Homocysteine Thiolactone: Biology and Сhemistry: Comparison
Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Alexey Chubarov.

Homocysteine thiolactone is a five-membered cyclic thioester of amino acid homocysteine. It is generated from homocysteine as a result of an error-editing reaction, principally, of methionyl-tRNA synthetase. An elevated level of homocysteine thiolactone is associated with cardiovascular diseases, strokes, atherosclerosis, neurological abnormalities, etc., presumably because it reacts to the side chain of protein lysine causing protein damage and autoimmune responses. It is not only an important metabolite but also a versatile building block for organic and bioorganic synthesis. This entry contains data on the homocysteine thiolactone formation, metabolism, toxicity mechanism in vivo, and the bioorganic chemistry applications as a powerful synthetic tool in polymer science, sustainable materials development, and probes.

  • homocysteine
  • homocysteine thiolactone
  • protein N-homocysteinylation
  • thiolactone chemistry
  • thiolactone building blocks
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References

  1. McCully, K.S. Homocysteine and the pathogenesis of atherosclerosis. Expert Rev. Clin. Pharmacol. 2015, 8, 1–9.
  2. McCully, K.S. The biomedical significance of homocysteine. J. Sci. Explor. 2001, 15, 5–20.
  3. Paganelli, F.; Mottola, G.; Fromonot, J.; Marlinge, M.; Deharo, P.; Guieu, R.; Ruf, J. Hyperhomocysteinemia and cardiovascular disease: Is the adenosinergic system the missing link? Int. J. Mol. Sci. 2021, 22, 1690.
  4. Baggott, J.E.; Tamura, T. Homocysteine, iron and cardiovascular disease: A hypothesis. Nutrients 2015, 7, 1108–1118.
  5. Perła-Kaján, J.; Twardowski, T.; Jakubowski, H.; Perla-Kajan, J.; Twardowski, T.; Jakubowski, H. Mechanisms of homocysteine toxicity in humans. Amino Acids 2007, 32, 561–572.
  6. Wu, L.L.; Wu, J.T. Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker. Clin. Chim. Acta 2002, 322, 21–28.
  7. Smith, A.D.; Refsum, H. Homocysteine–from disease biomarker to disease prevention. J. Intern. Med. 2021.
  8. Rehman, T.; Shabbir, M.A.; Inam-Ur-Raheem, M.; Manzoor, M.F.; Ahmad, N.; Liu, Z.W.; Ahmad, M.H.; Siddeeg, A.; Abid, M.; Aadil, R.M. Cysteine and homocysteine as biomarker of various diseases. Food Sci. Nutr. 2020, 8, 4696–4707.
  9. Tawfik, A.; Mohamed, R.; Elsherbiny, N.; DeAngelis, M.; Bartoli, M.; Al-Shabrawey, M. Homocysteine: A Potential Biomarker for Diabetic Retinopathy. J. Clin. Med. 2019, 8, 121.
  10. Azzini, E.; Ruggeri, S.; Polito, A. Homocysteine: Its possible emerging role in at-risk population groups. Int. J. Mol. Sci. 2020, 21, 1421.
  11. Cordaro, M.; Siracusa, R.; Fusco, R.; Cuzzocrea, S.; Di Paola, R.; Impellizzeri, D. Involvements of hyperhomocysteinemia in neurological disorders. Metabolites 2021, 11, 37.
  12. Škovierová, H.; Vidomanová, E.; Mahmood, S.; Sopková, J.; Drgová, A.; Červeňová, T.; Halašová, E.; Lehotský, J. The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int. J. Mol. Sci. 2016, 17, 1733.
  13. Salvio, G.; Ciarloni, A.; Cutini, M.; Balercia, G. Hyperhomocysteinemia: Focus on endothelial damage as a cause of erectile dysfunction. Int. J. Mol. Sci. 2021, 22, 418.
  14. Veeranki, S.; Tyagi, S.C. Mechanisms of hyperhomocysteinemia induced skeletal muscle myopathy after ischemia in the CBS−/+ mouse model. Int. J. Mol. Sci. 2015, 16, 1252–1265.
  15. McCully, K.S. Chemical pathology of homocysteine. I. Atherogenesis. Ann. Clin. Lab. Sci. 1993, 23, 477–493.
  16. McCully, K.S. Chemical pathology of homocysteine. II. Carcinogenesis and homocysteine thiolactone metabolism. Ann. Clin. Lab. Sci. 1994, 24, 27–59.
