ABSTRACT
Although it is well appreciated that metabolic pathways in mammalian cells often use products of other pathways and provide their metabolites to yet different pathways, we are only beginning to appreciate how metabolic systems might directly and indirectly cross-regulate each other. Thus, all metabolic activities in a cell or organism are coordinated into a highly interactive system. In recent years, it has become apparent that cytosolic thioredoxin reductase-1, a flavin-containing NADPHdependent selenoprotein, exerts considerable influence over other redox pathways, drug-metabolism pathways, and energy metabolism pathways. Thus, within the integrated system, thioredoxin reductase-1 behaves as a “keystone component” to coordinate the activities of other pathways. Coincidentally, it has been independently
13.1 Introduction .................................................................................................. 273 13.2 Redox Metabolism ........................................................................................ 274
13.2.1 Universal Need for Reductive Systems ............................................. 274 13.2.2 GSH System in Cellular Redox Homeostasis ................................... 275 13.2.3 Trx System in Cellular Redox Homeostasis ..................................... 275 13.2.4 Why Do We Have Both a GSH and a Trx System? .......................... 276
13.3 Coordinated Activities of Metabolic Systems .............................................. 277 13.3.1 Evidence That TrxR1 Coordinates Other Metabolic Pathways ........ 277
13.4 Potential TrxR1-Interacting Regulators of Metabolic Processes..................280 13.4.1 Thioredoxin-Interacting Protein (Txnip) ..........................................280 13.4.2 Nrf2/Keap1 Stress Response ............................................................ 281 13.4.3 Protein Tyrosine Phosphatase 1B ..................................................... 282 13.4.4 5′-AMP-Activated Protein Kinase (AMPK) ..................................... 283 13.4.5 p53 ..................................................................................................... 283
13.5 Integration of Metabolic Systems into a “Metabolic Ecosystem” ................284 Acknowledgments ..................................................................................................285 References ..............................................................................................................286
coming to light that the thioredoxin pathway is, itself, regulated by each of these other pathways and, indeed, that most if not all of these pathways might in some way influence the activities of all of the other pathways.
