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However, the underlying mechanism of these abnormalities is not understood. Hcy\u2010thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates\n                    <jats:italic>N<\/jats:italic>\n                    \u2010homocysteinylated protein. Because lysine residues are involved in collagen cross\u2010linking,\n                    <jats:italic>N<\/jats:italic>\n                    \u2010homocysteinylation of these lysines should impair cross\u2010linking. Using a\n                    <jats:italic>Tg\u2010I278T Cbs<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mousemodel of hyperhomocysteinemia(HHcy)which replicates the connective tissue abnormalities observed in CBS\u2010deficient patients, we found that\n                    <jats:italic>N<\/jats:italic>\n                    \u2010Hcy\u2010collagen was elevated in bone, tail, and heartof\n                    <jats:italic>Cbs<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice, whereas pyridinoline cross\u2010links were significantly reduced. Plasma deoxypyridinoline cross\u2010link and cross\u2010linked carboxyterminal telopeptide of type I collagen were also significantly reduced in the\n                    <jats:italic>Cbs<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Lysine oxidase activity and mRNA level were not reduced by the\n                    <jats:italic>Cbs<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    genotype. We also showed that collagen carries S\u2010linked Hcy bound to the thiol of\n                    <jats:italic>N<\/jats:italic>\n                    \u2010linked Hcy.\n                    <jats:italic>in vitro<\/jats:italic>\n                    experiments showed that Hcy\u2010thiolactone modifies lysine residues in collagen type I \u03b1\u20101 chain. Residue K\n                    <jats:sup>160<\/jats:sup>\n                    , located in the nonhelical\n                    <jats:italic>N<\/jats:italic>\n                    \u2010telopeptide region and involved in pyridinoline cross\u2010link formation, was also\n                    <jats:italic>N<\/jats:italic>\n                    \u2010homocysteinylated\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Taken together, our findings showed that\n                    <jats:italic>N<\/jats:italic>\n                    \u2010homocysteinylation of collagen in\n                    <jats:italic>\n                      Cbs\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice impairs its cross\u2010linking. These findings explain, at least in part, connective tissue abnormalities observed in HHcy.\u2014Perla\u2010Kajan, J., Utyro, O., Rusek, M., Malinowska, A., Sitkiewicz, E., Jakubowski, H.\n                    <jats:italic>N<\/jats:italic>\n                    \u2010Homocysteinylation impairs collagen cross\u2010linking in cystathionine \u03b2\u2010synthase\u2010deficient mice: a novel mechanism of connective tissue abnormalities. FASEB J. 30, 3810\u20133821 (2016)\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201600539","type":"journal-article","created":{"date-parts":[[2016,8,16]],"date-time":"2016-08-16T23:08:45Z","timestamp":1471388925000},"page":"3810-3821","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["<i>N<\/i>\n                    \u2010Homocysteinylation impairs collagen cross\u2010linking in cystathionine \u03b2\u2010synthase\u2010deficient mice: a novel mechanism of connective tissue abnormalities"],"prefix":"10.1096","volume":"30","author":[{"given":"Joanna","family":"Perla\u2010Kajan","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biotechnology University of Life Sciences  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Utyro","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Rusek","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Biochemistry Molecular Genetics International Center for Public Health Rutgers\u2013New Jersey Medical School Rutgers University  Newark New Jersey USA"},{"name":"Department of Pathophysiology Medical University  Lublin Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Malinowska","sequence":"additional","affiliation":[{"name":"Proteomics Laboratory Biophysics Department Institute of Biochemistry and Biophysics  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Sitkiewicz","sequence":"additional","affiliation":[{"name":"Proteomics Laboratory Biophysics Department Institute of Biochemistry and Biophysics  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hieronim","family":"Jakubowski","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology University of Life Sciences  Pozna\u0144 Poland"},{"name":"Institute of Bioorganic Chemistry  Pozna\u0144 Poland"},{"name":"Department of Microbiology, Biochemistry Molecular Genetics International Center for Public Health Rutgers\u2013New Jersey Medical School Rutgers University  Newark New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,8,16]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"2007","volume-title":"Disorders of transsulfuration. 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