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.