title: Lysosomal metal, redox and proton cycles influencing the CysHis cathepsin reaction.
abstract: In the 1930's pioneers discovered that maximal autolysis in tissue homogenates requires metal chelator, sulfhydryl reducing agent and acid pH. However, metals, reducing equivalents and protons (MR&P) have been overlooked as combined catalytic controls. Three categories of lysosomal machinery drive three distinguishable cycles importing and exporting MR&P. Zn(2+) preemptively inhibits CysHis catalysis under otherwise optimal protonation and reduction. Protein-bound cell Zn(2+) concentration is 200-2000 times the non-sequestered inhibitory concentration. Following autophagy, lysosomal proteolysis liberates much inhibitory Zn(2+). The vacuolar proton pump is the driving force for Zn(2+) export, as well as protonation of the peptidolytic mechanism. Other machinery of lysosomal cycles includes proton-driven Zn(2+) exporters (e.g. SLC11A1), Zn(2+) channels (e.g. TRPML-1), lysosomal thiol reductase, etc. The CysHis dyad is a sensor of the vacuolar environment of MR&P, an integrator of these simultaneous variables, and a catalytic responder. Rate-determination can shift between autophagic substrate acquisition (swallowing) and substrate degradation (digesting). Zn(2+) recycling from degraded proteins to new proteins is a fourth cycle that might pace lysosomal function under some conditions. Heritable insufficient or excess functions of CysHis cathepsins are associated with dysfunctional inflammation and immunity/auto-immunity, including diabetic pathogenesis.
authors.affiliation: Dept. of Pharmacology, School of Medicine, Wright State University, Dayton, Ohio 45435, USA. thomas.lockwood@wright.edu
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Lockwood
mesh_terms: D001343:Autophagy; D055162:Biocatalysis; D002403:Cathepsins / Q000737:chemistry / Q000378:metabolism*; D003545:Cysteine / Q000737:chemistry*; D006639:Histidine / Q000737:chemistry*; D008247:Lysosomes / Q000378:metabolism*; D008670:Metals / Q000378:metabolism*; D010084:Oxidation-Reduction; D011522:Protons
chemical_list: D008670:Metals; D011522:Protons; D006639:Histidine; D002403:Cathepsins; D003545:Cysteine