Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter February 19, 2021

Revisiting the interaction of heme with hemopexin

  • Milena Sophie Detzel , Benjamin Franz Schmalohr , Francèl Steinbock , Marie-Thérèse Hopp , Anuradha Ramoji , Ajay Abisheck Paul George , Ute Neugebauer and Diana Imhof ORCID logo EMAIL logo
From the journal Biological Chemistry

Abstract

In hemolytic disorders, erythrocyte lysis results in massive release of hemoglobin and, subsequently, toxic heme. Hemopexin is the major protective factor against heme toxicity in human blood and currently considered for therapeutic use. It has been widely accepted that hemopexin binds heme with extraordinarily high affinity of <1 pM in a 1:1 ratio. However, several lines of evidence point to a higher stoichiometry and lower affinity than determined 50 years ago. Here, we re-analyzed these data. SPR and UV/Vis spectroscopy were used to monitor the interaction of heme with the human protein. The heme-binding sites of hemopexin were characterized using hemopexin-derived peptide models and competitive displacement assays. We obtained a KD value of 0.32 ± 0.04 nM and the ratio for the interaction was determined to be 1:1 at low heme concentrations and at least 2:1 (heme:hemopexin) at high concentrations. We were able to identify two yet unknown potential heme-binding sites on hemopexin. Furthermore, molecular modelling with a newly created homology model of human hemopexin suggested a possible recruiting mechanism by which heme could consecutively bind several histidine residues on its way into the binding pocket. Our findings have direct implications for the potential administration of hemopexin in hemolytic disorders.


Corresponding author: Diana Imhof, Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121Bonn, Germany, E-mail:
Milena Sophie Detzel and Benjamin Franz Schmalohr contributed equally to this work.

Funding source: Leibniz-Gemeinschaft

Funding source: Rheinische Friedrich-Wilhelms-Universität Bonn

Funding source: Federal Government of Germany

Acknowledgements

The authors would like to thank Sabrina Linden (University of Bonn, Germany) for technical assistance. The authors would like to thank Britta Nubbemeyer for performing MS measurements. Financial support by the University of Bonn is gratefully acknowledged. The Leibniz-IPHT is member of the Leibniz Association and financially supported by the Federal Government of Germany and the State of Thuringia.

  1. Author contributions: D.I. designed and planned the project. M.S.D, B.F.S., and D.I. conceived the study and workflow. M.S.D., M.-T.H., B.F.S., and A.R. performed the experiments and collected the data. M.S.D., B.F.S., A.A.P.G., M.-T.H., A.R., U.N., and D.I. analyzed the data. A.A.P.G. and F.S. performed the computational studies. The manuscript was written through the contribution of all authors.

  2. Research funding: University of Bonn and Federal Government of Germany and State of Thuringia through the Leibniz Association.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

References

Banerjee, R. (1962). Thermodynamic study of the heme-globin association. II. Methemoglobin. Biochim. Biophys. Acta Gen. Subj. 64: 385–395.10.1016/0006-3002(62)90747-3Search in Google Scholar

Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., and Bourne, P.E. (2000). The protein data bank. Nucleic Acids Res. 28: 235–242.10.1093/nar/28.1.235Search in Google Scholar

Böhm, M., Kühl, T., Hardes, K., Coch, R., Arkona, C., Schlott, B., Steinmetzer, T., and Imhof, D. (2012). Synthesis and functional characterization of tridegin and its analogues: inhibitors and substrates of factor XIIIa. ChemMedChem 7: 326–333.10.1002/cmdc.201100405Search in Google Scholar

Brewitz, H.H., Goradia, N., Schubert, E., Galler, K., Kühl, T., Syllwasschy, B.F., Popp, J., Neugebauer, U., Hagelueken, G., Schiemann, O., Ohlenschläger, O., and Imhof, D. (2016). Heme interacts with histidine- and tyrosine-based protein motifs and inhibits enzymatic activity of chloramphenicol acetyltransferase from Escherichia coli. Biochim. Biophys. Acta Gen. Subj. 1860: 1343–1353.10.1016/j.bbagen.2016.03.027Search in Google Scholar

