scholar] [CrossRef] [PubMed]
- Vassar, R. BACE1 inhibition as a therapeutic strategy for Alzheimer’s disease. J. Sport Health Sci. 2016, 5, 388–390. [Google Scholar] [CrossRef] [PubMed]
- Roberds, S.L.; Anderson, J.; Basi, G.; Bienkowski, M.J.; Branstetter, D.G.; Chen, K.S.; Freedman, S.B.; Frigon, N.L.; Games, D.; Hu, K.; et al. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: Implications for Alzheimer’s disease therapeutics. Hum. Mol. Genet. 2001, 10, 1317–1324. [Google Scholar] [CrossRef]
- Luo, Y.; Bolon, B.; Kahn, S.; Bennett, B.D.; Babu-Khan, S.; Denis, P.; Fan, W.; Kha, H.; Zhang, J.; Gong, Y.; et al. Mice deficient in BACE1, the Alzheimer’s β-secretase, have normal phenotype and abolished β-amyloid generation. Nat. Neurosci. 2001, 4, 231–232. [Google Scholar] [CrossRef] [PubMed]
- Dominguez, D.; Tournoy, J.; Hartmann, D.; Huth, T.; Cryns, K.; Deforce, S.; Serneels, L.; Camacho, I.E.; Marjaux, E.; Craessaerts, K.; et al. Phenotypic and Biochemical Analyses of BACE1- and BACE2-deficient Mice. J. Biol. Chem. 2005, 280, 30797–30806. [Google Scholar] [CrossRef] [Green Version]
- Ohno, M.; Sametsky, E.A.; Younkin, L.H.; Oakley, H.; Younkin, S.G.; Citron, M.; Vassar, R.; Disterhoft, J.F. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron 2004, 41, 27–33. [Google Scholar] [CrossRef]
- Ohno, M.; Cole, S.L.; Yasvoina, M.; Zhao, J.; Citron, M.; Berry, R.; Disterhoft, J.F.; Vassar, R. BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol. Dis. 2007, 26, 134–145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McConlogue, L.; Buttini, M.; Anderson, J.P.; Brigham, E.F.; Chen, K.S.; Freedman, S.B.; Games, D.; Johnson-Wood, K.; Lee, M.; Zeller, M.; et al. Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice. J. Biol. Chem. 2007, 282, 26326–26334. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vassar, R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimer’s Res. Ther. 2014, 6, 89. [Google Scholar] [CrossRef] [PubMed]
- Scholefield, Z.; Yates, E.A.; Wayne, G.; Amour, A.; McDowell, W.; Turnbull, J.E. Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer’s beta-secretase. J. Cell Biol. 2003, 163, 97–107. [Google Scholar] [CrossRef] [PubMed]
- Patey, S.J.; Edwards, E.A.; Yates, E.A.; Turnbull, J.E. Heparin derivatives as inhibitors of BACE-1, the Alzheimer’s β-secretase, with reduced activity against factor Xa and other proteases. J. Med. Chem. 2006, 49, 6129–6132. [Google Scholar] [CrossRef]
- Patey, S.J.; Edwards, E.A.; Yates, E.A.; Turnbull, J.E. Engineered heparins: Novel beta-secretase inhibitors as potential Alzheimer’s disease therapeutics. Neurodegener. Dis. 2008, 5, 197–199. [Google Scholar] [CrossRef]
- Bergamaschini, L.; Rossi, E.; Storini, C.; Pizzimenti, S.; Distaso, M.; Perego, C.; De Luigi, A.; Vergani, C.; De Simoni, M.G. Peripheral Treatment with Enoxaparin, a Low Molecular Weight Heparin, Reduces Plaques and β-Amyloid Accumulation in a Mouse Model of Alzheimer’s Disease. J. Neurosci. 2004, 24, 4181–4186. [Google Scholar] [CrossRef]
- Timmer, N.M.; van Dijk, L.; van der Zee, C.E.; Kiliaan, A.; de Waal, R.M.; Verbeek, M.M. Enoxaparin treatment administered at both early and late stages of amyloid β deposition improves cognition of APPswe/PS1dE9 mice with differential effects on brain Aβ levels. Neurobiol. Dis. 2010, 40, 340–347. [Google Scholar] [CrossRef] [PubMed]
- Bergamaschini, L.; Rossi, E.; Vergani, C.; De Simoni, M.G. Alzheimer’s disease: Another target for heparin therapy. Sci. World J. 2009, 9, 891–908. [Google Scholar] [CrossRef]
