title: The impact of nitric oxide toxicity on the evolution of the glutathione transferase superfamily: a proposal for an evolutionary driving force.
abstract: Glutathione transferases (GSTs) are protection enzymes capable of conjugating glutathione (GSH) to toxic compounds. During evolution an important catalytic cysteine residue involved in GSH activation was replaced by serine or, more recently, by tyrosine. The utility of these replacements represents an enigma because they yield no improvements in the affinity toward GSH or in its reactivity. Here we show that these changes better protect the cell from nitric oxide (NO) insults. In fact the dinitrosyl·diglutathionyl·iron complex (DNDGIC), which is formed spontaneously when NO enters the cell, is highly toxic when free in solution but completely harmless when bound to GSTs. By examining 42 different GSTs we discovered that only the more recently evolved Tyr-based GSTs display enough affinity for DNDGIC (KD < 10(-9) M) to sequester the complex efficiently. Ser-based GSTs and Cys-based GSTs show affinities 10(2)-10(4) times lower, not sufficient for this purpose. The NO sensitivity of bacteria that express only Cys-based GSTs could be related to the low or null affinity of their GSTs for DNDGIC. GSTs with the highest affinity (Tyr-based GSTs) are also over-represented in the perinuclear region of mammalian cells, possibly for nucleus protection. On the basis of these results we propose that GST evolution in higher organisms could be linked to the defense against NO.
authors.affiliation: Department of Chemical Sciences and Technologies, University of Rome, Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Bocedi
authors.forename: Raffaele
authors.initials: R
authors.lastname: Fabrini
authors.forename: Andrea
authors.initials: A
authors.lastname: Farrotti
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Stella
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Ketterman
authors.forename: Jens Z
authors.initials: JZ
authors.lastname: Pedersen
authors.forename: Nerino
authors.initials: N
authors.lastname: Allocati
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Lau
authors.forename: Stephan
authors.initials: S
authors.lastname: Grosse
authors.forename: Lindsay D
authors.initials: LD
authors.lastname: Eltis
authors.forename: Antonio
authors.initials: A
authors.lastname: Ruzzini
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Edwards
authors.forename: Laura
authors.initials: L
authors.lastname: Morici
authors.forename: Erica
authors.initials: E
authors.lastname: Del Grosso
authors.forename: Leonardo
authors.initials: L
authors.lastname: Guidoni
authors.forename: Daniele
authors.initials: D
authors.lastname: Bovi
authors.forename: Mario
authors.initials: M
authors.lastname: Lo Bello
authors.forename: Giorgio
authors.initials: G
authors.lastname: Federici
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.forename: Philip G
authors.initials: PG
authors.lastname: Board
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ricci
mesh_terms: D000818:Animals; D001419:Bacteria / Q000201:enzymology / Q000235:genetics; D019143:Evolution, Molecular; D005982:Glutathione Transferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D009569:Nitric Oxide; D005982:Glutathione Transferase
keywords: Dinitrosyl Iron Complex; Enzyme Inhibitors; Enzyme Structure; Enzymes; Evolution; Glutathione Transferase; Nitric Oxide