A New Pathway for Protein Haptenation by beta-Lactams

"This is the peer reviewed version of the following article: Pérez-Ruíz, Raúl, Emilio Lence, Inmaculada Andreu, Daniel Limones-Herrero, Concepción González-Bello, Miguel A. Miranda, and M. Consuelo Jiménez. 2017. A New Pathway for Protein Haptenation by β-Lactams. Chemistry - A European Journal 23 (56). Wiley: 13986 94. doi:10.1002/chem.201702643, which has been published in final form at https://doi.org/10.1002/chem.201702643. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."[EN] The covalent binding of beta-lactams to proteins upon photochemical activation has been demonstrated by using an integrated approach that combines photochemical, proteomic and computational studies, selecting human serum albumin (HSA) as a target protein and ezetimibe (1) as a probe. The results have revealed a novel protein haptenation pathway for this family of drugs that is an alternative to the known nucleophilic ring opening of beta-lactams by the free amino group of lysine residues. Thus, photochemical ring splitting of the beta-lactam ring, following a formal retro-Staudinger reaction, gives a highly reactive ketene intermediate that is trapped by the neighbouring lysine residues, leading to an amide adduct. For the investigated 1/HSA system, covalent modification of residues Lys414 and Lys525, which are located in sub-domains IIIA and IIIB, respectively, occurs. The observed photobinding may constitute the key step in the sequence of events leading to photoallergy. Docking and molecular dynamics simulation studies provide an insight into the molecular basis of the selectivity of 1 for these HSA sub-domains and the covalent modification mechanism. Computational studies also reveal positive cooperative binding of sub-domain IIIB that explains the experimentally observed modification of Lys414, which is located in a barely accessible pocket (sub-domain IIIA).Financial support from Ministerio de Economia, Industria y Competitividad (CTQ2013-47872-C2-1-P, CTQ2016-78875-P, SAF2013-42899-R, SAF2016-75638-R), Instituto de Salud Carlos III (RD12/0013/0009 and RD16/0006/0030), Generalitat Valenciana (PROMETEOII/2013/005), Xunta de Galicia (Centro singular de investigacion de Galicia accreditation 2016-2019, ED431G/09) and European Union (European Regional Development Fund -ERDF) is gratefully acknowledged. E.L. thanks the Xunta de Galicia for a postdoctoral fellowship. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae II supercomputer. The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+i 2013-2016, funded by ISCIII and FEDER.Pérez-Ruiz, R.; Lence, E.; Andreu Ros, MI.; Limones Herrero, D.; González-Bello, C.; Miranda Alonso, MÁ.; Jiménez Molero, MC. (2017). A New Pathway for Protein Haptenation by beta-Lactams. Chemistry - A European Journal. 23(56):13986-13994. https://doi.org/10.1002/chem.20170264313986139942356Van Boeckel, T. P., Gandra, S., Ashok, A., Caudron, Q., Grenfell, B. T., Levin, S. A., & Laxminarayan, R. (2014). Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. The Lancet Infectious Diseases, 14(8), 742-750. doi:10.1016/s1473-3099(14)70780-7Elander, R. P. (2003). Industrial production of β-lactam antibiotics. Applied Microbiology and Biotechnology, 61(5-6), 385-392. doi:10.1007/s00253-003-1274-yRodriguez-Pena, R., Antunez, C., Martin, E., Blanca-Lopez, N., Mayorga, C., & Torres, M. J. (2005). Allergic reactions to β-lactams. Expert Opinion on Drug Safety, 5(1), 31-48. doi:10.1517/14740338.5.1.31Blanca, M., Romano, A., Torres, M. J., Férnandez, J., Mayorga, C., Rodriguez, J., … Atanasković-Marković, M. (2009). Update on the evaluation of hypersensitivity reactions to betalactams. Allergy, 64(2), 183-193. doi:10.1111/j.1398-9995.2008.01924.xSolensky, R. (2014). Penicillin allergy as a public health measure. Journal of Allergy and Clinical Immunology, 133(3), 797-798. doi:10.1016/j.jaci.2013.10.032Romano, A., Mayorga, C., Torres, M. J., Artesani, M. C., Suau, R., Sánchez, F., … Blanca, M. (2000). Immediate allergic reactions to cephalosporins: Cross-reactivity and selective responses. Journal of Allergy and Clinical Immunology, 106(6), 1177-1183. doi:10.1067/mai.2000.111147Prescott, Jr., W. A., DePestel, D. D., Ellis, J. J., & Regal, R. E. (2004). Incidence of Carbapenem‐Associated Allergic‐Type Reactions among Patients with versus Patients without a Reported Penicillin Allergy. Clinical Infectious Diseases, 38(8), 1102-1107. doi:10.1086/382880Torres, M. J., Ariza, A., Mayorga, C., Doña, I., Blanca-Lopez, N., Rondon, C., & Blanca, M. (2010). Clavulanic acid can be the component in amoxicillin-clavulanic acid responsible for immediate hypersensitivity reactions. Journal of Allergy and Clinical Immunology, 125(2), 502-505.e2. doi:10.1016/j.jaci.2009.11.032Fernandez-Rivas, M., Carral, C. P., Cuevas, M., Marti, C., Moral, A., & Senent, C. J. (1995). Selective allergic reactions to clavulanic acid☆☆☆★. Journal of Allergy and Clinical Immunology, 95(3), 748-750. doi:10.1016/s0091-6749(95)70181-8Baggaley, K. H., Brown, A. G., & Schofield, C. J. (1997). Chemistry and biosynthesis of clavulanic acid and other clavams. Natural Product Reports, 14(4), 309. doi:10.1039/np9971400309Edwards, R. G., Dewdney, J. M., Dobrzanski, R. J., & Lee, D. (1988). Immunogenicity and Allergenicity Studies on Two Beta-Lactam Structures, a Clavam, Clavulanic Acid, and a Carbapenem: Structure-Activity Relationships. International Archives of Allergy and Immunology, 85(2), 184-189. doi:10.1159/000234500Gerberick, G. F., Troutman, J. A., Foertsch, L. M., Vassallo, J. D., Quijano, M., Dobson, R. L. M., … Lepoittevin, J.-P. (2009). Investigation of Peptide Reactivity of Pro-hapten Skin Sensitizers Using a Peroxidase-Peroxide Oxidation System. Toxicological Sciences, 112(1), 164-174. doi:10.1093/toxsci/kfp192Martin, S. F., Esser, P. R., Schmucker, S., Dietz, L., Naisbitt, D. J., Park, B. K., … Sallusto, F. (2010). T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays. Cellular and Molecular Life Sciences, 67(24), 4171-4184. doi:10.1007/s00018-010-0495-3Chipinda, I., Hettick, J. M., & Siegel, P. D. (2011). Haptenation: Chemical Reactivity and Protein Binding. Journal of Allergy, 2011, 1-11. doi:10.1155/2011/839682Schnyder, B., & Pichler, W. J. (2009). Mechanisms of Drug-Induced Allergy. Mayo Clinic Proceedings, 84(3), 268-272. doi:10.4065/84.3.268DiPiro, J. T., Adkinson, N. F., & Hamilton, R. G. (1993). Facilitation of penicillin haptenation to serum proteins. Antimicrobial Agents and Chemotherapy, 37(7), 1463-1467. doi:10.1128/aac.37.7.1463Naisbitt, D. J., Nattrass, R. G., & Ogese, M. O. (2014). In Vitro Diagnosis