Early effects of copper accumulation on methionine metabolism.
Wilson's disease is characterized by longterm hepatic accumulation of copper leading to liver disease with reduction of S-adenosylmethionine synthesis. However, the initial changes in this pathway remain unknown and constitute the objective of the present study. Using the Long Evans Cinnamon rat model, early alterations were detected in the mRNA and protein levels, as well as in the activities of several enzymes of the methionine cycle. Notably, the main change was a redox-mediated 80% decrease in the mRNA levels of the methionine adenosyltransferase regulatory subunit as compared to the control group. Moreover, changes in S-adenosylmethionine, S-adenosylhomocysteine, methionine and glutathione levels were also observed. In addition, in vitro experiments show that copper affects the activity and folding of methionine adenosyltransferase catalytic subunits. Taken together, these observations indicate that early copper accumulation alters methionine metabolism with a pattern distinct from that described previously for other liver diseases.
Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain.
M
M
Delgado
J
J
Pérez-Miguelsanz
F
F
Garrido
G
G
Rodríguez-Tarduchy
D
D
Pérez-Sala
M A
MA
Pajares
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050940:Betaine-Homocysteine S-Methyltransferase / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D006527:Hepatolenticular Degeneration / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008715:Methionine / Q000378:metabolism*; D008716:Methionine Adenosyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D010084:Oxidation-Reduction; D017510:Protein Folding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020332:Rats, Inbred LEC; D020318:Rats, Long-Evans
D027682:Cation Transport Proteins; D012333:RNA, Messenger; D003300:Copper; D008715:Methionine; D050940:Betaine-Homocysteine S-Methyltransferase; C494550:Bhmt protein, rat; D008716:Methionine Adenosyltransferase; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases