N-Homocysteinylation impairs collagen cross-linking in cystathionine β-synthase-deficient mice: a novel mechanism of connective tissue abnormalities.
PBN-AR
Instytucja
Instytut Biochemii i Biofizyki Polskiej Akademii Nauk
Źródłowe zdarzenia ewaluacyjne
Informacje podstawowe
Główny język publikacji
EN
Czasopismo
FASEB journal
ISSN
0892-6638
EISSN
1530-6860
Wydawca
Federation of American Societies for Experimental Biology
DOI
Rok publikacji
2016
Numer zeszytu
11
Strony od-do
3810-3821
Numer tomu
30
Link do pełnego tekstu
Identyfikator DOI
Liczba arkuszy
Słowa kluczowe
EN
Col1A1;
collagen modification;
homocysteine thiolactone;
hyperhomocysteinemia;
pyridinoline cross-links;
Streszczenia
Język
EN
Treść
Cystathionine -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 -1 chain. Residue K-160, 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.Pera-Kajan, J., Utyro, O., Rusek, M., Malinowska, A., Sitkiewicz, E., Jakubowski, H. N-Homocysteinylation impairs collagen cross-linking in cystathionine -synthase-deficient mice: a novel mechanism of connective tissue abnormalities.
Inne
System-identifier
5331
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