Brewitz, H.H., Hagelueken, G., and Imhof, D. (2017). Structural and functional diversity of transient heme binding to bacterial proteins. Biochim. Biophys. Acta Gen. Subj. 1861: 683–697.10.1016/j.bbagen.2016.12.021Search in Google Scholar

Chen, L., Zhang, X., Chen-Roetling, J., and Regan, R.F. (2011). Increased striatal injury and behavioral deficits after intracerebral hemorrhage in hemopexin knockout mice: laboratory investigation. J. Neurosurg. 114: 1159–1167.10.3171/2010.10.JNS10861Search in Google Scholar

Chen, Y.-C. (2015). Beware of docking! Trends Pharmacol. Sci. 36: 78–95.10.1016/j.tips.2014.12.001Search in Google Scholar

Comer, J. and Zhang, L. (2018). Experimental methods for studying cellular heme signaling. Cells 7: 47.10.3390/cells7060047Search in Google Scholar

Cox, M.C., Le Brun, N., Thomson, A.J., Smith, A., Morgan, W.T., Moore, G.R., Lodge, J.K., Sadler, P.J., Kus, M.L., and Winyard, P.G. (1995). MCD, EPR and NMR spectroscopic studies of rabbit hemopexin and its heme binding domain. Biochim. Biophys. Acta Protein Struct. Mol. Enzymol. 1253: 215–223.10.1016/0167-4838(95)00163-4Search in Google Scholar

Deniau, C., Gilli, R., Izadi-Pruneyre, N., Létoffé, S., Delepierre, M., Wandersman, C., Briand, C., and Lecroisey, A. (2003). Thermodynamics of heme binding to the HasA SM Hemophore: effect of mutations at three key residues for heme uptake. Biochemistry 42: 10627–10633.10.1021/bi030015kSearch in Google Scholar PubMed

Dimitrov, J.D., Roumenina, L.T., Doltchinkova, V.R., Mihaylova, N.M., Lacroix-Desmazes, S., Kaveri, S.V., and Vassilev, T.L. (2007). Antibodies use heme as a cofactor to extend their pathogen elimination activity and to acquire new effector functions. J. Biol. Chem. 282: 26696–26706.10.1074/jbc.M702751200Search in Google Scholar

Dutra, F.F., Alves, L.S., Rodrigues, D., Fernandez, P.L., De Oliveira, R.B., Golenbock, D.T., Zamboni, D.S., and Bozza, M.T. (2014). Hemolysis-induced lethality involves inflammasome activation by heme. Proc. Natl. Acad. Sci. U.S.A. 111: E4110–E4118.10.1073/pnas.1405023111Search in Google Scholar

Eldor, A., and Rachmilewitz, E.A. (2002). The hypercoagulable state in thalassemia. Blood 99: 36–43.10.1182/blood.V99.1.36Search in Google Scholar

Englert, F.A., Seidel, R.A., Galler, K., Gouveia, Z., Soares, M.P., Neugebauer, U., Clemens, M.G., Sponholz, C., Heinemann, S.H., Pohnert, G., Bauer, M., and Weis, S. (2019). Labile heme impairs hepatic microcirculation and promotes hepatic injury. Arch. Biochem. Biophys. 672: 108075.10.1016/j.abb.2019.108075Search in Google Scholar

Faber, H.R., Groom, C.R., Baker, H.M., Morgan, W.T., Smith, A., and Baker, E.N. (1995). 1.8 Å crystal structure of the C-terminal domain of rabbit serum haemopexin. Structure 3: 551–559.10.1016/S0969-2126(01)00189-7Search in Google Scholar