- Leveugle, B.; Ding, W.; Laurence, F.; Dehouck, M.P.; Scanameo, A.; Cecchelli, R.; Fillit, H. Heparin oligosaccharides that pass the blood-brain barrier inhibit beta-amyloid precursor protein secretion and heparin binding to beta-amyloid peptide. J. Neurochem. 1998, 70, 736–744. [Google Scholar] [CrossRef] [PubMed]
- Hoffart, V.; Lamprecht, A.; Maincent, P.; Lecompte, T.; Vigneron, C.; Ubrich, N. Oral bioavailability of a low molecular weight heparin using a polymeric delivery system. J. Control. Release 2006, 113, 38–42. [Google Scholar] [CrossRef]
- Stewart, K.L.; Hughes, E.; Yates, E.A.; Middleton, D.A.; Radford, S.E. Molecular Origins of the Compatibility between Glycosaminoglycans and Aβ40 Amyloid Fibrils. J. Mol. Biol. 2017, 429, 2449–2462. [Google Scholar] [CrossRef] [PubMed]
- Mycroft-West, C.J.; Yates, E.A.; Skidmore, M.A. Marine glycosaminoglycan-like carbohydrates as potential drug candidates for infectious disease. Biochem. Soc. Trans. 2018, 46, 919–929. [Google Scholar] [CrossRef] [PubMed]
- Valcarcel, J.; Nova-Carballal, R.; Perez-Martin, I.R.; Reis, L.R.; Vazeuez, A.J. Glycosaminoglycans from Marine Sources as therapeutic Agents. Biotechnol. Adv. 2017, 35, 711–725. [Google Scholar] [CrossRef]
- Bergefall, K.; Trybala, E.; Johansson, M.; Uyama, T.; Yamada, S.; Kitagawa, H.; Sugahara, K.; Bergstrom, T. Chondroitin sulfate characterized by the E-disaccharide unit is a poten inhibtor of herpes simplex virus infectivity and provides the virus binding sites on gro2C cells. J. Biol. Chem. 2005, 280, 32193–32199. [Google Scholar] [CrossRef]
- Huang, N.; Wu, M.Y.; Zheng, C.B.; Zhu, L.; Zhao, J.H.; Zheng, Y.T. The depolymerized fucosylated chondroitin sulfate from sea cucumber potently inhibits HIV replication via interfering with virus entry. Carbohydr. Res. 2013, 380, 64–69. [Google Scholar] [CrossRef]
- Bastos, F.M.; Albrecht, L.; Kozlowski, O.E.; Lopes, P.C.S.; Blanco, C.Y.; Carlos, C.B.; Castineiras, C.; Vicente, P.C.; Werneck, C.C.; Gerhard, W.; et al. Fucosylated Chondroitin Sulphate Inhibits Plasmodium falciparum Cytoadhesion and Merozoite Invasion. Antimicrob. Agents Chemother. 2014, 58, 1862–1871. [Google Scholar] [CrossRef] [PubMed]
- Marques, J.; Vilanova, E.; Mourao, S.A.P.; Fernandez-Busquets, X. Marine organism sulfated polysaccharides exhibiting significant antimalarial activity and inhibition of red blood cell invasion by plasmodium. Sci. Rep. 2016, 6, 24368. [Google Scholar] [CrossRef]
- Brito, A.S.; Arimatéia, D.S.; Souza, L.R.; Lima, M.A.; Santos, V.O.; Medeiros, V.P.; Ferreira, P.A.; Silva, R.A.; Ferreira, C.V.; Justo, G.Z.; et al. Anti-inflammatory properties of a heparin-like glycosaminoglycan with reduced anti-coagulant activity isolated from a marine shrimp. Bioorg. Med. Chem. 2008, 16, 9588–9595. [Google Scholar] [CrossRef]
- Suleria, H.A.R.; Masci, P.P.; Addepalli, R.; Chen, W.; Gobe, G.C.; Osborne, S.A. In vitro anti-thrombotic and anti-coagulant properties of blacklip abalone (Haliotis rubra) viscera hydrolysate. Anal. Bioanal. Chem. 2017, 409, 4195–4205. [Google Scholar] [CrossRef]
- Gomes, A.M.; Kozlowski, E.O.; Borsig, L.; Teixeira, F.C.; Vlodavsky, I.; Pavão, M.S.G. Antitumor properties of a new non-anticoagulant heparin analog from the mollusk Nodipecten nodosus: Effect on P-selectin, heparanase, metastasis and cellular recruitment. Glycobiology 2015, 25, 386–393. [Google Scholar] [CrossRef] [PubMed]
- Khurshid, C.; Pye, D.; Khurshid, C.; Pye, D.A. Isolation and Composition Analysis of Bioactive Glycosaminoglycans from Whelk. Mar. Drugs 2018, 16, 171. [Google Scholar] [CrossRef] [PubMed]
