Metal Chelation as a Release Mechanism for the Epidermal Kallikreins

In prostatic fluid, zinc at millimolar concentration holds the kallikreins inactive; on ejaculation the semenogelins, each binding at least ten Zn²⁺ ions, redistribute that zinc away from the enzymes and release KLK3 to liquefy the coagulum. Chelation-mediated kallikrein release is therefore an established physiological mechanism. The epidermis has the same architecture without a known trigger: KLK5 and KLK7 are non-competitively suppressed by zinc and copper through structurally defined sites that displace the catalytic histidine, at constants overlapping the free-ion range in skin, and zinc inhibition of KLK5 is reversible by EDTA. This paper proposes that pharmacological chelation of those ions releases the epidermal kallikreins and increases generation of LL-37 from hCAP18, with consequences for cathelicidin-driven dermatoses and for patients taking chelating drugs. No dithiocarbamate has ever been assayed against KLK5 or KLK7. Two tests are specified: a bench experiment, including the three-buffer design that distinguishes chelation from direct inhibition and the artefact controls the assay class requires, which also resolves as a by-product the standing two-order-of-magnitude discrepancy in published KLK5 zinc constants; and a parallel pharmacovigilance analysis in patients on long-term chelating therapy, offered as hypothesis-generating rather than decisive. The paper distinguishes throughout between biochemical disinhibition of the purified enzymes, which the experiment can establish, and activation of the epidermal cascade in tissue, which it cannot. Predictions are stated numerically in advance, including an explicit negative; the principal phenotypic counterargument, that zinc-deficiency dermatitis does not resemble Netherton syndrome, is addressed and converted into a sharper prediction. No data are reported.