Tesis doctoral de Joaquin Fernández Irigoyen
Methylthioadenosine phosphorylase (mtap) catalyzes the reversible phosphorolytic cleavage of methylthioadenosine leading to the production of methylthioribose-1-phosphate and adenine. Deficient mtap activity has been correlated with human diseases including cirrhosis and hepatocellular carcinoma, in the present work we have investigated the regulation of mtap by reactive oxygen species, we show data supporting the inactivation of mtap in the liver of bacterial lipopolysaccharide (lps) challenged mice as well as in hepg2 cells after exposure to tert-butyl hydroperoxide. Reversible inactivation of purified mtap by hydrogen peroxide results from a reduction of vmax and involves the specific oxidation of cys136 and cys223 thiols to sulfenic acid that may be further stabilized to sulfenyl amide intermediates. Additionally, we found that cys145 and cys211 were disulfide bonded upon hydrogen peroxide exposure. However, this modification is not relevant to mediate the loss of mtap activity as assessed by site directed mutagenesis. Regulation of mtap by ros might participate in the redox regulation of methionine catabolic pathway in the liver. Reduced mta degrading activity may compensate the deficient production of the precursor s-adenosylmetnionine, allowing maintenance of intracellular mta levels that may be critical to ensure cellular adaptation to physiopathological conditions such as inflammation.
Datos académicos de la tesis doctoral «Regulación redox de la metiltioandenosina fosforilasa en células hepáticas. implicaciones funcionales y caracterización de los mecanismos moleculares«
- Título de la tesis: Regulación redox de la metiltioandenosina fosforilasa en células hepáticas. implicaciones funcionales y caracterización de los mecanismos moleculares
- Autor: Joaquin Fernández Irigoyen
- Universidad: Navarra
- Fecha de lectura de la tesis: 30/05/2008
Dirección y tribunal
- Director de la tesis
- Fernando Jose Corrales Izquierdo
- Tribunal
- Presidente del tribunal: Francisco Borras cuesta
- Manuel Sánchez del pino (vocal)
- Luis Torres asensi (vocal)
- Antonio Rodriguez ariza (vocal)