- Aldairi, A.F.; Ogundipe, O.D.; Pye, D.A.; Aldairi, A.F.; Ogundipe, O.D.; Pye, D.A. Antiproliferative Activity of Glycosaminoglycan-Like Polysaccharides Derived from Marine Molluscs. Mar. Drugs 2018, 16, 63. [Google Scholar] [CrossRef]
- Hu, S.; Jiang, W.; Li, S.; Song, W.; Ji, L.; Cai, L.; Liu, X. Fucosylated chondroitin sulphate from sea cucumber reduces hepatic endoplasmic reticulum stress-associated inflammation in obesity mice. J. Funct. Foods 2015, 16, 352–363. [Google Scholar] [CrossRef]
- Gomes, A.M.; Kozlowski, E.O.; Pomin, V.H.; de Barros, C.M.; Zaganeli, J.L.; Pavão, M.S. Unique Extracellular Matrix Heparan Sulfate from the Bivalve Nodipecten nodosus (Linnaeus, 1758) Safely Inhibits Arterial Thrombosis after Photochemically Induced Endothelial Lesion. J. Biol. Chem. 2010, 285, 7312–7323. [Google Scholar] [CrossRef]
- Hikino, M.; Mikami, T.; Faissner, A.; Vilela-Silva, A.-C.E.; Pavão, M.S.G.; Sugahara, K. Oversulfated Dermatan Sulfate Exhibits Neurite Outgrowth-promoting Activity toward Embryonic Mouse Hippocampal Neurons. J. Biol. Chem. 2003, 278, 43744–43754. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Devlin, A.; Mycroft-west, C.J.; Guerrini, M.; Yates, E.A. Analysis of solid-state heparin samples by ATR-FTIR spectroscopy. bioRxiv 2019. [Google Scholar] [CrossRef]
- Skidmore, M.A.; Guimond, S.E.; Turnbull, J.E.; Dumax-Vorzet, A.F.; Yates, E.A.; Atrih, A. High sensitivity separation and detection of heparan sulfate disaccharides. J. Chromatogr. A 2006, 1135, 52–56. [Google Scholar] [CrossRef]
- Andrade, P.V.G.; Lima, A.M.; de Souza Junior, A.A.; Fareed, J.; Hoppensteadt, A.D.; Santos, E.; Chavante, F.S.; Oliveira, W.F.; Rocha, A.O.H.; Nader, B.H. A heparin-like compound isolated from a marine crab rich in glucuronic acid 2-O-sulfate presents low anticoagulant activity. Carbohydr. Polym. 2013, 94, 647–654. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dietrich, C.P.; Tersariol, I.L.; Toma, L.; Moraes, C.T.; Porcionatto, M.A.; Oliveira, F.W.; Nader, H.B. Structure of heparan sulfate: Identification of variable and constant oligosaccharide domains in eight heparan sulfates of different origins. Cell. Mol. Biol. 1998, 44, 417–429. [Google Scholar]
- Zhang, Z.; Xie, J.; Liu, H.; Liu, J.; Linhardt, R.J. Quantification of heparan sulfate disaccharides using ion-pairing reversed-phase microflow high-performance liquid chromatography with electrospray ionization trap mass spectrometry. Anal. Chem. 2009, 81, 4349–4355. [Google Scholar] [CrossRef]
- Klaver, D.W.; Wilce, M.C.J.; Gasperini, R.; Freeman, C.; Juliano, J.P.; Parish, C.; Foa, L.; Aguilar, M.-I.; Small, D.H. Glycosaminoglycan-induced activation of the β-secretase (BACE1) of Alzheimer’s disease. J. Neurochem. 2010, 112, 1552–1561. [Google Scholar] [CrossRef] [Green Version]
- Beckman, M.; Holsinger, R.M.D.; Small, D.H. Heparin activates β-secretase (BACE1) of Alzheimer’s disease and increases autocatalysis of the enzyme. Biochemistry 2006, 45, 6703–6714. [Google Scholar] [CrossRef] [PubMed]
- Micsonai, A.; Wien, F.; Kernya, L.; Lee, Y.-H.; Goto, Y.; Réfrégiers, M.; Kardos, J. Accurate secondary structure prediction and fold recognition for circular dichroism spectroscopy. Proc. Natl. Acad. Sci. USA 2015, 112, E3095–E3103. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gasymov, O.K.; Abduragimov, A.R.; Glasgow, B.J. Probing tertiary structure of proteins using single Trp mutations with circular dichroism at low temperature. J. Phys. Chem. B 2014, 118, 986–995. [Google Scholar] [CrossRef] [PubMed]