of Delayed-type Drug Hypersensitivity. Immunology and Allergy Clinics of North America, 34(3), 691-705. doi:10.1016/j.iac.2014.04.009Torres, M. J., Blanca, M., Fernandez, J., Romano, A., Weck, A., … Aberer, W. (2003). Diagnosis of immediate allergic reactions to beta-lactam antibiotics. Allergy, 58(10), 961-972. doi:10.1034/j.1398-9995.2003.00280.xLevine, B. B., & Ovary, Z. (1961). STUDIES ON THE MECHANISM OF THE FORMATION OF THE PENICILLIN ANTIGEN. Journal of Experimental Medicine, 114(6), 875-940. doi:10.1084/jem.114.6.875Perez-Inestrosa, E., Suau, R., Montañez, M. I., Rodriguez, R., Mayorga, C., Torres, M. J., & Blanca, M. (2005). Cephalosporin chemical reactivity and its immunological implications. Current Opinion in Allergy and Clinical Immunology, 5(4), 323-330. doi:10.1097/01.all.0000173788.73401.69Sánchez-Sancho, F., Perez-Inestrosa, E., Suau, R., Montañez, M. I., Mayorga, C., Torres, M. J., … Blanca, M. (2003). Synthesis, characterization and immunochemical evaluation of cephalosporin antigenic determinants. Journal of Molecular Recognition, 16(3), 148-156. doi:10.1002/jmr.621Moreno, F., Blanca, M., Mayorga, C., Terrados, S., Moya, M., Pérez, E., … Carmona, M. J. (1995). Studies of the Specificities of IgE Antibodies Found in Sera from Subjects with Allergic Reactions to Penicillins. International Archives of Allergy and Immunology, 108(1), 74-81. doi:10.1159/000237121De Haan, P., de Jonge, A. J. R., Verbrugge, T., & Boorsma, D. M. (1985). Three Epitope-Specific Monoclonal Antibodies against the Hapten Penicillin. International Archives of Allergy and Immunology, 76(1), 42-46. doi:10.1159/000233659Mayorgaa, C., Obispo, T., Jimeno, L., Blanca, M., Del Prado, J. M., Carreira, J., … Juarez, C. (1995). Epitope mapping of β-lactam antibiotics with the use of monoclonal antibodies. Toxicology, 97(1-3), 225-234. doi:10.1016/0300-483x(94)02983-2Meng, X., Jenkins, R. E., Berry, N. G., Maggs, J. L., Farrell, J., Lane, C. S., … Park, B. K. (2011). Direct Evidence for the Formation of Diastereoisomeric Benzylpenicilloyl Haptens from Benzylpenicillin and Benzylpenicillenic Acid in Patients. Journal of Pharmacology and Experimental Therapeutics, 338(3), 841-849. doi:10.1124/jpet.111.183871BATCHELOR, F. R., DEWDNEY, J. M., & GAZZARD, D. (1965). Penicillin Allergy: The Formation of the Penicilloyl Determinant. Nature, 206(4982), 362-364. doi:10.1038/206362a0Ariza, A., Garzon, D., Abánades, D. R., de los Ríos, V., Vistoli, G., Torres, M. J., … Pérez-Sala, D. (2012). Protein haptenation by amoxicillin: High resolution mass spectrometry analysis and identification of target proteins in serum. Journal of Proteomics, 77, 504-520. doi:10.1016/j.jprot.2012.09.030Blanca, M., Mayorga, C., Sanchez, F., Vega, J. M., Fernandez, J., Juarez, C., … Perez, E. (1991). Differences in serum IgE antibody activity to benzylpenicillin and amoxicillin measured by RAST in a group of penicillin allergic patients. Allergy, 46(8), 632-638. doi:10.1111/j.1398-9995.1991.tb00635.xKelkar, P. S., & Li, J. T.