| First Author | Perła-Kajan J | Year | 2016 |
| Journal | FASEB J | Volume | 30 |
| Issue | 11 | Pages | 3810-3821 |
| PubMed ID | 27530978 | Mgi Jnum | J:239688 |
| Mgi Id | MGI:5829504 | Doi | 10.1096/fj.201600539 |
| Citation | Perla-Kajan J, et al. (2016) N-Homocysteinylation impairs collagen cross-linking in cystathionine beta-synthase-deficient mice: a novel mechanism of connective tissue abnormalities. FASEB J 30(11):3810-3821 |
| abstractText | Cystathionine beta-synthase (CBS) deficiency, a genetic disorder in homocysteine (Hcy) metabolism in humans, elevates plasma Hcy-thiolactone and leads to connective tissue abnormalities that affect the cardiovascular and skeletal systems. However, the underlying mechanism of these abnormalities is not understood. Hcy-thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates N-homocysteinylated protein. Because lysine residues are involved in collagen cross-linking, N-homocysteinylation of these lysines should impair cross-linking. Using a Tg-I278T Cbs-/- mouse model of hyperhomocysteinemia (HHcy) which replicates the connective tissue abnormalities observed in CBS-deficient patients, we found that N-Hcy-collagen was elevated in bone, tail, and heart of Cbs-/- mice, whereas pyridinoline cross-links were significantly reduced. Plasma deoxypyridinoline cross-link and cross-linked carboxyterminal telopeptide of type I collagen were also significantly reduced in the Cbs-/- mice. Lysine oxidase activity and mRNA level were not reduced by the Cbs-/- genotype. We also showed that collagen carries S-linked Hcy bound to the thiol of N-linked Hcy. In vitro experiments showed that Hcy-thiolactone modifies lysine residues in collagen type I alpha-1 chain. Residue K160, located in the nonhelical N-telopeptide region and involved in pyridinoline cross-link formation, was also N-homocysteinylated in vivo Taken together, our findings showed that N-homocysteinylation of collagen in Cbs-/- mice impairs its cross-linking. These findings explain, at least in part, connective tissue abnormalities observed in HHcy.-Perla-Kajan, J., Utyro, O., Rusek, M., Malinowska, A., Sitkiewicz, E., Jakubowski, H. N-Homocysteinylation impairs collagen cross-linking in cystathionine beta-synthase-deficient mice: a novel mechanism of connective tissue abnormalities. |
