Department of Pharmacology & Toxicology

Norma C. Adragna, Ph.D., Interim Chair

Thomas Lockwood

 

Thomas D. Lockwood, Ph.D.

Associate Professor

Campus address: 061 Medical Sciences Bldg.
Phone: (937) 775-4402
Fax: (937) 775-7221
e-mail: thomas.lockwood@wright.edu


Education

B.A., Biology, Gettysburg College, Gettysburg, PA
Ph.D., Toxicology, University of Rochester, Rochester, NY

Research Interests

  • Metal-redox control of cysteine proteases. The functions of many cell proteins are redox-modified in conjunction with multiple other controls. A protein sulfur site can be reversibly or irreversibly oxidized to many derivatives. The redox proteome consists of hundreds of cell proteins which undergo changes in partition among multiple redox states. The activity of many enzymes represents the balance between oxidations and reductions. The redox code which links the redox state of many proteins to the cell transfer of reductive energy is not yet deciphered. Responsiveness to metal redox might be among factors of the protein redox code. It has long been common practice to assay CysHis cathepsins with excess amounts of metal chelator (EDTA), strong reductant (5-10 mM dithiothreitol), and optimal acid pH. It has not been considered that some metals, protein redox state, and protonation of Cys and His might be endogenous, energy-dependent controls which are hidden by the over-familiarity of biochemical technology. In the artificial absence of metals, CysHis protease reaction rates are continuously graded in relation to concentration of disulfhydryl activators. The presence of some types of amino acids in close proximity to cysteine can create a metal sharing site with extreme sensitivity to metal binding and metal redox. Fe3+, but not Fe2+, preemptively inhibits CysHis proteases. Metal /redox /proton factors are messengers linking the reaction rates of mature proteases to higher level cell controls. Insofar as the pro-region cleavage is now attributed to auto-activation the factors influencing the reaction rate of the mature protease might also influence the activation of pro-proteases. I propose that CysHis proteases are "wired" to the cell redox network.
  • Anti-proteolytic therapy against malaria. Among many applications of this theory are metal-interactive, anti-malarial protease inhibitors. Some drugs co-bind Fe3+ and the substrate binding regions of proteases so as to enhance the natural inhibitory action of oxidized Fe3+. Derivatives of the biguanide pharmacophore are among such agents. It is hoped that anti-malarial protease inhibitors will be developed in order to take advantage of the large amounts of Fe3+ present in erythrocytes, synergistically treated with combinations of pro-oxidative drugs and Fe3+ binding protease inhibitors.

Sponsorship: American Heart Association, Regional Affiliate, and commercial sources


Selected Publications

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]