- De Simone, A.; Mancini, F.; Real Fernàndez, F.; Rovero, P.; Bertucci, C.; Andrisano, V. Surface plasmon resonance, fluorescence, and circular dichroism studies for the characterization of the binding of BACE-1 inhibitors. Anal. Bioanal. Chem. 2013, 405, 827–835. [Google Scholar] [CrossRef] [PubMed]
- Greenfield, N.J. Using circular dichroism spectra to estimate protein secondary structure. Nat. Protoc. 2006, 1, 2876. [Google Scholar] [CrossRef] [PubMed]
- Shimizu, H.; Tosaki, A.; Kaneko, K.; Hisano, T.; Sakurai, T.; Nukina, N. Crystal Structure of an Active Form of BACE1, an Enzyme Responsible for Amyloid β Protein Production. Mol. Cell. Biol. 2008, 28, 3663–3671. [Google Scholar] [CrossRef]
- Sreerama, N.; Woody, R.W. On the analysis of membrane protein circular dichroism spectra. Protein Sci. 2004, 13, 100–112. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lo, M.-C.; Aulabaugh, A.; Jin, G.; Cowling, R.; Bard, J.; Malamas, M.; Ellestad, G. Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery. Anal. Biochem. 2004, 332, 153–159. [Google Scholar] [CrossRef]
- Casu, B.; Grazioli, G.; Razi, N.; Guerrini, M.; Naggi, A.; Torri, G.; Oreste, P.; Tursi, F.; Zoppetti, G.; Lindahl, U. Heparin-like compounds prepared by chemical modification of capsular polysaccharide from E. coli K5. Carbohydr. Res. 1994, 263, 271–284. [Google Scholar] [CrossRef]
- Yates, E.A.; Santini, F.; Guerrini, M.; Naggi, A.; Torri, G.; Casu, B. 1H and 13C NMR spectral assignments of the major sequences of twelve systematically modified heparin derivatives. Carbohydr. Res. 1996, 294, 15–27. [Google Scholar] [CrossRef]
- Cavalcante, R.S.; Brito, A.S.; Palhares, L.C.; Lima, M.A. 2,3-Di-O-sulfo glucuronic acid: An unmodified and unusual residue in a highly sulfated chondroitin sulfate from Litopenaeus vannamei. Carbohydr. Polym. 2018, 183, 192–200. [Google Scholar] [CrossRef]
- Vasconcelos, A.; Pomin, V.H. The Sea as a Rich Source of Structurally Unique Glycosaminoglycans and Mimetics. Microorganisms 2017, 5, 51. [Google Scholar] [CrossRef] [PubMed]
- Pavão, M.S. Glycosaminoglycans analogs from marine invertebrates: Structure, biological effects, and potential as new therapeutics. Front. Cell. Infect. Microbiol. 2014, 4, 123. [Google Scholar] [CrossRef]
- Dietrich, C.P.; Paiva, J.F.; Castro, R.A.B.; Chavante, S.F.; Jeske, W.; Fareed, J.; Gorin, P.A.J.; Mendes, A.; Nader, H.B. Structural features and anticoagulant activities of a novel natural low molecular weight heparin from the shrimp Penaeus brasiliensis. Biochim. Biophys. Acta Gen. Subj. 1999, 1428, 273–283. [Google Scholar] [CrossRef]
- Medeiros, G.F.; Mendes, A.; Castro, R.A.B.; Baú, E.C.; Nader, H.B.; Dietrich, C.P. Distribution of sulfated glycosaminoglycans in the animal kingdom: Widespread occurrence of heparin-like compounds in invertebrates. Biochim. Biophys. Acta Gen. Subj. 2000, 1475, 287–294. [Google Scholar] [CrossRef]
- Brito, A.S.; Cavalcante, R.S.; Palhares, L.C.; Hughes, A.J.; Andrade, G.P.V.; Yates, E.A.; Nader, H.B.; Lima, M.A.; Chavante, S.F. A non-hemorrhagic hybrid heparin/heparan sulfate with anticoagulant potential. Carbohydr. Polym. 2014, 99, 372–378. [Google Scholar] [CrossRef] [Green Version]
- Chavante, S.F.; Brito, A.S.; Lima, M.; Yates, E.; Nader, H.; Guerrini, M.; Torri, G.; Bisio, A. A heparin-like glycosaminoglycan from shrimp containing high levels of 3-O-sulfated d-glucosamine groups in an unusual trisaccharide sequence. Carbohydr. Res. 2014, 390, 59–66. [Google Scholar] [CrossRef] [PubMed]
