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Chirality Effect on Cholesterol Modulation of Protein Function

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Cholesterol Modulation of Protein Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1115))

Abstract

Cholesterol is a key steroidal, lipid biomolecule found abundantly in plasma membranes of eukaryotic cells. It is an important structural component of cellular membranes and regulates membrane fluidity and permeability. Cholesterol is also essential for normal functioning of key proteins including ion-channels, G protein-coupled receptors (GPCRs), membrane bound steroid receptors, and receptor kinases. It is thought that cholesterol exerts its actions via specific binding to chiral proteins and lipids as well as through non-specific physiochemical interactions. Distinguishing between the specific and the non-specific interactions can be difficult. Although much remains unclear, progress has been made in recent years by utilizing ent-cholesterol, the enantiomer of natural cholesterol (nat-cholesterol) as a probe. Ent-Cholesterol is the non-superimposable mirror image of nat-cholesterol and exhibits identical physiochemical properties as nat-cholesterol. Hence, if the biological effects of cholesterol result solely due to membrane effects, it is expected that there will be no difference between ent-cholesterol and nat-cholesterol. However, when direct binding with chiral proteins and lipids is involved, the enantiomer is expected to potentially elicit significantly different, measurable effects due to formation of diastereomeric complexes. In this chapter, we have reviewed the literature related to ent-cholesterol and its use as a probe for various biophysical and biological interactions of cholesterol.

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References

  1. Yoder RA, Johnston JN. A case study in biomimetic total synthesis: polyolefin carbocyclizations to terpenes and steroids. Chem Rev. 2005;105(12):4730–56. https://doi.org/10.1021/cr040623l.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Woodward RB, Sondheimer F, Taub D, et al. The total synthesis of steroids. J Am Chem Soc. 1952;74(17):4223–51. https://doi.org/10.1021/ja01137a001.

    Article  CAS  Google Scholar 

  3. Johnson WS, Marshall JA, Keana JFW, et al. Steroid total synthesis—hydrochrysene approach—XVI: racemic conessine, progesterone, cholesterol, and some related natural products. Tetrahedron. 1966;22:541–601.

    Article  Google Scholar 

  4. Keana JFW, Johnson WS. Racemic cholesterol. Steroids. 1964;4(3):457–62.

    Article  CAS  Google Scholar 

  5. Arnett EM, Gold JM. Chiral aggregation phenomena. 4. A search for stereospecific interactions between highly purified enantiomeric and racemic dipalmitoyl phosphatidylcholines and other chiral surfactants in monolayers, vesicles, and gels. J Am Chem Soc. 1982;104(2):636–9. https://doi.org/10.1021/ja00366a054.

    Article  CAS  Google Scholar 

  6. Rychnovsky SD, Mickus DE. Synthesis of ent-cholesterol, the unnatural enantiomer. J Org Chem. 1992;57(9):2732–6. https://doi.org/10.1021/jo00035a036.

    Article  CAS  Google Scholar 

  7. Micheli RA, Hojos ZG, Cohen N, et al. Total syntheses of optically active 19-nor steroids. (+)-Estr-4-ene-3,17-dione and (+)-13.beta.-ethylgon-4-ene-3,17-dione. J Org Chem. 1975;40(6):675–81. https://doi.org/10.1021/jo00894a003.

    Article  PubMed  Google Scholar 

  8. Jiang X, Covey DF. Total synthesis of ent-cholesterol via a steroid C,D-ring side-chain synthon. J Org Chem. 2002;67(14):4893–900.

    Article  CAS  Google Scholar 

  9. Belani JD, Rychnovsky SD. A concise synthesis of ent-Cholesterol. J Org Chem. 2008;73(7):2768–73. https://doi.org/10.1021/jo702694g.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Kumar AS, Covey DF. A new method for the preparation of ent-cholesterol from ent-testosterone. Tetrahedron Lett. 1999;40(5):823–6.

    Article  CAS  Google Scholar 

  11. Westover EJ, Covey DF. First synthesis of ent-desmosterol and its conversion to ent-deuterocholesterol. Steroids. 2003;68(2):159–66.

    Article  CAS  Google Scholar 

  12. McConathy J, Owens MJ. Stereochemistry in drug action. Prim Care Companion J Clin Psychiatry. 2003;5(2):70–3.

    Article  Google Scholar 

  13. Demel RA, Bruckdorfer KR, Van Deenen LLM. The effect of sterol structure on the permeability of lipomes to glucose, glycerol and Rb+. Biochim Biophys Acta Biomembr. 1972;255(1):321–30.

    Article  CAS  Google Scholar 

  14. Demel RA, Bruckdorfer KR, van Deenen LLM. Structural requirements of sterols for the interaction with lecithin at the air-water interface. Biochim Biophys Acta Biomembr. 1972;255(1):311–20.

    Article  CAS  Google Scholar 

  15. Biellmann JF. Enantiomeric steroids: synthesis, physical, and biological properties. Chem Rev. 2003;103(5):2019–33. https://doi.org/10.1021/cr020071b.