-C. (2001). Cephalosporin Allergy. New England Journal of Medicine, 345(11), 804-809. doi:10.1056/nejmra993637Fasano, M., Curry, S., Terreno, E., Galliano, M., Fanali, G., Narciso, P., … Ascenzi, P. (2005). The extraordinary ligand binding properties of human serum albumin. IUBMB Life (International Union of Biochemistry and Molecular Biology: Life), 57(12), 787-796. doi:10.1080/15216540500404093Ghuman, J., Zunszain, P. A., Petitpas, I., Bhattacharya, A. A., Otagiri, M., & Curry, S. (2005). Structural Basis of the Drug-binding Specificity of Human Serum Albumin. Journal of Molecular Biology, 353(1), 38-52. doi:10.1016/j.jmb.2005.07.075Garzon, D., Ariza, A., Regazzoni, L., Clerici, R., Altomare, A., Sirtori, F. R., … Aldini, G. (2014). Mass Spectrometric Strategies for the Identification and Characterization of Human Serum Albumin Covalently Adducted by Amoxicillin: Ex Vivo Studies. Chemical Research in Toxicology, 27(9), 1566-1574. doi:10.1021/tx500210eKosoglou, T., Statkevich, P., Johnson-Levonas, A. O., Paolini, J. F., Bergman, A. J., & Alton, K. B. (2005). Ezetimibe. Clinical Pharmacokinetics, 44(5), 467-494. doi:10.2165/00003088-200544050-00002Baťová, J., Imramovský, A., HájÍček, J., Hejtmánková, L., & Hanusek, J. (2014). Kinetics and Mechanism of the Base-Catalyzed Rearrangement and Hydrolysis of Ezetimibe. Journal of Pharmaceutical Sciences, 103(8), 2240-2247. doi:10.1002/jps.24070Baťová, J., Imramovský, A., & Hanusek, J. (2015). Aminolysis of ezetimibe. Journal of Pharmaceutical and Biomedical Analysis, 107, 495-500. doi:10.1016/j.jpba.2015.01.019Fischer, M. (1968). Photochemische Reaktionen, IV. Photochemische Fragmentierungen von β-Lactamen. Chemische Berichte, 101(8), 2669-2678. doi:10.1002/cber.19681010809Fabre, H., Ibork, H., & Lerner, D. A. (1994). Photoisomerization Kinetics of Cefuroxime Axetil and Related Compounds. Journal of Pharmaceutical Sciences, 83(4), 553-558. doi:10.1002/jps.2600830422Rossi, E., Abbiati, G., & Pini, E. (1999). Substituted 1-benzyl-4-(benzylidenimino)-4-phenylazetidin-2-ones: Synthesis, thermal and photochemical reactions. Tetrahedron, 55(22), 6961-6970. doi:10.1016/s0040-4020(99)00325-7Gómez-Gallego, M., Alcázar, R., Ramírez, P., Vincente, R., J. Mancheño, M., & A. Sierra, M. (2001). A Study of the Photochemical Isomerization in b-Lactam Rings. HETEROCYCLES, 55(3), 511. doi:10.3987/com-00-9127MUKERJEE, A. K., & SINGH, A. K. (1975). Reactions of Natural and Synthetic β-Lactams. Synthesis, 1975(09), 547-589. doi:10.1055/s-1975-23842Mukerjee, A. K., & Singh, A. K. (1978). β-Lactams: retrospect and prospect. Tetrahedron, 34(12), 1731-1767. doi:10.1016/0040-4020(78)80209-9Pérez-Ruiz, R., Sáez, J. A., Jiménez, M. C., & Miranda, M. A. (2014). Cycloreversion of β-lactams via photoinduced electron transfer. Org. Biomol. Chem., 12(42), 8428-8432. doi:10.1039/c4ob01416bPérez-Ruiz, R., Sáez, J. A., Domingo, L. R., Jiménez, M. C., & Miranda, M. A. (2012). Ring splitting of azetidin-2-ones via radical anions. Organic & Biomolecular Chemistry, 10(39), 7928. doi:10.1039/c2ob26528aZhou, L., Liu, X., Ji, J., Zhang, Y., Wu, W., Liu, Y., … Feng, X. (2014). Regio- and Enantioselective Baeyer–Villiger Oxidation: Kinetic Resolution of Racemic 2-Substituted Cyclopentanones. Organic Letters, 16(15), 3938-3941. doi:10.1021/ol501737aAndersen, M. L., Benneche, T., Undheim, K., de Azevedo, N. R., Ferri, P. H., Pedersen, K. R., … Weinhold, E. G. (1996). Substituent Effects on Homolytic Bond Dissociation Free Energies of Oxygen--Acetyl Bonds in Phenyl Acetates and Nitrogen--Acetyl Bonds in Acetanilides. Acta Chemica Scandinavica, 50, 