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 | Thomas D Lockwood |
| Journal | Metallomics : integrated biometal science (Metallomics) Vol. 5 Issue 2 Pg. 110-24 (Feb 2013) ISSN: 1756-591X [Electronic] England |
| PMID | 23302864 (Publication Type: Journal Article, Review) |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!