    Article  PubMed  CAS  Google Scholar 

  16. Mickus DE, Levitt DG, Rychnovsky SD. Enantiomeric cholesterol as a probe of ion-channel structure. J Am Chem Soc. 1992;114(1):359–60. https://doi.org/10.1021/ja00027a055.

    Article  CAS  Google Scholar 

  17. Richter RK, Mickus DE, Rychnovsky SD, et al. Differential modulation of the antifungal activity of amphotericin B by natural and ent-cholesterol. Bioorg Med Chem Lett. 2004;14(1):115–8.

    Article  CAS  Google Scholar 

  18. Luker GD, Pica CM, Kumar AS, et al. Effects of cholesterol and enantiomeric cholesterol on P-glycoprotein localization and function in low-density membrane domains. Biochemistry. 2000;39(29):8692.

    Article  CAS  Google Scholar 

  19. Palmer M. The family of thiol-activated, cholesterol-binding cytolysins. Toxicon. 2001;39(11):1681–9.

    Article  CAS  Google Scholar 

  20. Zitzer A, Westover EJ, Covey DF, et al. Differential interaction of the two cholesterol-dependent, membrane-damaging toxins, streptolysin O and Vibrio cholerae cytolysin, with enantiomeric cholesterol. FEBS Lett. 2003;553(3):229–31.

    Article  CAS  Google Scholar 

  21. Li Y, Ge M, Ciani L, et al. Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids: implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages. J Biol Chem. 2004;279(35):37030–9. https://doi.org/10.1074/jbc.M405195200.

    Article  PubMed  CAS  Google Scholar 

  22. Got PA, Scherrmann JM. Stereoselectivity of antibodies for the bioanalysis of chiral drugs. Pharm Res. 1997;14(11):1516–23.

    Article  CAS  Google Scholar 

  23. Knox JP, Galfre G. Use of monoclonal antibodies to separate the enantiomers of abscisic acid. Anal Biochem. 1986;155(1):92–4.

    Article  CAS  Google Scholar 

  24. Merav G, David I, Mickus DE, et al. Stereoselective recognition of monolayers of cholesterol, ent-cholesterol, and epicholesterol by an antibody. Chembiochem. 2001;2(4):265–71. https://doi.org/10.1002/1439-7633(20010401)2:4<265::AID-CBIC265>3.0.CO;2-V.

    Article  Google Scholar 

  25. Geva M, Addadi L. Stereospecific and structure specific recognition of two- and three- dimensionally organized surfaces by biological macromolecules. Mol Cryst Liq Cryst. 2003;390(1):57–66. https://doi.org/10.1080/15421400390193413.

    Article  CAS  Google Scholar 

  26. Zhang Y, Yu C, Liu J, et al. Cholesterol is superior to 7-ketocholesterol or 7 alpha-hydroxycholesterol as an allosteric activator for acyl-coenzyme A:cholesterol acyltransferase 1. J Biol Chem. 2003;278(13):11642–7. https://doi.org/10.1074/jbc.M211559200.

    Article  PubMed  CAS  Google Scholar 

  27. Rogers MA, Liu J, Song BL, et al. Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): enzymes with multiple sterols as substrates and as activators. J Steroid Biochem Mol Biol. 2015;151:102–7. https://doi.org/10.1016/j.jsbmb.2014.09.008.

    Article  PubMed  CAS  Google Scholar 

  28. Liu J, Chang CC, Westover EJ, et al. Investigating the allosterism of acyl-CoA:cholesterol acyltransferase (ACAT) by using various sterols: in vitro and intact cell studies. Biochem J. 2005;391(Pt 2):389–97. https://doi.org/10.1042/BJ20050428.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Rogers MA, Liu J, Kushnir MM, et al. Cellular pregnenolone esterification by acyl-CoA:cholesterol acyltransferase. J Biol Chem. 2012;287(21):17483–92. https://doi.org/10.1074/jbc.M111.331306.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Bukiya AN, Belani JD, Rychnovsky S, et al. Specificity of cholesterol and analogs to modulate BK channels points to direct sterol-channel protein interactions. J Gen Physiol. 2011;137(1):93–110. https://doi.org/10.1085/jgp.201010519.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. D’Avanzo N, Hyrc K, Enkvetchakul D, et al. Enantioselective protein-sterol interactions mediate regulation of both prokaryotic and eukaryotic inward rectifier K+ channels by cholesterol. PLoS One. 2011;6(4):e19393. https://doi.org/10.1371/journal.pone.0019393.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Bisen S, Seleverstov O, Belani J, et al. Distinct mechanisms underlying cholesterol protection against alcohol-induced BK channel inhibition and resulting vasoconstriction. Biochim Biophys Acta. 2016;1861(11):1756–66.

