Skip to main content

Advertisement

SpringerLink
Log in

Mechanisms of homocysteine toxicity in humans

  • Review Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Summary.

Homocysteine, a non-protein amino acid, is an important risk factor for ischemic heart disease and stroke in humans. This review provides an overview of homocysteine influence on endothelium function as well as on protein metabolism with a special respect to posttranslational modification of protein with homocysteine thiolactone. Homocysteine is a pro-thrombotic factor, vasodilation impairing agent, pro-inflammatory factor and endoplasmatic reticulum-stress inducer. Incorporation of Hcy into protein via disulfide or amide linkages (S-homocysteinylation or N-homocysteinylation) affects protein structure and function. Protein N-homocysteinylation causes cellular toxicity and elicits autoimmune response, which may contribute to atherogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

APC:

activated protein C

BLH:

bleomycin hydrolase

ER:

endoplasmatic reticulum

HDL:

high density lipoprotein

HTL:

homocysteine thiolactone

LDL:

low density lipoprotein

MetRS:

methionyl-tRNA synthetase

MS:

methionine synthase

PON:

paraoxonase

SAH:

S-adenosylhomocysteine

SAM:

S-adenosylmethionine

TPA:

tissue plasminogen activator

UPR:

unfolded protein response

VEGF:

vascular endothelial growth factor

References

  • SF Abcouwer PL Marjon RK Loper DL Vander Jagt (2002) ArticleTitleResponse of VEGF expression to amino acid deprivation and inducers of endoplasmic reticulum stress Invest Ophthalmol Vis Sci 43 2791–2798 Occurrence Handle12147617

    PubMed  Google Scholar 

  • JL Anderson JB Muhlestein BD Horne JF Carlquist TL Bair TE Madsen RR Pearson (2000) ArticleTitlePlasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease Circulation 102 1227–1232 Occurrence Handle10982535 Occurrence Handle1:CAS:528:DC%2BD3cXntFCgtrk%3D

    PubMed  CAS  Google Scholar 

  • RC Austin SR Lentz GH Werstuck (2004) ArticleTitleRole of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease Cell Death Differ 11 IssueIDSuppl 1 S56–S64 Occurrence Handle15243582 Occurrence Handle10.1038/sj.cdd.4401451 Occurrence Handle1:CAS:528:DC%2BD2cXlsFelu7w%3D

    Article  PubMed  CAS  Google Scholar 

  • JA Berliner M Navab AM Fogelman JS Frank LL Demer PA Edwards AD Watson AJ Lusis (1995) ArticleTitleAtherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics Circulation 91 2488–2496 Occurrence Handle7729036 Occurrence Handle1:CAS:528:DyaK2MXlvFCrsrY%3D

    PubMed  CAS  Google Scholar 

  • CJ Binder MK Chang PX Shaw YI Miller K Hartvigsen A Dewan JL Witztum (2002) ArticleTitleInnate and acquired immunity in atherogenesis Nat Med 8 1218–1226 Occurrence Handle12411948 Occurrence Handle10.1038/nm1102-1218 Occurrence Handle1:CAS:528:DC%2BD38XotlWmu74%3D

    Article  PubMed  CAS  Google Scholar 

  • JT Brosnan RL Jacobs LM Stead ME Brosnan (2004) ArticleTitleMethylation demand: a key determinant of homocysteine metabolism Acta Biochim Pol 51 405–413 Occurrence Handle15218538 Occurrence Handle1:CAS:528:DC%2BD2cXnslWjt7g%3D

    PubMed  CAS  Google Scholar 

  • DC Carter JX Ho (1994) ArticleTitleStructure of serum albumin Adv Protein Chem 45 153–203 Occurrence Handle8154369 Occurrence Handle1:CAS:528:DyaK2cXltVajtLk%3D

    PubMed  CAS  Google Scholar 

  • V Cavalca G Cighetti F Bamonti A Loaldi L Bortone C Novembrino M De Franceschi R Belardinelli MD Guazzi (2001) ArticleTitleOxidative stress and homocysteine in coronary artery disease Clin Chem 47 887–892 Occurrence Handle11325893 Occurrence Handle1:CAS:528:DC%2BD3MXjsVaksb4%3D

    PubMed  CAS  Google Scholar 

  • JC Chambers OA Obeid JS Kooner (1999) ArticleTitlePhysiological increments in plasma homocysteine induce vascular endothelial dysfunction in normal human subjects Arterioscler Thromb Vasc Biol 19 2922–2927 Occurrence Handle10591670 Occurrence Handle1:CAS:528:DC%2BD3cXivVantw%3D%3D

    PubMed  CAS  Google Scholar 

  • G Chwatko H Jakubowski (2005a) ArticleTitleThe determination of homocysteine-thiolactone in human plasma Anal Biochem 337 271–277 Occurrence Handle10.1016/j.ab.2004.11.035 Occurrence Handle1:CAS:528:DC%2BD2MXhtVKiu7Y%3D