1045-1049. doi:10.3891/acta.chem.scand.50-1045Dobbins, R. A., Mohammed, K., & Sullivan, D. A. (1988). Pressure and Density Series Equations of State for Steam as Derived from the Haar–Gallagher–Kell Formulation. Journal of Physical and Chemical Reference Data, 17(1), 1-8. doi:10.1063/1.555819Jisha, V. S., Arun, K. T., Hariharan, M., & Ramaiah, D. (2006). Site-Selective Binding and Dual Mode Recognition of Serum Albumin by a Squaraine Dye. Journal of the American Chemical Society, 128(18), 6024-6025. doi:10.1021/ja061301xLucas, L. H., Price, K. E., & Larive, C. K. (2004). Epitope Mapping and Competitive Binding of HSA Drug Site II Ligands by NMR Diffusion Measurements. Journal of the American Chemical Society, 126(43), 14258-14266. doi:10.1021/ja0479538Epps, D. E., Raub, T. J., & Kezdy, F. J. (1995). A General, Wide-Range Spectrofluorometric Method for Measuring the Site-Specific Affinities of Drugs Toward Human Serum Albumin. Analytical Biochemistry, 227(2), 342-350. doi:10.1006/abio.1995.1290Marin, M., Lhiaubet-Vallet, V., & Miranda, M. A. (2011). Site-Dependent Photo-Fries Rearrangement within Serum Albumins. The Journal of Physical Chemistry B, 115(12), 2910-2915. doi:10.1021/jp2009463Li, Z.-M., Wei, C.-W., Zhang, Y., Wang, D.-S., & Liu, Y.-N. (2011). Investigation of competitive binding of ibuprofen and salicylic acid with serum albumin by affinity capillary electrophoresis. Journal of Chromatography B, 879(21), 1934-1938. doi:10.1016/j.jchromb.2011.05.020Aleksic, M., Pease, C. K., Basketter, D. A., Panico, M., Morris, H. R., & Dell, A. (2007). Investigating protein haptenation mechanisms of skin sensitisers using human serum albumin as a model protein. Toxicology in Vitro, 21(4), 723-733. doi:10.1016/j.tiv.2007.01.008Carter, D., He, X., Munson, S., Twigg, P., Gernert, K., Broom, M., & Miller, T. (1989). Three-dimensional structure of human serum albumin. Science, 244(4909), 1195-1198. doi:10.1126/science.2727704Carter, D., & He, X. (1990). Structure of human serum albumin. Science, 249(4966), 302-303. doi:10.1126/science.2374930http://www.ccdc.cam.ac.uk/solutions/csd-discovery/components/gold/Sivertsen, A., Isaksson, J., Leiros, H.-K. S., Svenson, J., Svendsen, J.-S., & Brandsdal, B. (2014). Synthetic cationic antimicrobial peptides bind with their hydrophobic parts to drug site II of human serum albumin. BMC Structural Biology, 14(1), 4. doi:10.1186/1472-6807-14-4Gordon, J. C., Myers, J. B., Folta, T., Shoja, V., Heath, L. S., & Onufriev, A. (2005). H++: a server for estimating pKas and adding missing hydrogens to macromolecules. Nucleic Acids Research, 33(Web Server), W368-W371. doi:10.1093/nar/gki464http://biophysics.cs.vt.edu/H++Curry, S., Mandelkow, H., Brick, P., & Franks, N. (1998). Crystal structure of human serum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites. Nature Structural Biology, 5(9), 827-835. doi:10.1038/1869Sugio, S., Kashima, A., Mochizuki, S., Noda, M., & Kobayashi, K. (1999). Crystal structure of human serum albumin at 2.5 Å resolution. Protein Engineering, Design and Selection, 12(6), 439-446. doi:10.1093/protein/12.6.439Miller, B. R., McGee, T. D., Swails, J. M., Homeyer, N., Gohlke, H., & Roitberg, A. E. (2012). MMPBSA.py: An Efficient Program for End-State Free Energy Calculations. Journal of Chemical Theory and Computation, 8(9), 3314-3321. doi:10.1021/ct300418