    Article  CAS  Google Scholar 

  33. Kristiana I, Luu W, Stevenson J, et al. Cholesterol through the looking glass: ability of its enantiomer also to elicit homeostatic responses. J Biol Chem. 2012;287(40):33897–904. https://doi.org/10.1074/jbc.M112.360537.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Epand RM. Do proteins facilitate the formation of cholesterol-rich domains? Biochim Biophys Acta Biomembr. 2004;1666(1):227–38.

    Article  CAS  Google Scholar 

  35. Westover EJ, Covey DF, Brockman HL, et al. Cholesterol depletion results in site-specific increases in epidermal growth factor receptor phosphorylation due to membrane level effects. Studies with cholesterol enantiomers. J Biol Chem. 2003;278(51):51125–33. https://doi.org/10.1074/jbc.M304332200.

    Article  PubMed  CAS  Google Scholar 

  36. Epand RM, Rychnovsky SD, Belani JD, et al. Role of chirality in peptide-induced formation of cholesterol-rich domains. Biochem J. 2005;390(Pt 2):541–8. https://doi.org/10.1042/BJ20050649.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Lalitha S, Kumar AS, Stine KJ, et al. Enantiospecificity of sterol-lipid interactions: first evidence that the absolute configuration of cholesterol affects the physical properties of cholesterol-sphingomyelin membranes. Chem Commun. 2001;(13):1192–3. https://doi.org/10.1039/B104081M.

  38. Lalitha S, Sampath Kumar A, Stine KJ, et al. Chirality in membranes: first evidence that enantioselective interactions between cholesterol and cell membrane lipids can be a determinant of membrane physical properties. J Supramol Chem. 2001;1(2):53–61.

    Article  CAS  Google Scholar 

  39. Weis RM, McConnell HM. Cholesterol stabilizes the crystal-liquid interface in phospholipid monolayers. J Phys Chem. 1985;89(21):4453–9. https://doi.org/10.1021/j100267a011.

    Article  CAS  Google Scholar 

  40. Alakoskela JM, Sabatini K, Jiang X, et al. Enantiospecific interactions between cholesterol and phospholipids. Langmuir. 2008;24(3):830–6. https://doi.org/10.1021/la702909q.

    Article  PubMed  CAS  Google Scholar 

  41. Bandari S, Chakraborty H, Covey DF, et al. Membrane dipole potential is sensitive to cholesterol stereospecificity: implications for receptor function. Chem Phys Lipids. 2014;184:25–9. https://doi.org/10.1016/j.chemphyslip.2014.09.001.

    Article  PubMed  CAS  Google Scholar 

  42. Jafurulla M, Rao BD, Sreedevi S, et al. Stereospecific requirement of cholesterol in the function of the serotonin1A receptor. Biochim Biophys Acta. 2014;1838(1 Pt B):158–63. https://doi.org/10.1016/j.bbamem.2013.08.015.

    Article  PubMed  CAS  Google Scholar 

  43. Oakes V, Domene C. Stereospecific interactions of cholesterol in a model cell membrane: implications for the membrane dipole potential. J Membr Biol. 2018;251(3):507–19. https://doi.org/10.1007/s00232-018-0016-0.

    Article  PubMed  CAS  Google Scholar 

  44. Vinci G, Xia X, Veitia RA. Preservation of genes involved in sterol metabolism in cholesterol auxotrophs: facts and hypotheses. PLoS One. 2008;3(8):e2883. https://doi.org/10.1371/journal.pone.0002883.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Crowder CM, Westover EJ, Kumar AS, et al. Enantiospecificity of cholesterol function in vivo. J Biol Chem. 2001;276(48):44369–72. https://doi.org/10.1074/jbc.C100535200.

    Article  PubMed  CAS  Google Scholar 

  46. Xu F, Rychnovsky SD, Belani JD, et al. Dual roles for cholesterol in mammalian cells. Proc Natl Acad Sci U S A. 2005;102(41):14551–6. https://doi.org/10.1073/pnas.0503590102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Westover EJ, Lin X, Riehl TE, et al. Rapid transient absorption and biliary secretion of enantiomeric cholesterol in hamsters. J Lipid Res. 2006;47(11):2374–81. https://doi.org/10.1194/jlr.M600165-JLR200.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Thomas Jefferson University, College of Pharmacy, Philadelphia, PA, USA

    Jitendra D. Belani

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  1. Jitendra D. Belani
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Correspondence to Jitendra D. Belani .

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Editors and Affiliations

  1. Department of Chemistry, University of Illinois, Chicago, IL, USA

    Avia Rosenhouse-Dantsker

  2. The University of Tennessee Health Science Center, Memphis, TN, USA

    Anna N. Bukiya

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Belani, J.D. (2019). Chirality Effect on Cholesterol Modulation of Protein Function. In: Rosenhouse-Dantsker, A., Bukiya, A.N. (eds) Cholesterol Modulation of Protein Function. Advances in Experimental Medicine and Biology, vol 1115. Springer, Cham. https://doi.org/10.1007/978-3-030-04278-3_1

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