    Article  CAS  Google Scholar 

  • G Chwatko H Jakubowski (2005b) ArticleTitleUrinary excretion of homocysteine-thiolactone in humans Clin Chem 51 408–415 Occurrence Handle10.1373/clinchem.2004.042531 Occurrence Handle1:CAS:528:DC%2BD2MXhtVGgsrg%3D

    Article  CAS  Google Scholar 

  • P Daneshvar M Yazdanpanah C Cuthbert DE Cole (2003) ArticleTitleQuantitative assay of plasma homocysteine thiolactone by gas chromatography/mass spectrometry Rapid Commun Mass Spectrom 17 358–362 Occurrence Handle12569447 Occurrence Handle10.1002/rcm.915 Occurrence Handle1:CAS:528:DC%2BD3sXhtlGjtLw%3D

    Article  PubMed  CAS  Google Scholar 

  • K Demuth V Atger D Borderie MO Benoit D Sauvaget S Lotersztajn N Moatti (1999) ArticleTitleHomocysteine decreases endothelin-1 production by cultured human endothelial cells Eur J Biochem 263 367–376 Occurrence Handle10406944 Occurrence Handle10.1046/j.1432-1327.1999.00496.x Occurrence Handle1:CAS:528:DyaK1MXltVertrY%3D

    Article  PubMed  CAS  Google Scholar 

  • M den Heijer T Koster HJ Blom GM Bos E Briet PH Reitsma JP Vandenbroucke FR Rosendaal (1996) ArticleTitleHyperhomocysteinemia as a risk factor for deep-vein thrombosis N Engl J Med 334 759–762 Occurrence Handle8592549 Occurrence Handle10.1056/NEJM199603213341203 Occurrence Handle1:STN:280:BymC2s3os1I%3D

    Article  PubMed  CAS  Google Scholar 

  • S Drunat N Moatti JL Paul A Cogny MO Benoit K Demuth (2001) ArticleTitleHomocysteine-induced decrease in endothelin-1 production is initiated at the extracellular level and involves oxidative products Eur J Biochem 268 5287–5294 Occurrence Handle11606190 Occurrence Handle10.1046/j.0014-2956.2001.02460.x Occurrence Handle1:CAS:528:DC%2BD3MXnvFShurg%3D

    Article  PubMed  CAS  Google Scholar 

  • E Ferguson S Parthasarathy J Joseph B Kalyanaraman (1998) ArticleTitleGeneration and initial characterization of a novel polyclonal antibody directed against homocysteine thiolactone-modified low density lipoprotein J Lipid Res 39 925–933 Occurrence Handle9555955 Occurrence Handle1:CAS:528:DyaK1cXitlygsr4%3D

    PubMed  CAS  Google Scholar 

  • G Ferretti T Bacchetti E Marotti G Curatola (2003) ArticleTitleEffect of homocysteinylation on human high-density lipoproteins: a correlation with paraoxonase activity Metabolism 52 146–151 Occurrence Handle12601623 Occurrence Handle10.1053/meta.2003.50033 Occurrence Handle1:CAS:528:DC%2BD3sXhtlCltr8%3D

    Article  PubMed  CAS  Google Scholar 

  • R Glowacki H Jakubowski (2004) ArticleTitleCross-talk between Cys34 and lysine residues in human serum albumin revealed by N-homocysteinylation J Biol Chem 279 10864–10871 Occurrence Handle14701829 Occurrence Handle10.1074/jbc.M313268200 Occurrence Handle1:CAS:528:DC%2BD2cXitFyitL0%3D

    Article  PubMed  CAS  Google Scholar 

  • KA Hajjar (1993) ArticleTitleHomocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor J Clin Invest 91 2873–2879 Occurrence Handle8390492 Occurrence Handle1:CAS:528:DyaK3sXltFChtrs%3D

    PubMed  CAS  Google Scholar 

  • KA Hajjar L Mauri AT Jacovina F Zhong UA Mirza JC Padovan BT Chait (1998) ArticleTitleTissue plasminogen activator binding to the annexin II tail domain. Direct modulation by homocysteine J Biol Chem 273 9987–9993 Occurrence Handle9545344 Occurrence Handle10.1074/jbc.273.16.9987 Occurrence Handle1:CAS:528:DyaK1cXivVOrsLo%3D

    Article  PubMed  CAS  Google Scholar 

  • RF Huang SM Huang BS Lin JS Wei TZ Liu (2001) ArticleTitleHomocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells Life Sci 68 2799–2811 Occurrence Handle11432446 Occurrence Handle10.1016/S0024-3205(01)01066-9 Occurrence Handle1:CAS:528:DC%2BD3MXksFGnt7g%3D

    Article  PubMed  CAS  Google Scholar 

  • B Hultberg A Andersson A Isaksson (1998) ArticleTitleProtein binding of homocysteine and other thiols in HeLa cell cultures after addition of homocysteine and copper ions Clin Chim Acta 269 175–184 Occurrence Handle9526676 Occurrence Handle10.1016/S0009-8981(97)00197-6 Occurrence Handle1:CAS:528:DyaK1cXot1yqsw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • B Hultberg A Andersson A Isaksson (2000) ArticleTitleHypomethylation as a cause of homocysteine-induced cell damage in human cell lines Toxicology 147 69–75 Occurrence Handle10874154 Occurrence Handle10.1016/S0300-483X(00)00189-X Occurrence Handle1:CAS:528:DC%2BD3cXktlKmtb0%3D