  17. McCully, K.S. Chemical pathology of homocysteine III. Cellular function and aging. Ann. Clin. Lab. Sci. 1994, 24, 134–152.
  18. Selhub, J. Homocysteine metabolism. Annu. Rev. Nutr. 1999, 19, 217–246.
  19. Mielech, A.; Puścion-Jakubik, A.; Markiewicz-żukowska, R.; Socha, K. Vitamins in alzheimer’s disease—Review of the latest reports. Nutrients 2020, 12, 3458.
  20. Fratoni, V.; Brandi, M.L. B vitamins, Homocysteine and bone health. Nutrients 2015, 7, 2176–2192.
  21. Moretti, R.; Caruso, P. The controversial role of homocysteine in neurology: From labs to clinical practice. Int. J. Mol. Sci. 2019, 20, 231.
  22. Perła-Kaján, J.; Jakubowski, H. Dysregulation of epigenetic mechanisms of gene expression in the pathologies of hyperhomocysteinemia. Int. J. Mol. Sci. 2019, 20, 3140.
  23. Kowluru, R.A. Diabetic Retinopathy: Mitochondria Caught in a Muddle of Homocysteine. J. Clin. Med. 2020, 9, 3019.
  24. Shirafuji, N.; Hamano, T.; Yen, S.H.; Kanaan, N.M.; Yoshida, H.; Hayashi, K.; Ikawa, M.; Yamamura, O.; Kuriyama, M.; Nakamoto, Y. Homocysteine increases tau phosphorylation, truncation and oligomerization. Int. J. Mol. Sci. 2018, 19, 891.
  25. Kaplan, P.; Tatarkova, Z.; Sivonova, M.K.; Racay, P.; Lehotsky, J. Homocysteine and mitochondria in cardiovascular and cerebrovascular systems. Int. J. Mol. Sci. 2020, 21, 7698.
  26. Tóthová, B.; Kovalská, M.; Kalenská, D.; Tomašcová, A.; Lehotský, J. Histone hyperacetylation as a response to global brain ischemia associated with hyperhomocysteinemia in rats. Int. J. Mol. Sci. 2018, 19, 3147.
  27. Jakubowski, H. Quality control in tRNA charging—Editing of homocysteine. Acta Biochim. Pol. 2011, 58, 149–163.
  28. Jakubowski, H. Aminoacyl-tRNA Synthetases and the Evolution of Coded Peptide Synthesis: The Thioester World. FEBS Lett. 2016, 590, 469–481.
  29. Jakubowski, H. Homocysteine Editing, Thioester Chemistry, Coenzyme A, and the Origin of Coded Peptide Synthesis. Life 2017, 7, 6.
  30. Jakubowski, H. Homocysteine in Protein Structure/Function and Human Disease; Springer: Wien, Austria, 2013.
  31. Jakubowski, H. Homocysteine modification in protein structure/function and human disease. Physiol. Rev. 2019, 99, 555–604.
  32. Jakubowski, H.; Głowacki, R. Chemical Biology of Homocysteine Thiolactone and Related Metabolites. Adv. Clin. Chem. 2011, 55, 81–103.
  33. Jakubowski, H. The molecular basis of homocysteine thiolactone-mediated vascular disease. Clin. Chem. Lab. Med. 2007, 45, 1704–1716.
  34. Jakubowski, H. Molecular basis of homocysteine toxicity in humans. Cell. Mol. Life Sci. 2004, 61, 470–487.
  35. Chwatko, G.; Boers, G.H.J.; Strauss, K.A.; Shih, D.M.; Jakubowski, H. Mutations in methylenetetrahydrofolate reductase or cystathionine beta-synthase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice. FASEB J. 2007, 21, 1707–1713.
  36. Jakubowski, H. The pathophysiological hypothesis of homocysteine thiolactone mediated vascular disease. J. Physiol. Pharmacol. 2008, 59, 155–167.
  37. Gątarek, P.; Rosiak, A.; Borowczyk, K.; Głowacki, R.; Kałuzna-Czaplińska, J. Higher levels of low molecular weight sulfur compounds and homocysteine thiolactone in the urine of autistic children. Molecules 2020, 25, 973.