Figueiredo, R.T., Fernandez, P.L., Mourao-Sa, D.S., Porto, B.N., Dutra, F.F., Alves, L.S., Oliveira, M.F., Oliveira, P.L., Graça-Souza, A.V., and Bozza, M.T. (2007). Characterization of heme as activator of toll-like receptor 4. J. Biol. Chem. 282: 20221–20229.10.1074/jbc.M610737200Search in Google Scholar PubMed

Ghosh, A. and Stuehr, D.J. (2019). Hsp90 and its role in heme-maturation of client proteins: implications for human diseases. In: Asea, A. and Kaur, P. (Eds.), Heat shock protein 90 in human Diseases and disorders. Springer, pp. 251–268.10.1007/978-3-030-23158-3_12Search in Google Scholar

Hargrove, M.S., Barrick, D., and Olson, J.S. (1996). The association rate constant for heme binding to globin is independent of protein structure. Biochemistry 35: 11293–11299.10.1021/bi960371lSearch in Google Scholar PubMed

Heimer, P., Tietze, A.A., Bäuml, C.A., Resemann, A., Mayer, F.J., Suckau, D., Ohlenschläger, O., Tietze, D., and Imhof, D. (2018). Conformational μ-conotoxin PIIIA isomers revisited: impact of cysteine pairing on disulfide-bond assignment and structure elucidation. Anal. Chem. 90: 3321–3327.10.1021/acs.analchem.7b04854Search in Google Scholar PubMed

Hooft, R.W.W., Sander, C., Scharf, M., and Vriend, G. (1996a). The PDBFINDER database: a summary of PDB, DSSP and HSSP information with added value. Bioinformatics 12: 525–529.10.1093/bioinformatics/12.6.525Search in Google Scholar PubMed

Hooft, R.W.W., Vriend, G., Sander, C., and Abola, E.E. (1996b). Errors in protein structures. Nature 381: 272.10.1038/381272a0Search in Google Scholar

Hopp, M.-T., Alhanafi, N., Paul George, A.A., Hamedani, N.S., Biswas, A., Oldenburg, J., Pötzsch, B., and Imhof, D. (2021). Molecular insights and functional consequences of the interaction of heme with activated protein C. Antioxid. Redox Signal. 34: 32–48.10.1089/ars.2019.7992Search in Google Scholar

Hrkal, Z., Vodrážka, Z., and Kalousek, I. (1974). Transfer of heme from ferrihemoglobin and ferrihemoglobin isolated chains to hemopexin. Eur. J. Biochem. 43: 73–78.10.1111/j.1432-1033.1974.tb03386.xSearch in Google Scholar

Hub, J.S., De Groot, B.L., Grubmüller, H., and Groenhof, G. (2014). Quantifying artifacts in Ewald simulations of inhomogeneous systems with a net charge. J. Chem. Theor. Comput. 10: 381–390.10.1021/ct400626bSearch in Google Scholar

Humphrey, W., Dalke, A., and Schulten, K. (1996). VMD: visual molecular dynamics. J. Mol. Graph. 14: 33–38.10.1016/0263-7855(96)00018-5Search in Google Scholar

Hvidberg, V., Maniecki, M.B., Jacobsen, C., Højrup, P., Møller, H.J., and Moestrup, S.K. (2005). Identification of the receptor scavenging hemopexin-heme complexes. Blood 106: 2572–2579.10.1182/blood-2005-03-1185Search in Google Scholar PubMed

Igarashi, J., Murase, M., Iizuka, A., Pichierri, F., Martinkova, M., and Shimizu, T. (2008). Elucidation of the heme binding site of heme-regulated eukaryotic initiation factor 2α kinase and the role of the regulatory motif in heme sensing by spectroscopic and catalytic studies of mutant proteins. J. Biol. Chem. 283: 18782–18791.10.1074/jbc.M801400200Search in Google Scholar PubMed

