Thomas Lockwood, Ph.D.
Nature invented lysosomes in order to separate the environment of metals, redox and protons from other cell compartments. Complex lysosomal machinery differentially regulates such factors. The CysHis dyad of 11 cathepsins is (a) a sensor of these variables, (b) an integrator of their combined status, and (c) a catalytic responder to intra-vacuolar third messengers. Protein turnover involves recycling of liberated Zn2+ from degraded binding sites to new proteins. Zn2+ is a preemptive inhibitory influence under optimal protonation and reduction. Based upon this and the work of many others, it appears that Zn2+ influences the function of more than 35 CysHis proteases including extra-lysosomal caspases and calpains and the ubiquitin-proteasomal pathway. Zn2+ maintains a safe pace of proteolysis; chronic excess invites excessive inflammation and immunity/auto-immunity. Metformin is an anti-lysosomal "zincophore", decreasing age-related diseases.
Lockwood T.D. Metformin, Zn2+, CysHis peptidolysis, and the pathogenesis of time. (Submitted)
Lockwood T.D. Lysosomal metal, redox and proton cycles influencing the CysHis cathepsin reaction. Metallomics, 2013, 5(2), 110-124).
Lockwood T.D., Responsiveness of parasite Cys His proteases to iron redox. Parasitol Res.; 100:175-81, 2006. [Abstract]
Lockwood T.D., The transfer of reductive energy and pace of proteome turnover: a theory of integrated catabolic control. Antioxid Redox Signal., 7:982-98, 2005. Review. [Abstract]
Lockwood T.D., Cys-His proteases are among the wired proteins of the cell. Arch Biochem Biophys.; 432:12-24, 2004. [Abstract]
Sweeney D., Raymer M.L., and Lockwood T.D., Antidiabetic and antimalarial biguanide drugs are metal-interactive antiproteolytic agents. Biochem Pharmacol.; 66:663-77, 2003. [Abstract]
Lockwood T.D., Cathepsin B responsiveness to glutathione and lipoic acid redox. Antioxid Redox Signal.; 4:681-91, 2002. [Abstract]
Lockwood T.D., Redox-dependent and redox-independent subcomponents of protein degradation in perfused myocardium. Am J Physiol.; 276 (5 Pt 1):E945-54, 1999. [Abstract]
B.A., Biology, Gettysburg College, Gettysburg, PA
Ph.D., Toxicology, University of Rochester, Rochester, NY