  38. Jakubowski, H. Mechanism of the condensation of homocysteine thiolactone with aldehydes. Chem. Eur. J. 2006, 12, 8039–8043.
  39. Zimny, J.J.; Sikora, M.; Guranowski, A.; Jakubowski, H. Protective mechanisms against homocysteine toxicity: The role of bleomycin hydrolase. J. Biol. Chem. 2006, 281, 22485–22492.
  40. Zang, T. Analysis of Protein Modifications: Protein N-Homocysteinylation and Covalent Inhibition of the Luxs Enzyme by Brominated Furanones; Northeastern University: Boston, MA, USA, 2012.
  41. Gurda, D.; Handschuh, L.; Kotkowiak, W.; Jakubowski, H. Homocysteine thiolactone and N-homocysteinylated protein induce proatherogenic changes in gene expression in human vascular endothelial cells. Amino Acids 2015, 47, 1319–1339.
  42. Paoli, P.; Sbrana, F.; Tiribilli, B.; Caselli, A.; Pantera, B.; Cirri, P.; De Donatis, A.; Formigli, L.; Nosi, D.; Manao, G.; et al. Protein N-homocysteinylation induces the formation of toxic amyloid-like protofibrils. J. Mol. Biol. 2010, 400, 889–907.
  43. Chubarov, A.; Spitsyna, A.; Krumkacheva, O.; Mitin, D.; Suvorov, D.; Tormyshev, V.; Fedin, M.; Bowman, M.K.; Bagryanskaya, E. Reversible Dimerization of Human Serum Albumin. Molecules 2021, 26, 108.
  44. Glowacki, R.; Jakubowski, H. Cross-talk between Cys34 and lysine residues in human serum albumin revealed by N-homocysteinylation. J. Biol. Chem. 2004, 279, 10864–10871.
  45. Sibrian-Vazquez, M.; Escobedo, J.O.; Lim, S.; Samoei, G.K.; Strongin, R.M. Homocystamides promote free-radical and oxidative damage to proteins. Proc. Natl. Acad. Sci. USA 2010, 107, 551–554.
  46. Sharma, G.S.; Kumar, T.; Dar, T.A.; Singh, L.R. Protein N-homocysteinylation: From cellular toxicity to neurodegeneration. Biochim. Biophys. Acta Gen. Subj. 2015, 1850, 2239–2245.
  47. Chubarov, A.S.; Zakharova, O.D.; Koval, O.A.; Romaschenko, A.V.; Akulov, A.E.; Zavjalov, E.L.; Razumov, I.A.; Koptyug, I.V.; Knorre, D.G.; Godovikova, T.S. Design of protein homocystamides with enhanced tumor uptake properties for 19F magnetic resonance imaging. Bioorg. Med. Chem. 2015, 23, 6943–6954.
  48. Włoczkowska, O.; Perła-Kaján, J.; Smith, A.D.; Jager, C.; Refsum, H.; Jakubowski, H. Anti-N-homocysteineprotein autoantibodies are associated with impaired cognition. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2021, 7, e12159.
  49. Frank, D.; Espeel, P.; Claessens, S.; Mes, E.; Du Prez, F.E. Synthesis of thiolactone building blocks as potential precursors for sustainable functional materials. Tetrahedron 2016, 72, 6616–6625.
  50. Leichner, C.; Jelkmann, M.; Bernkop-Schnürch, A. Thiolated polymers: Bioinspired polymers utilizing one of the most important bridging structures in nature. Adv. Drug Deliv. Rev. 2019, 151–152, 191–221.
  51. Espeel, P.; Prez, F. One-pot double modification of polymers based on thiolactone chemistry. Adv. Polym. Sci. 2015, 269, 105–132.
  52. Espeel, P.; Du Prez, F.E. One-pot multi-step reactions based on thiolactone chemistry: A powerful synthetic tool in polymer science. Eur. Polym. J. 2015, 62, 247–272.
  53. Chubarov, A.S.; Shakirov, M.M.; Koptyug, I.V.; Sagdeev, R.Z.; Knorre, D.G.; Godovikova, T.S. Synthesis and characterization of fluorinated homocysteine derivatives as potential molecular probes for 19F magnetic resonance spectroscopy and imaging. Bioorg. Med. Chem. Lett. 2011, 21, 4050–4053.