    Article  PubMed  CAS  Google Scholar 

  • R Humbert DA Adler CM Disteche C Hassett CJ Omiecinski CE Furlong (1993) ArticleTitleThe molecular basis of the human serum paraoxonase activity polymorphism Nat Genet 3 73–76 Occurrence Handle8098250 Occurrence Handle10.1038/ng0193-73 Occurrence Handle1:CAS:528:DyaK3sXpsFCitQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • DW Jacobsen (1998) ArticleTitleHomocysteine and vitamins in cardiovascular disease Clin Chem 44 1833–1843 Occurrence Handle9702993 Occurrence Handle1:CAS:528:DyaK1cXlsVajt7Y%3D

    PubMed  CAS  Google Scholar 

  • DW Jacobsen O Catanescu PM Dibello JC Barbato (2005) ArticleTitleMolecular targeting by homocysteine: a mechanism for vascular pathogenesis Clin Chem Lab Med 43 1076–1083 Occurrence Handle16197301 Occurrence Handle10.1515/CCLM.2005.188 Occurrence Handle1:CAS:528:DC%2BD2MXhtFyjsr7J

    Article  PubMed  CAS  Google Scholar 

  • H Jakubowski (1997) ArticleTitleMetabolism of homocysteine thiolactone in human cell cultures. Possible mechanism for pathological consequences of elevated homocysteine levels J Biol Chem 272 1935–1942 Occurrence Handle8999883 Occurrence Handle1:CAS:528:DyaK2sXls12qug%3D%3D

    PubMed  CAS  Google Scholar 

  • H Jakubowski (1999) ArticleTitleProtein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels Faseb J 13 2277–2283 Occurrence Handle10593875 Occurrence Handle1:CAS:528:DyaK1MXotVKitbs%3D

    PubMed  CAS  Google Scholar 

  • H Jakubowski (2000a) ArticleTitleCalcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation J Biol Chem 275 3957–3962 Occurrence Handle10.1074/jbc.275.6.3957 Occurrence Handle1:CAS:528:DC%2BD3cXht12gs7c%3D

    Article  CAS  Google Scholar 

  • H Jakubowski (2000b) ArticleTitleHomocysteine thiolactone: metabolic origin and protein homocysteinylation in humans J Nutr 130 377S–381S Occurrence Handle1:CAS:528:DC%2BD3cXhtVSlsLs%3D

    CAS  Google Scholar 

  • H Jakubowski (2001) ArticleTitleTranslational accuracy of aminoacyl-tRNA synthetases: implications for atherosclerosis J Nutr 131 2983S–2987S Occurrence Handle11694633 Occurrence Handle1:STN:280:DC%2BD3MnktFyhtw%3D%3D

    PubMed  CAS  Google Scholar 

  • H Jakubowski (2002a) ArticleTitleThe determination of homocysteine-thiolactone in biological samples Anal Biochem 308 112–119 Occurrence Handle10.1016/S0003-2697(02)00224-5 Occurrence Handle1:CAS:528:DC%2BD38XmvFSitLg%3D

    Article  CAS  Google Scholar 

  • H Jakubowski (2002b) ArticleTitleHomocysteine is a protein amino acid in humans. Implications for homocysteine-linked disease J Biol Chem 277 30425–30428 Occurrence Handle10.1074/jbc.C200267200 Occurrence Handle1:CAS:528:DC%2BD38XmsFyqsb4%3D

    Article  CAS  Google Scholar 

  • H Jakubowski (2003) ArticleTitleHomocysteine-thiolactone and S-nitroso-homocysteine mediate incorporation of homocysteine into protein in humans Clin Chem Lab Med 41 1462–1466 Occurrence Handle14656026 Occurrence Handle10.1515/CCLM.2003.224 Occurrence Handle1:CAS:528:DC%2BD3sXpsV2hsLc%3D

    Article  PubMed  CAS  Google Scholar 

  • H Jakubowski (2004) ArticleTitleMolecular basis of homocysteine toxicity in humans Cell Mol Life Sci 61 470–487 Occurrence Handle14999406 Occurrence Handle10.1007/s00018-003-3204-7 Occurrence Handle1:CAS:528:DC%2BD2cXjt1yhu7w%3D

    Article  PubMed  CAS  Google Scholar 

  • H Jakubowski (2005) ArticleTitleAnti-N-homocysteinylated protein autoantibodies and cardiovascular disease Clin Chem Lab Med 43 1011–1014 Occurrence Handle16197290 Occurrence Handle10.1515/CCLM.2005.177 Occurrence Handle1:CAS:528:DC%2BD2MXhtFOqu7fI