Ingoglia, G., Sag, C.M., Rex, N., De Franceschi, L., Vinchi, F., Cimino, J., Petrillo, S., Wagner, S., Kreitmeier, K., Silengo, L., Altruda, F., Maier, L.S., Hirsch, E., Ghigo, A., and Tolosano, E. (2017). Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress. Free Radic. Biol. Med. 108: 452–464.10.1016/j.freeradbiomed.2017.04.003Search in Google Scholar PubMed

Konagurthu, A.S., Whisstock, J.C., Stuckey, P.J., and Lesk, A.M. (2006). MUSTANG: a multiple structural alignment algorithm. Proteins Struct. Funct. Bioinforma. 64: 559–574.10.1002/prot.20921Search in Google Scholar PubMed

Krieger, E., Darden, T., Nabuurs, S.B., Finkelstein, A., and Vriend, G. (2004). Making optimal use of empirical energy functions: force-field parameterization in crystal space. Proteins Struct. Funct. Bioinformat. 57: 678–683.10.1002/prot.20251Search in Google Scholar PubMed

Krieger, E., Dunbrack, R.L., Hooft, R.W.W., and Krieger, B. (2012). Assignment of protonation states in proteins and ligands: combining pKa prediction with hydrogen bonding network optimization. Methods Mol. Biol.: 405–4210.10.1007/978-1-61779-465-0_25Search in Google Scholar PubMed

Krieger, E. and Vriend, G. (2014). YASARA View – molecular graphics for all devices – from smartphones to workstations. Bioinformatics 30: 2981–2982.10.1093/bioinformatics/btu426Search in Google Scholar PubMed PubMed Central

Krieger, E. and Vriend, G. (2015). New ways to boost molecular dynamics simulations. J. Comput. Chem. 36: 996–1007.10.1002/jcc.23899Search in Google Scholar PubMed PubMed Central

Kühl, T., Sahoo, N., Nikolajski, M., Schlott, B., Heinemann, S.H., and Imhof, D. (2011). Determination of hemin-binding characteristics of proteins by a combinatorial peptide library approach. ChemBioChem 12: 2846–2855.10.1002/cbic.201100556Search in Google Scholar PubMed

Kühl, T., Wißbrock, A., Goradia, N., Sahoo, N., Galler, K., Neugebauer, U., Popp, J., Heinemann, S.H., Ohlenschläger, O., and Imhof, D. (2013). Analysis of Fe(III) heme binding to cysteine-containing heme-regulatory motifs in proteins. ACS Chem. Biol. 8: 1785–1793.10.1021/cb400317xSearch in Google Scholar PubMed

Kumar, A., Wißbrock, A., Bellstedt, P., Lang, A., Ramachandran, R., Wiedemann, C., Imhof, D., and Ohlenschläger, O. (2019). 1H, 13C, and 15N resonance assignments of the cytokine interleukin-36β isoform-2. Biomol. NMR Assign 13: 155–161.10.1007/s12104-018-09869-4Search in Google Scholar PubMed

Kumar, S. and Bandyopadhyay, U. (2005). Free heme toxicity and its detoxification systems in human. Toxicol. Lett. 157: 175–188.10.1016/j.toxlet.2005.03.004Search in Google Scholar PubMed

Langer, M.D., Guo, H., Shashikanth, N., Pierce, J.M., and Leckband, D.E. (2012). N-glycosylation alters cadherin-mediated intercellular binding kinetics. J. Cell Sci. 125: 2478–2485.10.1242/jcs.101147Search in Google Scholar PubMed

Leclerc, J.L., Santiago-Moreno, J., Dang, A., Lampert, A.S., Cruz, P.E., Rosario, A.M., Golde, T.E., and Doré, S. (2018). Increased brain hemopexin levels improve outcomes after intracerebral hemorrhage. J. Cereb. Blood Flow Metab. 38: 1032–1046.10.1177/0271678X16679170Search in Google Scholar PubMed PubMed Central

Lux, A., Yu, X., Scanlan, C.N., and Nimmerjahn, F. (2013). Impact of immune complex size and glycosylation on IgG binding to human FcγRs. J. Immunol. 190: 4315–4323.10.4049/jimmunol.1200501Search in Google Scholar PubMed

Martins, R., Maier, J., Gorki, A.D., Huber, K.V.M., Sharif, O., Starkl, P., Saluzzo, S., Quattrone, F., Gawish, R., Lakovits, K., Aichinger, M.C., Radic-Sarikas, B., Lardeau, C.H., Hladik, A., Korosec, A., Brown, M., Vaahtomeri, K., Duggan, M., Kerjaschki, D., Esterbauer, H., Colinge, J., Eisenbarth, S.C., Decker, T., Bennett, K.L., Kubicek, S., Sixt, M., Superti-Furga, G., and Knapp, S. (2016). Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nat. Immunol. 17: 1361–1372.10.1038/ni.3590Search in Google Scholar

McGuffin, L.J., Bryson, K., and Jones, D.T. (2000). The PSIPRED protein structure prediction server. Bioinformatics 16: 404–405.10.1093/bioinformatics/16.4.404Search in Google Scholar

Montecinos, L., Eskew, J.D., and Smith, A. (2019). What is next in this “age” of heme-driven pathology and protection by hemopexin? An update and links with iron. Pharmaceuticals 12: 144.10.3390/ph12040144Search in Google Scholar

Morgan, W.T., Heng Liem, H., Sutor, R.P., and Muller-Eberhard, U. (1976). Transfer of heme from heme-albumin to hemopexin. Biochem. Biophys. Acta Gen. Subj. 444: 435–445.10.1016/0304-4165(76)90387-1Search in Google Scholar

Morgan, W.T., Smith, A., and Koskelo, P. (1980). The interaction of human serum albumin and hemopexin with porphyrins. Biochim. Biophys. Acta Protein Struct. 624: 271–285.10.1016/0005-2795(80)90246-9Search in Google Scholar

Morgan, W.T., Muster, P., Tatum, F., Kao, S.M., Alam, J., and Smith, A. (1993). Identification of the histidine residues of hemopexin that coordinate with heme-iron and of a receptor-binding region. J. Biol. Chem. 268: 6256–6262.10.1016/S0021-9258(18)53247-6Search in Google Scholar

Morgan, W.T. and Muller-Eberhard, U. (1972). Interactions of porphyrins with rabbit hemopexin. J. Biol. Chem. 247: 7181–7187.10.1016/S0021-9258(19)44611-5Search in Google Scholar

Mrázová, B., Martínková, M., Martínek, V., Frei, E., and Stiborová, M. (2008). Optimalization of preparation of apocytochrome b5 utilizing apo-myoglobin. Interdiscip. Toxicol. 1.10.2478/v10102-010-0037-8Search in Google Scholar PubMed PubMed Central

Nath, K.A., Grande, J.P., Belcher, J.D., Garovic, V.D., Croatt, A.J., Hillestad, M.L., Barry, M.A., Nath, M.C., Regan, R.F., and Vercellotti, G.M. (2020). Antithrombotic effects of heme-degrading and heme-binding proteins. Am. J. Physiol. Circ. Physiol. 318: H671–H681.10.1152/ajpheart.00280.2019Search in Google Scholar PubMed PubMed Central

Noé, R., Bozinovic, N., Lecerf, M., Lacroix-Desmazes, S., and Dimitrov, J.D. (2019). Use of cysteine as a spectroscopic probe for determination of heme-scavenging capacity of serum proteins and whole human serum. J. Pharm. Biomed. Anal. 172: 311–319.10.1016/j.jpba.2019.05.013Search in Google Scholar PubMed

Novoa, E.M., De Pouplana, L.R., Barril, X., and Orozco, M. (2010). Ensemble docking from homology models. J. Chem. Theor. Comput. 6: 2547–2557.10.1021/ct100246ySearch in Google Scholar

