Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in Mice
Genetic or nutritional deficiencies in homocysteine (Hcy) metabolism increase Hcy-thiolactone, which causes protein damage by forming isopetide bonds with lysine residues, generating N-Hcy-protein. In the present work, we studied the prevalence and genetic determinants of keratin damage caused by ho...
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| Format: | Article |
| Language: | English |
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Wiley
2018-01-01
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| Series: | International Journal of Genomics |
| Online Access: | http://dx.doi.org/10.1155/2018/7570850 |
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| author | Kamila Borowczyk Jacek Wróblewski Joanna Suliburska Noriyuki Akahoshi Isao Ishii Hieronim Jakubowski |
| author_facet | Kamila Borowczyk Jacek Wróblewski Joanna Suliburska Noriyuki Akahoshi Isao Ishii Hieronim Jakubowski |
| author_sort | Kamila Borowczyk |
| collection | DOAJ |
| description | Genetic or nutritional deficiencies in homocysteine (Hcy) metabolism increase Hcy-thiolactone, which causes protein damage by forming isopetide bonds with lysine residues, generating N-Hcy-protein. In the present work, we studied the prevalence and genetic determinants of keratin damage caused by homocysteinylation. We found that in mammals and birds, 35 to 98% of Hcy was bound to hair keratin via amide or isopeptide bond (Hcy-keratin), while 2 to 65% was S-Hcy-keratin. A major fraction of hair Hcy-keratin (56% to 93%), significantly higher in birds than in mammals, was sodium dodecyl sulfate-insoluble. Genetic hyperhomocysteinemia significantly increased N-Hcy-keratin levels in the mouse pelage. N-Hcy-keratin was elevated 3.5-, 6.3-, and 11.7-fold in hair from Mthfr−/−, Cse−/−, or Cbs−/− mice, respectively. The accumulation of N-Hcy in hair keratin led to a progressive reduction of N-Hcy-keratin solubility in sodium dodecyl sulfate, from 0.39 ± 0.04 in wild-type mice to 0.19 ± 0.03, 0.14 ± 0.01, and 0.07 ± 0.03 in Mthfr−/−, Cse−/−, or Cbs−/−animals, respectively. N-Hcy-keratin accelerated aggregation of unmodified keratin in Cbs−/− mouse hair. Keratin methionine, copper, and iron levels in mouse hair were not affected by hyperhomocysteinemia. These findings provide evidence that pelage keratin is N-homocysteinylated in vivo in mammals and birds, and that this process causes keratin damage, manifested by a reduced solubility. |
| format | Article |
| id | doaj-art-c0519a92f1b842dc85e1e060116cb313 |
| institution | Kabale University |
| issn | 2314-436X 2314-4378 |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Genomics |
| spelling | doaj-art-c0519a92f1b842dc85e1e060116cb3132025-02-03T01:33:11ZengWileyInternational Journal of Genomics2314-436X2314-43782018-01-01201810.1155/2018/75708507570850Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in MiceKamila Borowczyk0Jacek Wróblewski1Joanna Suliburska2Noriyuki Akahoshi3Isao Ishii4Hieronim Jakubowski5Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers-New Jersey Medical School, International Center for Public Health, Newark, NJ 07103, USAInstitute of Bioorganic Chemistry, 71-704 Poznań, PolandInstitute of Human Nutrition and Dietetics, Poznań University of Life Sciences, 60-632 Poznań, PolandDepartment of Health Chemistry, Showa Pharmaceutical University, Tokyo 194-8543, JapanDepartment of Health Chemistry, Showa Pharmaceutical University, Tokyo 194-8543, JapanDepartment of Microbiology, Biochemistry and Molecular Genetics, Rutgers-New Jersey Medical School, International Center for Public Health, Newark, NJ 07103, USAGenetic or nutritional deficiencies in homocysteine (Hcy) metabolism increase Hcy-thiolactone, which causes protein damage by forming isopetide bonds with lysine residues, generating N-Hcy-protein. In the present work, we studied the prevalence and genetic determinants of keratin damage caused by homocysteinylation. We found that in mammals and birds, 35 to 98% of Hcy was bound to hair keratin via amide or isopeptide bond (Hcy-keratin), while 2 to 65% was S-Hcy-keratin. A major fraction of hair Hcy-keratin (56% to 93%), significantly higher in birds than in mammals, was sodium dodecyl sulfate-insoluble. Genetic hyperhomocysteinemia significantly increased N-Hcy-keratin levels in the mouse pelage. N-Hcy-keratin was elevated 3.5-, 6.3-, and 11.7-fold in hair from Mthfr−/−, Cse−/−, or Cbs−/− mice, respectively. The accumulation of N-Hcy in hair keratin led to a progressive reduction of N-Hcy-keratin solubility in sodium dodecyl sulfate, from 0.39 ± 0.04 in wild-type mice to 0.19 ± 0.03, 0.14 ± 0.01, and 0.07 ± 0.03 in Mthfr−/−, Cse−/−, or Cbs−/−animals, respectively. N-Hcy-keratin accelerated aggregation of unmodified keratin in Cbs−/− mouse hair. Keratin methionine, copper, and iron levels in mouse hair were not affected by hyperhomocysteinemia. These findings provide evidence that pelage keratin is N-homocysteinylated in vivo in mammals and birds, and that this process causes keratin damage, manifested by a reduced solubility.http://dx.doi.org/10.1155/2018/7570850 |
| spellingShingle | Kamila Borowczyk Jacek Wróblewski Joanna Suliburska Noriyuki Akahoshi Isao Ishii Hieronim Jakubowski Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in Mice International Journal of Genomics |
| title | Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in Mice |
| title_full | Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in Mice |
| title_fullStr | Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in Mice |
| title_full_unstemmed | Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in Mice |
| title_short | Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in Mice |
| title_sort | mutations in homocysteine metabolism genes increase keratin n homocysteinylation and damage in mice |
| url | http://dx.doi.org/10.1155/2018/7570850 |
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