The effect of vitamin D and paricalcitol on protein disulfide isomerase

Year 2025, Volume: 29 Issue: 1, 20 - 29

Muhammed Murat Köksal Turgut Şekerler , Azize Şener

Abstract

Protein disulfide isomerase (PDI), a multifunctional protein plays an important role as oxidoreductase, isomerase and chaperone in the cell. Prior studies have identified PDI is highly expressed in many different cancer types and presented as a new potential target for cancer treatment. Here, we investigated vitamin D and its analogue paricalcitol in silico interaction of the human PDI and inhibition of PDI reductase activity in vitro. We observed a non-covalent mechanism where the main skeleton of the vitamin D3 ans paricalcitol sturcture is located at the hydrophobic site in the b' domain of PDI and forms a hydrogen bond with a residue (His138) in tihs domain. They also form multiple weak hydrophobic interactions with various chemical groups of the b' subunit. For the first time, we demonstrate that 1,25-dihydroxyvitamin D3 (1a,25(OH)2 vitamin D3) and paricalcitol inhibit the PDI reductase activity in vitro and their IC50 values are 20.79±1.43 nmol/L and 32.83±3.15 nmol/L respectively. The two compounds can also block the denistrosation activity of PDI.

Keywords

Protein disulfide isomerase, paricalcitol, vitamin D3, molecular docking, activity of enzymes