  54. Lisitskiy, V.A.; Khan, H.; Popova, T.V.; Chubarov, A.S.; Zakharova, O.D.; Akulov, A.E.; Shevelev, O.B.; Zavjalov, E.L.; Koptyug, I.V.; Moshkin, M.P.; et al. Multifunctional human serum albumin-therapeutic nucleotide conjugate with redox and pH-sensitive drug release mechanism for cancer theranostics. Bioorg. Med. Chem. Lett. 2017, 27, 3925–3930.
  55. Popova, T.V.; Khan, H.; Chubarov, A.S.; Lisitskiy, V.A.; Antonova, N.M.; Akulov, A.E.; Shevelev, O.B.; Zavjalov, E.L.; Silnikov, V.N.; Ahmad, S.; et al. Biotin-decorated anti-cancer nucleotide theranostic conjugate of human serum albumin: Where the seed meets the soil? Bioorg. Med. Chem. Lett. 2018, 28, 260–264.
  56. Dobrynin, S.; Kutseikin, S.; Morozov, D.; Krumkacheva, O.; Spitsyna, A.; Gatilov, Y.; Silnikov, V.; Angelovski, G.; Bowman, M.K.; Kirilyuk, I.; et al. Human Serum Albumin Labelled with Sterically-Hindered Nitroxides as Potential MRI Contrast Agents. Molecules 2020, 25, 1709.
  57. Vigneaud, V.; Patterson, W.I.; Hunt, M. Opeining of the ring of the thiolactone of homocysteine. J. Biol. Chem 1938, 126, 217–231.
  58. Leichert, L.I.; Dick, T.P. Incidence and physiological relevance of protein thiol switches. Biol. Chem. 2015, 396, 389–399.
  59. Zeida, A.; Guardia, C.M.; Lichtig, P.; Perissinotti, L.L.; Defelipe, L.A.; Turjanski, A.; Radi, R.; Trujillo, M.; Estrin, D.A. Thiol redox biochemistry: Insights from computer simulations. Biophys. Rev. 2014, 6, 27–46.
  60. Torres, M.; Forman, H.J. Signal transduction: Thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers. Encycl. Respir. Med. Four-Vol. Set 2006, 10–18.
  61. Essex, D.W. The role of thiols and disulfides in platelet function. Antioxid. Redox Signal. 2004, 6, 736–746.
  62. Chubarov, A. Albumin Conjugates as MRI Agents. Encycl. Platf. 2021. Available online: (accessed on 25 May 2021).
  63. Belinskaia, D.A.; Voronina, P.A.; Batalova, A.A.; Goncharov, N. V Serum Albumin. Encyclopedia 2021, 1, 65–75.
  64. Fanali, G.; di Masi, A.; Trezza, V.; Marino, M.; Fasano, M.; Ascenzi, P. Human serum albumin: From bench to bedside. Mol. Aspects Med. 2012, 33, 209–290.
  65. Elsadek, B.; Kratz, F. Impact of albumin on drug delivery—New applications on the horizon. J. Control. Release 2012, 157, 4–28.
  66. Otagiri, M.; Giam Chuang, V.T. Albumin in medicine: Pathological and clinical applications. Albumin Med. Pathol. Clin. Appl. 2016, 1–277.
  67. Loureiro, A.; Azoia, N.G.; Gomes, A.C.; Cavaco-Paulo, A. Albumin-Based Nanodevices as Drug Carriers. Curr. Pharm. Des. 2016, 22, 1371–1390.
  68. Ruiz-Cabello, J.; Barnett, B.P.; Bottomley, P.A.; Bulte, J.W.M. Fluorine 19F MRS and MRI in biomedicine. NMR Biomed. 2011, 24, 114–129.
  69. Nguyen, H.V.T.; Detappe, A.; Harvey, P.; Gallagher, N.; Mathieu, C.; Agius, M.P.; Zavidij, O.; Wang, W.; Jiang, Y.; Rajca, A.; et al. Pro-organic radical contrast agents (“pro-ORCAs”) for real-time MRI of pro-drug activation in biological systems. Polym. Chem. 2020, 11, 4768–4779.