Paoli, M., Anderson, B.F., Baker, H.M., Morgan, W.T., Smith, A., and Baker, E.N. (1999). Crystal structure of hemopexin reveals a novel high-affinity heme site formed between two β-propeller domains. Nat. Struct. Biol. 6: 926–931.10.1038/13294Search in Google Scholar

Peherstorfer, S., Brewitz, H.H., Paul George, A.A., Wißbrock, A., Adam, J.M., Schmitt, L., and Imhof, D. (2018). Insights into mechanism and functional consequences of heme binding to hemolysin-activating lysine acyltransferase HlyC from Escherichia coli. Biochim. Biophys. Acta Gen. Subj. 1862: 1964–1972.10.1016/j.bbagen.2018.06.012Search in Google Scholar

Pence, H.E. and Williams, A. (2010). ChemSpider: an online chemical information resource. J. Chem. Educ. 87: 1123–1124.10.1021/ed100697wSearch in Google Scholar

R Core Team (2018). R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing.Search in Google Scholar

Roumenina, L.T., Radanova, M., Atanasov, B.P., Popov, K.T., Kaveri, S.V., Lacroix-Desmazes, S., Frémeaux-Bacchi, V., and Dimitrov, J.D. (2011). Heme interacts with C1q and inhibits the classical complement pathway. J. Biol. Chem. 286: 16459–16469.10.1074/jbc.M110.206136Search in Google Scholar

Roumenina, L.T., Chadebech, P., Bodivit, G., Vieira‐Martins, P., Grunenwald, A., Boudhabhay, I., Poillerat, V., Pakdaman, S., Kiger, L., Jouard, A., Audureau, E., Pirenne, F., Galactéros, F., Frémeaux‐Bacchi, V., and Bartolucci, P. (2020). Complement activation in sickle cell disease: dependence on cell density, hemolysis and modulation by hydroxyurea therapy. Am. J. Hematol. 95: 456–464.10.1002/ajh.25742Search in Google Scholar

Ryan, C.G., Clayton, E., Griffin, W.L., Sie, S.H., and Cousens, D.R. (1988). SNIP, a statistics-sensitive background treatment for the quantitative analysis of PIXE spectra in geoscience applications. Nucl. Instruments Methods Phys. Res. Sect. B Beam Interact. Mater. Atoms 34: 396–402.10.1016/0168-583X(88)90063-8Search in Google Scholar

Satoh, T., Satoh, H., Iwahara, S.I., Hrkal, Z.Z., Peyton, D.H., and Muller-Eberhard, U. (1994). Roles of heme iron-coordinating histidine residues of human hemopexin expressed in baculovirus-infected insect cells. Proc. Natl. Acad. Sci. U.S.A. 91: 8423–8427.10.1073/pnas.91.18.8423Search in Google Scholar PubMed PubMed Central

Schmalohr, B.F., Mustafa, A.M., Krämer, O.H., and Imhof, D. (2020). Structural insights into the interaction of heme with protein tyrosine kinase JAK2**. ChemBioChem, https://doi.org/10.1101/2020.08. 13. 246454.10.1002/cbic.202000730Search in Google Scholar PubMed PubMed Central

Shipulina, N., Smith, A., and Morgan, W.T. (2000). Heme binding by hemopexin: evidence for multiple modes of binding and functional implications. J. Protein Chem. 19: 239–248.10.1023/A:1007016105813Search in Google Scholar

Smith, L.J., Kahraman, A., and Thornton, J.M. (2010). Heme proteins – diversity in structural characteristics, function, and folding. Proteins Struct. Funct. Bioinformat. 78: 2349–2368.10.1002/prot.22747Search in Google Scholar

Smith, A. and Morgan, W.T. (1981). Hemopexin-mediated transport of heme into isolated rat hepatocytes. J. Biol. Chem. 256: 10902–10909.10.1016/S0021-9258(19)68530-3Search in Google Scholar

