The transfer of reductive energy and pace of proteome turnover: a theory of integrated catabolic control.
Hundreds of cell proteins undergo reversible transitions among redox states. Coordinate control and common functions served by redox-modified proteins are unknown. The suspect "redox code" integrating metabolome, proteome, and genome remains undefined. Protein redox control involves coupling of the population redox partition to transfer of reductive energy from source to sink. Lessons in metabolic programs under redox coordination might be found in nutritional desperation where reductive transfer from fuel fails to feed pathways to protein reduction. Upon nutritional interruption, proteolysis initially increases. However, catabolism secondarily declines in later starvation so as to postpone loss of the minimal proteome under synthetic failure and delay death. Integrated proteome turnover is paced by reductive transfer coupled to redox states of proteins serving diverse functions. Some continuing proteolysis is redox-independent. Cathepsin B is a model, redox-responsive, catabolic machine among proteins involved in turnover. The CysHis pair is simultaneously a redox-responsive site, an inhibitory metal-binding site, and a peptidolytic reaction mechanism. Pro-region cleavage generates permissive reaction conditions, but not necessarily the maximal peptidolytic rate. Mature cathepsin B can be inactivated by partition into multiple oxidation states. Cathepsin B can be reductively activated by glutathione or disulfhydryl reductases, and redox-buffered by glutathione homodisulfide/glutathione. Topics in protease regulation include: (a) the rate of total cell transfer of nutrient reductive energy from NADPH source potential to reductive pathways, (b) the distribution of reductive energy routed through parallel interactive pathways to protease, (c) the rate of transfer from protease through pathways to oxygen (reactive oxygen species) acceptor at sink potential, and (d) the linkage of protease state partition to relative rates of reductions and oxidations. Cell iron, sulfur, and oxygen redox are inseparable. The interaction of the CysHis site with iron provides a sensor, integrator, and effector switch coupling cathepsin B to metal-sulfuroxygen redox. Artificial metal-redox-proton switching is a new concept in protein engineering; however, nature has already applied "nanotechnology" to protein redox control.
Department of Pharmacology and Toxicology, School of Medicine, Wright State University, Dayton, OH 45429, USA. thomas.lockwood@wright.edu
Thomas D
TD
Lockwood
D000818:Animals; D004194:Disease; D006801:Humans; D008954:Models, Biological; D009747:Nutritional Physiological Phenomena; D010084:Oxidation-Reduction; D010447:Peptide Hydrolases / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*
D020543:Proteome; D010447:Peptide Hydrolases