PMID- 27530978
OWN - NLM
STAT- MEDLINE
DCOM- 20170921
LR  - 20211204
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 30
IP  - 11
DP  - 2016 Nov
TI  - N-Homocysteinylation impairs collagen cross-linking in cystathionine 
      beta-synthase-deficient mice: a novel mechanism of connective tissue abnormalities.
PG  - 3810-3821
AB  - 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 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.-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.
CI  - (c) FASEB.
FAU - Perla-Kajan, Joanna
AU  - Perla-Kajan J
AD  - Department of Biochemistry and Biotechnology, University of Life Sciences, 
      Poznan, Poland.
FAU - Utyro, Olga
AU  - Utyro O
AD  - Institute of Bioorganic Chemistry, Poznan, Poland.
FAU - Rusek, Marta
AU  - Rusek M
AD  - Department of Microbiology, Biochemistry and Molecular Genetics, International 
      Center for Public Health, Rutgers-New Jersey Medical School, Rutgers University, 
      Newark, New Jersey, USA; and.
FAU - Malinowska, Agata
AU  - Malinowska A
AD  - Proteomics Laboratory, Biophysics Department, Institute of Biochemistry and 
      Biophysics, Warsaw, Poland.
FAU - Sitkiewicz, Ewa
AU  - Sitkiewicz E
AD  - Proteomics Laboratory, Biophysics Department, Institute of Biochemistry and 
      Biophysics, Warsaw, Poland.
FAU - Jakubowski, Hieronim
AU  - Jakubowski H
AD  - Department of Biochemistry and Biotechnology, University of Life Sciences, 
      Poznan, Poland; jakubows@rutgers.edu.
AD  - Institute of Bioorganic Chemistry, Poznan, Poland.
AD  - Department of Microbiology, Biochemistry and Molecular Genetics, International 
      Center for Public Health, Rutgers-New Jersey Medical School, Rutgers University, 
      Newark, New Jersey, USA; and.
LA  - eng
PT  - Journal Article
DEP - 20160816
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (COL1A1 protein, human)
RN  - 0 (Collagen Type I)
RN  - 0 (Collagen Type I, alpha 1 Chain)
RN  - 0 (Peptides)
RN  - 0 (collagen type I trimeric cross-linked peptide)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - D5H88XF24X (homocysteine thiolactone)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Animals
MH  - Collagen Type I/*metabolism
MH  - Collagen Type I, alpha 1 Chain
MH  - Connective Tissue/*metabolism
MH  - Cystathionine beta-Synthase/genetics/*metabolism
MH  - Homocysteine/*analogs & derivatives/metabolism
MH  - Homocystinuria/genetics
MH  - Hyperhomocysteinemia/*metabolism
MH  - Lysine/metabolism
MH  - Mice, Knockout
MH  - Peptides/metabolism
OTO - NOTNLM
OT  - Col1A1
OT  - collagen modification
OT  - homocysteine thiolactone
OT  - hyperhomocysteinemia
OT  - pyridinoline cross-links
EDAT- 2016/11/03 06:00
MHDA- 2017/09/22 06:00
CRDT- 2016/08/18 06:00
PHST- 2016/06/01 00:00 [received]
PHST- 2016/07/27 00:00 [accepted]
PHST- 2016/11/03 06:00 [pubmed]
PHST- 2017/09/22 06:00 [medline]
PHST- 2016/08/18 06:00 [entrez]
AID - fj.201600539 [pii]
AID - 10.1096/fj.201600539 [doi]
PST - ppublish
SO  - FASEB J. 2016 Nov;30(11):3810-3821. doi: 10.1096/fj.201600539. Epub 2016 Aug 16.