    Article  PubMed  CAS  Google Scholar 

  • H Jakubowski (2006) ArticleTitlePathophysiological consequences of homocysteine excess J Nutr 136 1741S–1749S Occurrence Handle16702349 Occurrence Handle1:CAS:528:DC%2BD28Xlt1Wmsrk%3D

    PubMed  CAS  Google Scholar 

  • H Jakubowski WT Ambrosius JH Pratt (2001) ArticleTitleGenetic determinants of homocysteine thiolactonase activity in humans: implications for atherosclerosis FEBS Lett 491 35–39 Occurrence Handle11226414 Occurrence Handle10.1016/S0014-5793(01)02143-3 Occurrence Handle1:CAS:528:DC%2BD3MXhsFShsro%3D

    Article  PubMed  CAS  Google Scholar 

  • H Jakubowski AR Fersht (1981) ArticleTitleAlternative pathways for editing non-cognate amino acids by aminoacyl-tRNA synthetases Nucleic Acids Res 9 3105–3117 Occurrence Handle7024910 Occurrence Handle10.1093/nar/9.13.3105 Occurrence Handle1:CAS:528:DyaL3MXlt1yhtL0%3D

    Article  PubMed  CAS  Google Scholar 

  • H Jakubowski E Goldman (1993) ArticleTitleSynthesis of homocysteine thiolactone by methionyl-tRNA synthetase in cultured mammalian cells FEBS Lett 317 237–240 Occurrence Handle8425610 Occurrence Handle10.1016/0014-5793(93)81283-6 Occurrence Handle1:CAS:528:DyaK3sXhsVCisrk%3D

    Article  PubMed  CAS  Google Scholar 

  • H Jakubowski L Zhang A Bardeguez A Aviv (2000) ArticleTitleHomocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis Circ Res 87 45–51 Occurrence Handle10884371 Occurrence Handle1:CAS:528:DC%2BD3cXkvFWju78%3D

    PubMed  CAS  Google Scholar 

  • RW James I Leviev J Ruiz P Passa P Froguel MC Garin (2000) ArticleTitlePromoter polymorphism T(-107)C of the paraoxonase PON1 gene is a risk factor for coronary heart disease in type 2 diabetic patients Diabetes 49 1390–1393 Occurrence Handle10923642 Occurrence Handle10.2337/diabetes.49.8.1390 Occurrence Handle1:CAS:528:DC%2BD3cXltlGltr4%3D

    Article  PubMed  CAS  Google Scholar 

  • A Kamudhamas L Pang SD Smith Y Sadovsky DM Nelson (2004) ArticleTitleHomocysteine thiolactone induces apoptosis in cultured human trophoblasts: a mechanism for homocysteine-mediated placental dysfunction? Am J Obstet Gynecol 191 563–571 Occurrence Handle15343238 Occurrence Handle10.1016/j.ajog.2004.01.037 Occurrence Handle1:CAS:528:DC%2BD2cXntlGntbs%3D

    Article  PubMed  CAS  Google Scholar 

  • SS Kang PW Wong MR Malinow (1992) ArticleTitleHyperhomocyst(e)inemia as a risk factor for occlusive vascular disease Annu Rev Nutr 12 279–298 Occurrence Handle1503807 Occurrence Handle10.1146/annurev.nu.12.070192.001431 Occurrence Handle1:CAS:528:DyaK3sXpvFSnsg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • RJ Kaufman (1999) ArticleTitleStress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls Genes Dev 13 1211–1233 Occurrence Handle10346810 Occurrence Handle1:CAS:528:DyaK1MXjslGjtbg%3D

    PubMed  CAS  Google Scholar 

  • HY Kim G Ghosh LH Schulman S Brunie H Jakubowski (1993) ArticleTitleThe relationship between synthetic and editing functions of the active site of an aminoacyl-tRNA synthetase Proc Natl Acad Sci USA 90 11553–11557 Occurrence Handle8265588 Occurrence Handle10.1073/pnas.90.24.11553 Occurrence Handle1:CAS:528:DyaK2cXhtVSgtrw%3D

    Article  PubMed  CAS  Google Scholar 

  • P Knekt A Reunanen G Alfthan M Heliovaara H Rissanen J Marniemi A Aromaa (2001) ArticleTitleHyperhomocystinemia: a risk factor or a consequence of coronary heart disease? Arch Intern Med 161 1589–1594 Occurrence Handle11434790 Occurrence Handle10.1001/archinte.161.13.1589 Occurrence Handle1:STN:280:DC%2BD3MvhsFamtw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • M Lacinski W Skorupski A Cieslinski J Sokolowska WH Trzeciak H Jakubowski (2004) ArticleTitleDeterminants of homocysteine-thiolactonase activity of the paraoxonase-1 (PON1) protein in humans Cell Mol Biol (Noisy-le-grand) 50 885–893 Occurrence Handle1:CAS:528:DC%2BD2MXht1eltrs%3D

