| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
,1
a-Kaján*,
* Department of Microbiology and Molecular Genetics, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, International Center for Public Health, Newark, New Jersey, USA;
Department of Biochemistry and Biotechnology, University of Life Sciences, Pozna
, Poland;
Texas Institute for Genomic Medicine, Institute of Biosciences and Technology, The Texas A&M University System Health Science Center, Houston, Texas, USA;
Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA;
|| Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA;
¶ Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA; and
# Department of Medicine, University of California–Los Angeles Medical School, Los Angeles, California, USA
1Correspondence: Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, 225 Warren St., Newark, NJ 07101-1709, USA. E-mail: jakubows{at}umdnj.edu
Genetic disorders of homocysteine (Hcy) or folate metabolism or high-methionine diets elevate plasma Hcy and its atherogenic metabolite Hcy-thiolactone. In humans, severe hyperhomocysteinemia due to genetic alterations in cystathionine β-synthase (Cbs) or methylenetetrahydrofolate reductase (Mthfr) results in neurological abnormalities and premature death from vascular complications. In mouse models, dietary or genetic hyperhomocysteinemia results in liver or brain pathological changes and accelerates atherosclerosis. Hcy-thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates modified proteins (N-Hcy-protein) with autoimmunogenic and prothrombotic properties. Our aim was to determine how N-Hcy-protein levels are affected by genetic or nutritional disorders in Hcy or folate metabolism in mice. We found that plasma N-Hcy-protein was elevated 10-fold in mice fed a high-methionine diet compared with the animals fed a normal commercial diet. We also found that inactivation of Cbs, Mthfr, or the proton-coupled folate transporter (Pcft) gene resulted in a 10- to 30-fold increase in plasma or serum N-Hcy-protein levels. Liver N-Hcy-protein was elevated 3.4-fold in severely and 11-fold in extremely hyperhomocysteinemic Cbs-deficient mice, 3.6-fold in severely hyperhomocysteinemic Pcft mice, but was not elevated in mildly hyperhomocysteinemic Mthfr-deficient animals, suggesting that mice have a capacity to prevent accumulation of N-Hcy-protein in their organs. These findings provide evidence that N-Hcy-protein is an important metabolite associated with Hcy pathophysiology in the mouse.—Jakubowski, H., Pera-Kaján, J., Finnell, R. H., Cabrera, R. M., Wang, H., Gupta, S., Kruger, W. D., Kraus, J. P., and Shih, D. M. Genetic or nutritional disorders in homocysteine or folate metabolism increase protein N-homocysteinylation in mice.
Key Words: methionine • thiolactone • liver damage • atherothrombosis
This article has been cited by other articles:
|
|
 |
|
  J. Beltowski, G. Wojcicka, and H. Jakubowski Modulation of paraoxonase 1 and protein N-homocysteinylation by leptin and the synthetic liver X receptor agonist T0901317 in the rat J. Endocrinol., February 1, 2010; 204(2): 191 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. D.E. Greene, P. Stanier, and A. J. Copp Genetics of human neural tube defects Hum. Mol. Genet., October 15, 2009; 18(R2): R113 - R129. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
