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Redox regulation of methylthioadenosine phosphorylase in liver cells: molecular mechanism and functional implications

Joaquín Fernández-Irigoyen1, Mónica Santamaría, Virginia Sánchez-Quiles

  • 1Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.

The Biochemical Journal
|February 2, 2008
PubMed

Insights

Reactive oxygen species (ROS) reversibly inactivate 5'-methylthioadenosine phosphorylase (MTAP) by oxidizing specific cysteine residues. This regulation may help maintain cellular adaptation during inflammation and liver disease.

Area of Science:

  • Biochemistry
  • Enzymology
  • Redox Biology

Background:

  • 5'-methylthioadenosine phosphorylase (MTAP) is crucial for methionine catabolism.
  • Deficient MTAP activity is linked to liver diseases like cirrhosis and hepatocellular carcinoma.
  • The role of reactive oxygen species (ROS) in MTAP regulation was previously unclear.

Purpose of the Study:

  • To investigate the regulation of MTAP by ROS.
  • To elucidate the molecular mechanisms underlying MTAP inactivation by ROS.
  • To understand the physiological implications of MTAP redox regulation in liver disease.

Main Methods:

  • In vitro studies using purified MTAP and hydrogen peroxide.
  • In vivo studies using lipopolysaccharide (LPS)-challenged mice.
  • Cell-based assays with HepG2 cells exposed to t-butyl hydroperoxide.
  • Site-directed mutagenesis to assess the role of specific cysteine residues.

Main Results:

  • MTAP activity was reduced in LPS-challenged mice livers and HepG2 cells treated with t-butyl hydroperoxide.
  • Hydrogen peroxide reversibly inactivated purified MTAP by reducing V(max).
  • Oxidation of Cys(136) and Cys(223) to sulfenic acid mediated MTAP inactivation; Cys(145) and Cys(211) disulfide bonding was not involved.

Conclusions:

  • ROS reversibly regulate MTAP activity through specific cysteine oxidation.
  • MTAP redox regulation may play a role in the methionine catabolic pathway during inflammation.
  • Maintaining intracellular methylthioadenosine (MTA) levels via MTAP regulation could be critical for cellular adaptation to disease states.

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