    CAS  Google Scholar 

  • SR Lentz DJ Piegors JA Fernandez RA Erger E Arning MR Malinow JH Griffin T Bottiglieri WG Haynes DD Heistad (2002) ArticleTitleEffect of hyperhomocysteinemia on protein C activation and activity Blood 100 2108–2112 Occurrence Handle12200374 Occurrence Handle10.1182/blood-2002-03-0727 Occurrence Handle1:CAS:528:DC%2BD38Xnt1yhs7c%3D

    Article  PubMed  CAS  Google Scholar 

  • SR Lentz JE Sadler (1991) ArticleTitleInhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine J Clin Invest 88 1906–1914 Occurrence Handle1661291 Occurrence Handle1:CAS:528:DyaK38Xls1Gluw%3D%3D

    PubMed  CAS  Google Scholar 

  • A Lim S Sengupta ME McComb R Theberge WG Wilson CE Costello DW Jacobsen (2003) ArticleTitleIn vitro and in vivo interactions of homocysteine with human plasma transthyretin J Biol Chem 278 49707–49713 Occurrence Handle14507924 Occurrence Handle10.1074/jbc.M306748200 Occurrence Handle1:CAS:528:DC%2BD3sXpslSrtbs%3D

    Article  PubMed  CAS  Google Scholar 

  • G Liu K Nellaiappan HM Kagan (1997) ArticleTitleIrreversible inhibition of lysyl oxidase by homocysteine thiolactone and its selenium and oxygen analogues. Implications for homocystinuria J Biol Chem 272 32370–32377 Occurrence Handle9405445 Occurrence Handle10.1074/jbc.272.51.32370 Occurrence Handle1:CAS:528:DyaK1cXis1Ojtg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • AK Majors S Sengupta B Willard MT Kinter RE Pyeritz DW Jacobsen (2002) ArticleTitleHomocysteine binds to human plasma fibronectin and inhibits its interaction with fibrin Arterioscler Thromb Vasc Biol 22 1354–1359 Occurrence Handle12171800 Occurrence Handle10.1161/01.ATV.0000023899.93940.7C Occurrence Handle1:CAS:528:DC%2BD38Xmt12ju7c%3D

    Article  PubMed  CAS  Google Scholar 

  • IF McDowell D Lang (2000) ArticleTitleHomocysteine and endothelial dysfunction: a link with cardiovascular disease J Nutr 130 369S–372S Occurrence Handle10721909 Occurrence Handle1:CAS:528:DC%2BD3cXhtVSlsL0%3D

    PubMed  CAS  Google Scholar 

  • P Mercie O Garnier L Lascoste M Renard C Closse F Durrieu G Marit RM Boisseau F Belloc (2000) ArticleTitleHomocysteine-thiolactone induces caspase-independent vascular endothelial cell death with apoptotic features Apoptosis 5 403–411 Occurrence Handle11256881 Occurrence Handle10.1023/A:1009652011466 Occurrence Handle1:CAS:528:DC%2BD3MXitV2ru7g%3D

    Article  PubMed  CAS  Google Scholar 

  • JL Mills JM Scott PN Kirke JM McPartlin MR Conley DG Weir AM Molloy YJ Lee (1996) ArticleTitleHomocysteine and neural tube defects J Nutr 126 756S–760S Occurrence Handle8598561 Occurrence Handle1:CAS:528:DyaK28XhsVykt7w%3D

    PubMed  CAS  Google Scholar 

  • SH Mudd JD Finkelstein H Refsum PM Ueland MR Malinow SR Lentz DW Jacobsen L Brattstrom B Wilcken DE Wilcken HJ Blom SP Stabler RH Allen J Selhub IH Rosenberg (2000) ArticleTitleHomocysteine and its disulfide derivatives: a suggested consensus terminology Arterioscler Thromb Vasc Biol 20 1704–1706 Occurrence Handle10894806 Occurrence Handle1:CAS:528:DC%2BD3cXlsFGnsLc%3D

    PubMed  CAS  Google Scholar 

  • M Naruszewicz E Mirkiewicz AJ Olszewski KS McCully (1994) ArticleTitleThiolation of low-density lipoprotein by homocysteine-thiolactone causes increased aggregation and interaction with cultured macrophages Nutr Metab Cardiovasc Dis 4 70–77 Occurrence Handle1:CAS:528:DyaK2cXmt1Oktbc%3D

    CAS  Google Scholar 

  • WL Nelen EA Steegers TK Eskes HJ Blom (1997) ArticleTitleGenetic risk factor for unexplained recurrent early pregnancy loss Lancet 350 861 Occurrence Handle9310606 Occurrence Handle10.1016/S0140-6736(97)24038-9 Occurrence Handle1:STN:280:ByiH2MnmsV0%3D

    Article  PubMed  CAS  Google Scholar 

  • M Nishinaga T Ozawa K Shimada (1993) ArticleTitleHomocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells J Clin Invest 92 1381–1386 Occurrence Handle8376590 Occurrence Handle1:CAS:528:DyaK3sXmsVegsbY%3D Occurrence Handle10.1172/JCI116712