Stein, P.D., Beemath, A., Meyers, F.A., Skaf, E., and Olson, R.E. (2006). Deep venous thrombosis and pulmonary embolism in hospitalized patients with sickle cell disease. Am. J. Med. 119: 897.e7–897.e11.10.1016/j.amjmed.2006.08.015Search in Google Scholar PubMed

Suzek, B.E., Wang, Y., Huang, H., McGarvey, P.B., and Wu, C.H. (2015). UniRef clusters: a comprehensive and scalable alternative for improving sequence similarity searches. Bioinformatics 31: 926–932.10.1093/bioinformatics/btu739Search in Google Scholar PubMed PubMed Central

Syllwasschy, B.F., Beck, M.S., Družeta, I., Hopp, M.-T., Ramoji, A., Neugebauer, U., Nozinovic, S., Menche, D., Willbold, D., Ohlenschläger, O., Kühl, T., and Imhof, D. (2020). High-affinity binding and catalytic activity of His/Tyr-based sequences: extending heme-regulatory motifs beyond CP. Biochim. Biophys. Acta Gen. Subj. 1864: 129603.10.1016/j.bbagen.2020.129603Search in Google Scholar PubMed

Takahashi, N., Takahashi, Y., and Putnam, F.W. (1984). Structure of human hemopexin: O-glycosyl and N-glycosyl sites and unusual clustering of tryptophan residues. Proc. Natl. Acad. Sci. U.S.A. 81: 2021–2025.10.1073/pnas.81.7.2021Search in Google Scholar PubMed PubMed Central

Takahashi, N., Takahashi, Y., and Putnam, F.W. (1985). Complete amino acid sequence of human hemopexin, the heme-binding protein of serum. Proc. Natl. Acad. Sci. U.S.A. 82: 73–77.10.1073/pnas.82.1.73Search in Google Scholar PubMed PubMed Central

Tang, X.D., Xu, R., Reynolds, M.F., Garcia, M.L., Heinemann, S.H., and Hoshi, T. (2003). Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels. Nature 425: 531–535.10.1038/nature02003Search in Google Scholar PubMed

Tolosano, E., Fagoonee, S., Morello, N., Vinchi, F., and Fiorito, V. (2010). Heme scavenging and the other facets of hemopexin. Antioxidants Redox Signal. 12: 305–320.10.1089/ars.2009.2787Search in Google Scholar PubMed

Trott, O. and Olson, A.J. (2009). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31: 455–461.10.1002/jcc.21334Search in Google Scholar PubMed PubMed Central

Vallelian, F., Schaer, C.A., Deuel, J.W., Ingoglia, G., Humar, R., Buehler, P.W., and Schaer, D.J. (2018). Revisiting the putative role of heme as a trigger of inflammation. Pharmacol. Res. Perspect. 6: e00392.10.1002/prp2.392Search in Google Scholar

Vaught, A. (1996). Graphing with Gnuplot and Xmgr. Linux J. 28: 7.Search in Google Scholar

Vinchi, F., De Franceschi, L., Ghigo, A., Townes, T., Cimino, J., Silengo, L., Hirsch, E., Altruda, F., and Tolosano, E. (2013). Hemopexin therapy improves cardiovascular function by preventing heme-induced endothelial toxicity in mouse models of hemolytic diseases. Circulation 127: 1317–1329.10.1161/CIRCULATIONAHA.112.130179Search in Google Scholar

Vinchi, F., Da Silva, M.C., Ingoglia, G., Petrillo, S., Brinkman, N., Zuercher, A., Cerwenka, A., Tolosano, E., and Muckenthaler, M.U. (2016). Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease. Blood 127: 473–486.10.1182/blood-2015-08-663245Search in Google Scholar

Wagener, F.A.D.T.G., Eggert, A., Boerman, O.C., Oyen, W.J.G., Verhofstad, A., Abraham, N.G., Adema, G., Van Kooyk, Y., De Witte, T., and Figdor, C.G. (2001). Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase. Blood 98: 1802–1811.10.1182/blood.V98.6.1802Search in Google Scholar