References

• [1] Veldurthy V, Wei R, Oz L, Dhawan P, Jeon YH, Christakos S. Vitamin D, calcium homeostasis and aging. Bone Res. 2016;4:16041. https://doi.org/10.1038/boneres.2016.41.
• [2] Young MRI, Xiong Y. Influence of vitamin D on cancer risk and treatment: Why the variability? Trends Cancer Res. 2018;13:43-53.
• [3] Pike JW, Meyer MB. The vitamin D receptor: new paradigms for the regulation of gene expression by 1,25 dihydroxyvitamin D3. Rheum Dis Clin North Am. 2012;38(1):13-27. https://doi.org/10.1016/j.rdc.2012.03.004.
• [4] Chichiarelli S, Altieri F, Paglia G, Rubini E, Minacori M, Eufemi M. ERp57/PDIA3: new insight. Cell Mol Biol Lett. 2022;27(1):12. https://doi.org/10.1186/s11658-022-00315-x.
• [5] Richard CL, Farach-Carson MC, Rohe B, Nemere I, Meckling KA. Involvement of 1,25D3-MARRS (membrane associated, rapid response steroid-binding), a novel vitamin D receptor, in growth inhibition of breast cancer cells. Exp Cell Res. 2010;316(5):695-703. https://doi.org/10.1016/j.yexcr.2009.12.015.
• [6] Nemere I, Farach-Carson MC, Rohe B, Sterling TM, Norman AW, Boyan BD, Safford SE. Ribozyme knockdown functionally links a 1,25(OH)2D3 membrane binding protein (1,25D3-MARRS) and phosphate uptake in intestinal cells. Proc Natl Acad Sci U S A. 2004;101(19):7392-7397. https://doi.org/10.1073/pnas.0402207101.
• [7] Ali Khan H, Mutus B. Protein disulfide isomerase a multifunctional protein with multiple physiological roles. Front Chem. 2014;2:70. https://doi.org/10.3389/fchem.2014.00070.
• [8] Fu J, Gao J, Liang Z, Yang D. PDI-Regulated Disulfide Bond Formation in Protein Folding and Biomolecular Assembly. Molecules. 2020;26(1):171. https://doi.org/10.3390/molecules26010171.
• [9] Schulman S, Bendapudi P, Sharda A, Chen V, Bellido-Martin L, Jasuja R, Furie BC, Flaumenhaft R, Furie B. Extracellular Thiol Isomerases and Their Role in Thrombus Formation. Antioxid Redox Signal. 2016;24(1):1-15. https://doi.org/10.1089/ars.2015.6530.
• [10] Galligan JJ, Petersen DR. The human protein disulfide isomerase gene family. Hum Genomics. 2012;6(1):6. https://doi.org/10.1186/1479-7364-6-6.
• [11] Parakh S, Atkin JD. Novel roles for protein disulphide isomerase in disease states: a double edged sword? Front Cell Dev Biol. 2015;3:30. https://doi.org/10.3389/fcell.2015.00030.
• [12] Xu S, Butkevich AN, Yamada R, Zhou Y, Debnath B, Duncan R, Zandi E, Petasis NA, Neamati N. Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment. Proc Natl Acad Sci U S A. 2012;109(40):16348-16353. https://doi.org/10.1073/pnas.1205226109.
• [13] Lee E, Lee DH. Emerging roles of protein disulfide isomerase in cancer. BMB Rep. 2017;50(8):401-410. https://doi.org/10.5483/bmbrep.2017.50.8.107.
• [14] Flaumenhaft R. Protein disulfide isomerase as an antithrombotic target. Trends Cardiovasc Med. 2013;23(7):264-268. https://doi.org/10.1016/j.tcm.2013.03.001.
• [15] Fu XM, Wang P, Zhu BT. Characterization of the estradiol-binding site structure of human pancreas-specific protein disulfide isomerase: indispensable role of the hydrogen bond between His278 and the estradiol 3-hydroxyl group. Biochemistry. 2011;50(1):106-115. https://doi.org/10.1021/bi101451g.
• [16] Adasme MF, Linnemann KL, Bolz SN, Kaiser F, Salentin S, Haupt VJ, Schroeder M. PLIP 2021: expanding the scope of the protein-ligand interaction profiler to DNA and RNA. Nucleic Acids Res. 2021;49(W1):W530-W534. https://doi.org/10.1093/nar/gkab294.
• [17] Bell EW, Zhang Y. DockRMSD: an open-source tool for atom mapping and RMSD calculation of symmetric molecules through graph isomorphism. J Cheminform. 2019;11(1):40. https://doi.org/10.1186/s13321-019-0362-7.
• [18] Hevener KE, Zhao W, Ball DM, Babaoglu K, Qi J, White SW, Lee RE. Validation of molecular docking programs for virtual screening against dihydropteroate synthase. J Chem Inf Model. 2009;49(2):444-460. https://doi.org/10.1021/ci800293n.
• [19] Dickerhof N, Kleffmann T, Jack R, McCormick S. Bacitracin inhibits the reductive activity of protein disulfide isomerase by disulfide bond formation with free cysteines in the substrate-binding domain. FEBS J. 2011;278(12):2034-2043. https://doi.org/10.1111/j.1742-4658.2011.08119.x.
• [20] Sliskovic I, Raturi A, Mutus B. Characterization of the S-denitrosation activity of protein disulfide isomerase. J Biol Chem. 2005;280(10):8733-8741. https://doi.org/10.1074/jbc.m408080200
• [21] Kozlov G, Määttänen P, Thomas DY, Gehring K. A structural overview of the PDI family of proteins. FEBS J. 2010;277(19):3924-3936. https://doi.org/10.1111/j.1742-4658.2010.07793.x.
• [22] Tian G, Xiang S, Noiva R, Lennarz WJ, Schindelin H. The crystal structure of yeast protein disulfide isomerase suggests cooperativity between its active sites. Cell. 2006 ;124(1):61-73. https://doi.org/10.1016/j.cell.2005.10.044. Erratum in: Cell. 2006 Mar 10;124(5):1085-1088.
• [23] Andreu CI, Woehlbier U, Torres M, Hetz C. Protein disulfide isomerases in neurodegeneration: from disease mechanisms to biomedical applications. FEBS Lett. 2012;586(18):2826-2834. https://doi.org/10.1016/j.febslet.2012.07.023.
• [24] Campos JLO, Doratioto TR, Videira NB, Ribeiro Filho HV, Batista FAH, Fattori J, Indolfo NC, Nakahira M, Bajgelman MC, Cvoro A, Laurindo FRM, Webb P, Figueira ACM. Protein Disulfide Isomerase Modulates the Activation of Thyroid Hormone Receptors. Front Endocrinol (Lausanne). 2019;9:784. https://doi.org/10.3389/fendo.2018.00784.
• [25] Stolf BS, Smyrnias I, Lopes LR, Vendramin A, Goto H, Laurindo FR, Shah AM, Santos CX. Protein disulfide isomerase and host-pathogen interaction. ScientificWorldJournal. 2011;11:1749-761. https://doi.org/10.1100/2011/289182.
• [26] Tsibris JC, Hunt LT, Ballejo G, Barker WC, Toney LJ, Spellacy WN. Selective inhibition of protein disulfide isomerase by estrogens. J Biol Chem. 1989;264(24):13967-13970.
• [27] Hoffstrom BG, Kaplan A, Letso R, Schmid RS, Turmel GJ, Lo DC, Stockwell BR. Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins. Nat Chem Biol. 2010;6(12):900-906. https://doi.org/10.1038/nchembio.467.
• [28] Watanabe MM, Laurindo FR, Fernandes DC. Methods of measuring protein disulfide isomerase activity: a critical overview. Front Chem. 2014;2:73. https://doi.org/10.3389/fchem.2014.00073.
• [29] Klett D, Cahoreau C, Villeret M, Combarnous Y. Effect of pharmaceutical potential endocrine disruptor compounds on protein disulfide isomerase reductase activity using di-eosin-oxidized-glutathione. PLoS One. 2010;5(3):e9507. https://doi.org/10.1371/journal.pone.0009507.
• [30] Primm TP, Gilbert HF. Hormone binding by protein disulfide isomerase, a high capacity hormone reservoir of the endoplasmic reticulum. J Biol Chem. 2001;276(1):281-286. https://doi.org/10.1074/jbc.m007670200.
• [31] Bekendam RH, Iyu D, Passam F, Stopa JD, De Ceunynck K, Muse O, Bendapudi PK, Garnier CL, Gopal S, Crescence L, Chiu J, Furie B, Panicot-Dubois L, Hogg PJ, Dubois C, Flaumenhaft R. Protein disulfide isomerase regulation by nitric oxide maintains vascular quiescence and controls thrombus formation. J Thromb Haemost. 2018;16(11):2322-2335. https://doi.org/10.1111/jth.14291.
• [32] Aleva FE, Tunjungputri RN, van der Vorm LN, Li Y, Heijdra YF, Oosting M, Smeekens SP, Jaeger M, Joosten LAB, de Groot PG, Netea MG, van der Ven AJAM, de Mast Q. Platelet Integrin αIIbβ3 Activation is Associated with 25 Hydroxyvitamin D Concentrations in Healthy Adults. Thromb Haemost. 2020;120(5):768-775. https://doi.org/10.1055/s-0040-1709523.
• [33] Sultan M, Twito O, Tohami T, Ramati E, Neumark E, Rashid G. Vitamin D diminishes the high platelet aggregation of type 2 diabetes mellitus patients. Platelets. 2019;30(1):120-125. https://doi.org/10.1080/09537104.2017.1386298.
• [34] Verouti SN, Tsoupras AB, Alevizopoulou F, Demopoulos CA, Iatrou C. Paricalcitol effects on activities and metabolism of platelet activating factor and on inflammatory cytokines in hemodialysis patients. Int J Artif Organs. 2013;36(2):87-96. https://doi.org/10.5301/ijao.5000187.