- Chavante, S.F.; Santos, E.A.; Oliveira, F.W.; Guerrini, M.; Torri, G.; Casu, B.; Dietrich, C.P.; Nader, H.B. A novel heparan sulphate with high degree of N-sulphation and high heparin cofactor-II activity from the brine shrimp Artemia franciscana. Int. J. Biol. Macromol. 2000, 27, 49–57. [Google Scholar] [CrossRef]
- Lima, M.; Rudd, T.; Yates, E. New Applications of Heparin and Other Glycosaminoglycans. Molecules 2017, 22, 749. [Google Scholar] [CrossRef] [PubMed]
- Pomin, V.H. Holothurian fucosylated chondroitin sulfate. Mar. Drugs 2014, 12, 232–254. [Google Scholar] [CrossRef] [PubMed]
- Spronk, S.A.; Carlson, H.A. The role of tyrosine 71 in modulating the flap conformations of BACE1. Proteins Struct. Funct. Bioinform. 2011, 79, 2247–2259. [Google Scholar] [CrossRef] [PubMed]
- Rudd, T.R.; Guimond, S.E.; Skidmore, M.A.; Duchesne, L.; Guerrini, M.; Torri, G.; Cosentino, C.; Brown, A.; Clarke, D.T.; Turnbull, J.E.; et al. Influence of substitution pattern and cation binding on conformation and activity in heparin derivatives. Glycobiology 2007, 17, 983–993. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rudd, T.; Skidmore, M.; Guimond, S.; Holman, J.; Turnbull, J. The potential for circular dichroism as an additional facile and sensitive method of monitoring low-molecular-weight heparins and heparinoids. Thromb. Haemost. 2009, 102, 874–878. [Google Scholar] [PubMed] [Green Version]
- Uniewicz, K.A.; Ori, A.; Xu, R.; Ahmed, Y.; Fernig, D.G.; Yates, E.A. Differential Scanning Fluorimetry measurement of protein stability changes upon binding to glycosaminoglycans: A rapid screening test for binding specificity. Anal. Chem. 2010, 82, 3796–3802. [Google Scholar] [CrossRef]
- Niesen, F.H.; Berglund, H.; Vedadi, M. The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat. Protoc. 2007, 2, 2212–2221. [Google Scholar] [CrossRef] [PubMed]
- Van der Meer, J.Y.; Kellenbach, E.; van den Bos, L. From Farm to Pharma: An Overview of Industrial Heparin Manufacturing Methods. Molecules 2017, 22, 1025. [Google Scholar] [CrossRef] [PubMed]
∆-Disaccharide | P. pelagicus F5 (%) | Hp (%) |
---|---|---|
∆-UA-GlcNAc | 2.8 | 4.3 |
∆-UA-GlcNS | 5.6 | 4.2 |
∆-UA-GlcNAc(6S) | 2.3 | 5.0 |
∆-UA(2S)-GlcNAc | 16.5 | 3.1 |
∆-UA-GlcNS(6S) | 20.2 | 22.9 |
∆-UA(2S)-GlcNS | 23.5 | 5.9 |
∆-UA(2S)-GlcNAc(6S) | 6.0 | 3.1 |
∆-UAs(2S)-GlcNS(6S) | 23.1 | 51.5 |
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Mycroft-West, C.J.; Cooper, L.C.; Devlin, A.J.; Procter, P.; Guimond, S.E.; Guerrini, M.; Fernig, D.G.; Lima, M.A.; Yates, E.A.; Skidmore, M.A. A Glycosaminoglycan Extract from Portunus pelagicus Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease. Mar. Drugs 2019, 17, 293. https://doi.org/10.3390/md17050293
Mycroft-West CJ, Cooper LC, Devlin AJ, Procter P, Guimond SE, Guerrini M, Fernig DG, Lima MA, Yates EA, Skidmore MA. A Glycosaminoglycan Extract from Portunus pelagicus Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease. Marine Drugs. 2019; 17(5):293. https://doi.org/10.3390/md17050293
Chicago/Turabian StyleMycroft-West, Courtney J., Lynsay C. Cooper, Anthony J. Devlin, Patricia Procter, Scott E. Guimond, Marco Guerrini, David G. Fernig, Marcelo A. Lima, Edwin A. Yates, and Mark A. Skidmore. 2019. "A Glycosaminoglycan Extract from Portunus pelagicus Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease" Marine Drugs 17, no. 5: 293. https://doi.org/10.3390/md17050293