    Article  PubMed  CAS  Google Scholar 

  • H Nonaka T Tsujino Y Watari N Emoto M Yokoyama (2001) ArticleTitleTaurine prevents the decrease in expression and secretion of extracellular superoxide dismutase induced by homocysteine: amelioration of homocysteine-induced endoplasmic reticulum stress by taurine Circulation 104 1165–1170 Occurrence Handle11535574 Occurrence Handle1:CAS:528:DC%2BD3MXotlWntrY%3D

    PubMed  CAS  Google Scholar 

  • Perdziak M, Zimny J, Jakubowski H, Guranowski A (2005) Human placental protein purified as homocysteine-thiolactone hydrolase has been identified as human bleomycin hydrolase. Acta Biochim Polon 50 [Suppl 1] (Abstract P11.49)

  • J Perla A Undas T Twardowski H Jakubowski (2004) ArticleTitlePurification of antibodies against N-homocysteinylated proteins by affinity chromatography on Nomega-homocysteinyl-aminohexyl-Agarose J Chromatogr B Analyt Technol Biomed Life Sci 807 257–261 Occurrence Handle15203038 Occurrence Handle10.1016/j.jchromb.2004.04.018 Occurrence Handle1:CAS:528:DC%2BD2cXltVKisLo%3D

    Article  PubMed  CAS  Google Scholar 

  • AF Perna E Satta F Acanfora C Lombardi D Ingrosso NG De Santo (2007) ArticleTitleIncreased plasma protein homocysteinylation in hemodialysis patients Kidney Int 69 869–876 Occurrence Handle10.1038/sj.ki.5000070 Occurrence Handle1:CAS:528:DC%2BD28Xhs1Kitrw%3D

    Article  CAS  Google Scholar 

  • T Peters (1996) All about albumin Academic Press Inc San Diego 51–54

    Google Scholar 

  • A Pirillo W Zhu GD Norata T Zanelli L Barberi P Roma AL Catapano (2000) ArticleTitleOxidized lipoproteins and endothelium Clin Chem Lab Med 38 155–160 Occurrence Handle10834403 Occurrence Handle10.1515/CCLM.2000.023 Occurrence Handle1:CAS:528:DC%2BD3cXktl2lu74%3D

    Article  PubMed  CAS  Google Scholar 

  • G Podda EM Faioni ML Zighetti M Cattaneo (2003) ArticleTitleNo effect of fasting plasma total homocysteine on protein C activity in vitro Blood 101 2446–2447 Occurrence Handle12609965 Occurrence Handle10.1182/blood-2002-12-3757 Occurrence Handle1:CAS:528:DC%2BD3sXit1egtLs%3D

    Article  PubMed  CAS  Google Scholar 

  • R Poddar N Sivasubramanian PM DiBello K Robinson DW Jacobsen (2001) ArticleTitleHomocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: implications for vascular disease Circulation 103 2717–2723 Occurrence Handle11390343 Occurrence Handle1:CAS:528:DC%2BD3MXltFCjurw%3D

    PubMed  CAS  Google Scholar 

  • B Raposo C Rodriguez J Martinez-Gonzalez L Badimon (2004) ArticleTitleHigh levels of homocysteine inhibit lysyl oxidase (LOX) and downregulate LOX expression in vascular endothelial cells Atherosclerosis 177 1–8 Occurrence Handle15488859 Occurrence Handle10.1016/j.atherosclerosis.2004.06.015 Occurrence Handle1:CAS:528:DC%2BD2cXos1eksLY%3D

    Article  PubMed  CAS  Google Scholar 

  • O Roda ML Valero S Peiro D Andreu FX Real P Navarro (2003) ArticleTitleNew insights into the tPA-annexin A2 interaction. Is annexin A2 CYS8 the sole requirement for this association? J Biol Chem 278 5702–5709 Occurrence Handle12468550 Occurrence Handle10.1074/jbc.M207605200 Occurrence Handle1:CAS:528:DC%2BD3sXht1aqsLY%3D

    Article  PubMed  CAS  Google Scholar 

  • R Ross (1999) ArticleTitleAtherosclerosis – an inflammatory disease N Engl J Med 340 115–126 Occurrence Handle9887164 Occurrence Handle10.1056/NEJM199901143400207 Occurrence Handle1:STN:280:DyaK1M%2FptFSqtQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • CN Roybal S Yang CW Sun D Hurtado DL Vander Jagt TM Townes SF Abcouwer (2004) ArticleTitleHomocysteine increases the expression of vascular endothelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4 J Biol Chem 279 14844–14852 Occurrence Handle14747470 Occurrence Handle10.1074/jbc.M312948200 Occurrence Handle1:CAS:528:DC%2BD2cXivVKhtbs%3D

    Article  PubMed  CAS  Google Scholar 

  • R Salvayre N Auge H Benoist A Negre-Salvayre (2002) ArticleTitleOxidized low-density lipoprotein-induced apoptosis Biochim Biophys Acta 1585 213–221 Occurrence Handle12531556 Occurrence Handle1:CAS:528:DC%2BD3sXivVyjtA%3D%3D

    PubMed  CAS  Google Scholar 

  • JO Sass T Nakanishi T Sato W Sperl A Shimizu (2003) ArticleTitleS-homocysteinylation of transthyretin is detected in plasma and serum of humans with different types of hyperhomocysteinemia Biochem Biophys Res Commun 310 242–246 Occurrence Handle14511677 Occurrence Handle10.1016/j.bbrc.2003.08.089 Occurrence Handle1:CAS:528:DC%2BD3sXnsVWkt78%3D

    Article  PubMed  CAS  Google Scholar 

  • Sauls DL, Lockhart E, Hoffman M (2005) Reaction of fibrinogen with homocysteine thiolactone renders the resulting fibrin clots resistant to lysis. J Thromb Haemost 3 [Suppl 1]: OR 130

  • DL Sauls AS Wolberg M Hoffman (2003) ArticleTitleElevated plasma homocysteine leads to alterations in fibrin clot structure and stability: implications for the mechanism of thrombosis in hyperhomocysteinemia J Thromb Haemost 1 300–306 Occurrence Handle12871504 Occurrence Handle10.1046/j.1538-7836.2003.00053.x Occurrence Handle1:CAS:528:DC%2BD2cXktFemsro%3D

    Article  PubMed  CAS  Google Scholar 

  • S Seshadri A Beiser J Selhub PF Jacques IH Rosenberg RB D’Agostino PW Wilson PA Wolf (2002) ArticleTitlePlasma homocysteine as a risk factor for dementia and Alzheimer’s disease N Engl J Med 346 476–483 Occurrence Handle11844848 Occurrence Handle10.1056/NEJMoa011613 Occurrence Handle1:CAS:528:DC%2BD38XhtFCktrw%3D

    Article  PubMed  CAS  Google Scholar 

  • UP Steinbrecher M Fisher JL Witztum LK Curtiss (1984) ArticleTitleImmunogenicity of homologous low density lipoprotein after methylation, ethylation, acetylation, or carbamylation: generation of antibodies specific for derivatized lysine J Lipid Res 25 1109–1116 Occurrence Handle6439810 Occurrence Handle1:CAS:528:DyaL2cXmt1yhsbk%3D

    PubMed  CAS  Google Scholar 

  • A Tawakol T Omland M Gerhard JT Wu MA Creager (1997) ArticleTitleHyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans Circulation 95 1119–1121 Occurrence Handle9054838 Occurrence Handle1:STN:280:ByiB3cjlsVE%3D

    PubMed  CAS  Google Scholar 

  • T Togawa S Sengupta H Chen K Robinson I Nonevski AK Majors DW Jacobsen (2000) ArticleTitleMechanisms for the formation of protein-bound homocysteine in human plasma Biochem Biophys Res Commun 277 668–674 Occurrence Handle11062011 Occurrence Handle10.1006/bbrc.2000.3723 Occurrence Handle1:CAS:528:DC%2BD3cXnslGjsrs%3D

    Article  PubMed  CAS  Google Scholar 

  • Y Uji Y Motomiya N Hanyu F Ukaji H Okabe (2002) ArticleTitleProtein-bound homocystamide measured in human plasma by HPLC Clin Chem 48 941–944 Occurrence Handle12029014 Occurrence Handle1:CAS:528:DC%2BD38XktlWltr0%3D

    PubMed  CAS  Google Scholar 

  • A Undas J Brozek M Jankowski Z Siudak A Szczeklik H Jakubowski (2006) ArticleTitlePlasma homocysteine affects fibrin clot permeability and resistance to lysis in human subjects Arterioscler Thromb Vasc Biol 26 1397–1404 Occurrence Handle16574890 Occurrence Handle10.1161/01.ATV.0000219688.43572.75 Occurrence Handle1:CAS:528:DC%2BD28XksVGls7s%3D

    Article  PubMed  CAS  Google Scholar 

  • A Undas M Jankowski M Twardowska A Padjas H Jakubowski A Szczeklik (2005) ArticleTitleAntibodies to N-homocysteinylated albumin as a marker for early-onset coronary artery disease in men Thromb Haemost 93 346–350 Occurrence Handle15711753 Occurrence Handle1:CAS:528:DC%2BD2MXhs1Kns7w%3D

    PubMed  CAS  Google Scholar 

  • A Undas J Perla M Lacinski W Trzeciak R Kazmierski H Jakubowski (2004) ArticleTitleAutoantibodies against N-homocysteinylated proteins in humans: implications for atherosclerosis Stroke 35 1299–1304 Occurrence Handle15131313 Occurrence Handle10.1161/01.STR.0000128412.59768.6e Occurrence Handle1:CAS:528:DC%2BD2cXktFykurk%3D

    Article  PubMed  CAS  Google Scholar 

  • A Undas EB Williams S Butenas T Orfeo KG Mann (2001) ArticleTitleHomocysteine inhibits inactivation of factor Va by activated protein C J Biol Chem 276 4389–4397 Occurrence Handle11083858 Occurrence Handle10.1074/jbc.M004124200 Occurrence Handle1:CAS:528:DC%2BD3MXht1Gnsbo%3D