  70. Dharmarwardana, M.; Martins, A.F.; Chen, Z.; Palacios, P.M.; Nowak, C.M.; Welch, R.P.; Li, S.; Luzuriaga, M.A.; Bleris, L.; Pierce, B.S.; et al. Nitroxyl Modified Tobacco Mosaic Virus as a Metal-Free High- Relaxivity MRI and EPR Active Superoxide Sensor. Physiol. Behav. 2017, 176, 139–148.
  71. Soikkeli, M.; Horkka, K.; Moilanen, J.O.; Timonen, M.; Kavakka, J.; Heikkinen, S. Synthesis, stability and relaxivity of teepo-met: An organic radical as a potential tumour targeting contrast agent for magnetic resonance imaging. Molecules 2018, 23, 1034.
  72. Nguyen, H.V.T.; Chen, Q.; Paletta, J.T.; Harvey, P.; Jiang, Y.; Zhang, H.; Boska, M.D.; Ottaviani, M.F.; Jasanoff, A.; Rajca, A.; et al. Nitroxide-Based Macromolecular Contrast Agents with Unprecedented Transverse Relaxivity and Stability for Magnetic Resonance Imaging of Tumors. ACS Cent. Sci. 2017, 3, 800–811.
  73. Nguyen, H.V.T.; Detappe, A.; Gallagher, N.M.; Zhang, H.; Harvey, P.; Yan, C.; Mathieu, C.; Golder, M.R.; Jiang, Y.; Ottaviani, M.F.; et al. Triply Loaded Nitroxide Brush-Arm Star Polymers Enable Metal-Free Millimetric Tumor Detection by Magnetic Resonance Imaging. ACS Nano 2018, 12, 11343–11354.
  74. Sannikova, N.E.; Timofeev, I.O.; Chubarov, A.S.; Lebedeva, N.S.; Semeikin, A.S.; Kirilyuk, I.A.; Tsentalovich, Y.P.; Fedin, M.V.; Bagryanskaya, E.G.; Krumkacheva, O.A. Application of EPR to porphyrin-protein agents for photodynamic therapy. J. Photochem. Photobiol. B Biol. 2020.
  75. Tormyshev, V.; Chubarov, A.; Krumkacheva, O.; Trukhin, D.; Rogozhnikova, O.; Spitsina, A.; Kuzhelev, A.; Koval, V.; Fedin, M.; Bowman, M.; et al. A Methanethiosulfonate Derivative of OX063 Trityl: A Promising and Efficient Reagent for SDSL of Proteins. Chem. Eur. J. 2020, 26, 1–9.
  76. Krumkacheva, O.A.; Timofeev, I.O.; Politanskaya, L.V.; Polienko, Y.F.; Tretyakov, E.V.; Rogozhnikova, O.Y.; Trukhin, D.V.; Tormyshev, V.M.; Chubarov, A.S.; Bagryanskaya, E.G.; et al. Triplet Fullerenes as Prospective Spin Labels for Nanoscale Distance Measurements by Pulsed Dipolar EPR. Angew. Chem. Int. Ed. 2019, 58, 13271–13275.
  77. Qin, P.Z.; Haworth, I.S.; Cai, Q.; Kusnetzow, A.K.; Grant, G.P.; Price, E.A.; Sowa, G.Z.; Popova, A.; Herreros, B.; He, H. Measuring nanometer distances in nucleic acids using a sequence-independent nitroxide probe. Nat. Protoc. 2007, 2, 2354–2365.
  78. History, B. Nitroxides; Springer International Publishing: Berlin/Heidelberg, Germany, 2020; ISBN 9783030348212.
  79. Sikora, M.; Marczak, Ł.; Kubalska, J.; Graban, A.; Jakubowski, H. Identification of N-homocysteinylation sites in plasma proteins. Amino Acids 2014, 46, 235–244.
  80. Marczak, L.; Sikora, M.; Stobiecki, M.; Jakubowski, H. Analysis of site-specific N-homocysteinylation of human serum albumin in vitro and in vivo using MALDI-ToF and LC-MS/MS mass spectrometry. J. Proteom. 2011, 74, 967–974.
  81. Sikora, M.; Marczak, Ł.; Twardowski, T.; Stobiecki, M.; Jakubowski, H. Direct monitoring of albumin lysine-525 N-homocysteinylation in human serum by liquid chromatography/mass spectrometry. Anal. Biochem. 2010, 405, 132–134.
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