Wang, J., Wolf, R.M., Caldwell, J.W., Kollman, P.A., and Case, D.A. (2004). Development and testing of a general Amber force field. J. Comput. Chem. 25: 1157–1174.10.1002/jcc.20035Search in Google Scholar

Wang, L., Vijayan, V., Jang, M.S., Thorenz, A., Greite, R., Rong, S., Chen, R., Shushakova, N., Tudorache, I., Derlin, K., Pradhan, P., Madyaningrana, K., Madrahimov, N., Bräsen, J.H., Lichtinghagen, R., van Kooten, C., Huber-Lang, M., Haller, H., Immenschuh, S., and Gueler, F. (2019). Labile heme aggravates renal inflammation and complement activation after ischemia reperfusion injury. Front. Immunol. 10: 2975.10.3389/fimmu.2019.02975Search in Google Scholar

Waterhouse, A., Bertoni, M., Bienert, S., Studer, G., Tauriello, G., Gumienny, R., Heer, F.T., de Beer, T.A.P., Rempfer, C., Bordoli, L., Lepore, R., and Schwede, T. (2018). SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 46: W296–W303.10.1093/nar/gky427Search in Google Scholar

Winterbourn, C.C. (1995). Toxicity of iron and hydrogen peroxide: the Fenton reaction. Toxicol. Lett. 82–83: 969–974.10.1016/0378-4274(95)03532-XSearch in Google Scholar

Wißbrock, A., Paul George, A.A., Brewitz, H.H., Kühl, T., and Imhof, D. (2019a). The molecular basis of transient heme-protein interactions: analysis, concept and implementation. Biosci. Rep. 39, https://doi.org/10.1042/BSR20181940.Search in Google Scholar

Wißbrock, A., Goradia, N.B., Kumar, A., Paul George, A.A., Kühl, T., Bellstedt, P., Ramachandran, R., Hoffmann, P., Galler, K., Popp, J., Neugebauer, U., Hampel, K., Zimmermann, B., Adam, S., Wiendl, M., Krönke, G., Hamza, I., Heinemann, S.H., Frey, S., Hueber, A.J., Ohlenschläger, O., and Imhof, D. (2019b). Structural insights into heme binding to IL-36α proinflammatory cytokine. Sci. Rep. 9: 16893.10.1038/s41598-019-53231-0Search in Google Scholar PubMed PubMed Central

Wißbrock, A., Goradia, N.B., Kumar, A., Paul George, A.A., Kühl, T., Bellstedt, P., Ramachandra, R., Hoffmann, P., Galler, K., Popp, J., Neugebauer, U., Hampel, K., Zimmermann, B., Adam, S., Wiendl, M., Schett, G., Hamza, I., Heinemann, S.H., Frey, S., Hueber, A.J., Ohlenschläger, O., and Imhof, D. (2019c). Heme regulates human proinflammatory IL-36 cytokines. Sci. Rep. 9: 16893.10.1038/s41598-019-53231-0Search in Google Scholar PubMed PubMed Central

Wu, M.‐L. and Morgan, W.T. (1995). Thermodynamics of heme‐induced conformational changes in hemopexin: role of domain‐domain interactions. Protein Sci. 4: 29–34.10.1002/pro.5560040105Search in Google Scholar PubMed PubMed Central

Yi, L., Morgan, J.T., and Ragsdale, S.W. (2010). Identification of a thiol/disulfide redox switch in the human BK channel that controls its affinity for heme and CO. J. Biol. Chem. 285: 20117–20127.10.1074/jbc.M110.116483Search in Google Scholar PubMed PubMed Central


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2020-0347).


Received: 2020-10-21
Accepted: 2021-02-06
Published Online: 2021-02-19
Published in Print: 2021-05-26

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 28.3.2024 from https://www.degruyter.com/document/doi/10.1515/hsz-2020-0347/html
Scroll to top button