    Article  PubMed  CAS  Google Scholar 

  • GR Upchurch SuffixJr GN Welch AJ Fabian JE Freedman JL Johnson JF Keaney SuffixJr J Loscalzo (1997) ArticleTitleHomocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase J Biol Chem 272 17012–17017 Occurrence Handle9202015 Occurrence Handle10.1074/jbc.272.27.17012 Occurrence Handle1:CAS:528:DyaK2sXksVeltbs%3D

    Article  PubMed  CAS  Google Scholar 

  • M Van den Berg GH Boers DG Franken HJ Blom GJ Van Kamp C Jakobs JA Rauwerda C Kluft CD Stehouwert (1995) ArticleTitleHyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease Eur J Clin Invest 25 176–181 Occurrence Handle7781664 Occurrence Handle1:STN:280:ByqA3c%2FosVI%3D Occurrence Handle10.1111/j.1365-2362.1995.tb01545.x

    Article  PubMed  CAS  Google Scholar 

  • G Wang K O (2001) ArticleTitleHomocysteine stimulates the expression of monocyte chemoattractant protein-1 receptor (CCR2) in human monocytes: possible involvement of oxygen free radicals Biochem J 357 233–240 Occurrence Handle11415454 Occurrence Handle10.1042/0264-6021:3570233 Occurrence Handle1:CAS:528:DC%2BD3MXlt1OjurY%3D

    Article  PubMed  CAS  Google Scholar 

  • G Wang YL Siow K O (2000) ArticleTitleHomocysteine stimulates nuclear factor kappaB activity and monocyte chemoattractant protein-1 expression in vascular smooth-muscle cells: a possible role for protein kinase C Biochem J 352 817–826 Occurrence Handle11104691 Occurrence Handle10.1042/0264-6021:3520817 Occurrence Handle1:CAS:528:DC%2BD3MXkvVSkug%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • J Wang NP Dudman DE Wilcken (1993) ArticleTitleEffects of homocysteine and related compounds on prostacyclin production by cultured human vascular endothelial cells Thromb Haemost 70 1047–1052 Occurrence Handle8165599 Occurrence Handle1:CAS:528:DyaK2cXis1Ohurw%3D

    PubMed  CAS  Google Scholar 

  • X Yang Y Gao J Zhou Y Zhen Y Yang J Wang L Song Y Liu H Xu Z Chen R Hui (2006) ArticleTitlePlasma homocysteine thiolactone adducts associated with risk of coronary heart disease Clin Chim Acta 364 230–234 Occurrence Handle16111668 Occurrence Handle10.1016/j.cccn.2005.07.007 Occurrence Handle1:CAS:528:DC%2BD28XmslWjsA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • JH Yoo SC Lee (2001) ArticleTitleElevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke Atherosclerosis 158 425–430 Occurrence Handle11583722 Occurrence Handle10.1016/S0021-9150(01)00444-0 Occurrence Handle1:CAS:528:DC%2BD3MXnt1Whur0%3D

    Article  PubMed  CAS  Google Scholar 

  • R Zarychanski DS Houston (2004) ArticleTitlePlasma homocysteine concentration is not associated with activated protein C resistance in patients investigated for hypercoagulability Thromb Haemost 91 1115–1122 Occurrence Handle15175797 Occurrence Handle1:CAS:528:DC%2BD2cXltFyqu7c%3D

    PubMed  CAS  Google Scholar 

  • J Zimny D Iwanowska E Starzynska H Jakubowski A Guranowski (2005) ArticleTitleHomocysteine thiolactone is a substrate of bleomycin hydrolase/cysteine protease/gal6 protein Clin Chem Lab Med 43 A23

    Google Scholar 

  • J Zimny M Sikora A Guranowski H Jakubowski (2006) ArticleTitleProtective mechanisms against homocysteine toxicity: the role of bleomycin hydrolase J Biol Chem 281 22485–22492 Occurrence Handle16769724 Occurrence Handle10.1074/jbc.M603656200 Occurrence Handle1:CAS:528:DC%2BD28XnvVSqu7w%3D

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland

    J. Perła-Kaján, T. Twardowski & H. Jakubowski

  2. UMDNJ-New Jersey Medical School, Newark, NJ, U.S.A.

    H. Jakubowski

Authors
  1. J. Perła-Kaján
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Twardowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Jakubowski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Perła-Kaján.

Additional information

Present address: Department of Biochemistry and Biotechnology, Agricultural University, 60637 Poznań, Poland

Rights and permissions

Reprints and permissions

About this article

Cite this article

Perła-Kaján, J., Twardowski, T. & Jakubowski, H. Mechanisms of homocysteine toxicity in humans. Amino Acids 32, 561–572 (2007). https://doi.org/10.1007/s00726-006-0432-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-006-0432-9

Search

Navigation