Glutathione transferase P1-1: self-preservation of an anti-cancer enzyme.
Self-preservation is a typical property of living organisms, observed in the simplest prokaryotic cell as well as in the more complex pluricellular organisms. Surprisingly we found a self-preservation mechanism operating at the level of a single enzyme. Human glutathione transferase P1-1 operates in such a way towards either killer compounds (competitive and irreversible inhibitors) or physical factors (temperature and UV-rays), which could suppress its detoxicating and anti-cancer activity in the cell. This property, here termed 'co-operative self-preservation', is based on a structural intersubunit communication, by which one subunit, as a consequence of an inactivating modification, triggers a defence arrangement in the other subunit. Paradoxically this ability, developed during evolution for the survival of the cell, may not always be advantageous for us. In fact, glutathione transferase P1-1 is overexpressed in most tumour cells and pharmacological attempts to inhibit this enzyme in vivo, to prevent the drug resistance phenomenon during chemotherapy, may be thwarted by such self-preservation.
Ricci
Giorgio
G
Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, 00133 Rome, Italy. riccig@uniroma2.it
Caccuri
Anna Maria
AM
Lo Bello
Mario
M
Parker
Michael W
MW
Nuccetelli
Marzia
M
Turella
Paola
P
Stella
Lorenzo
L
Di Iorio
Ernesto E
EE
Federici
Giorgio
G
D001665:Binding Sites; D003198:Computer Simulation; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008958:Models, Molecular; D021122:Protein Subunits
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D021122:Protein Subunits; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase