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.
Highlights
Why do ancestral GSTs utilize cysteine/serine as catalytic residues, whereas more recently evolved GSTs utilize tyrosine?
GST evolution could be linked to the defense against nitric oxide (NO)
During evolution an important catalytic cysteine residue involved in GSH activation was replaced by serine or, more recently, by tyrosine
Summary
GST evolution could be linked to the defense against NO. Significance: This represents a further piece in the puzzle of evolutive adaptation to NO toxicity. During evolution an important catalytic cysteine residue involved in GSH activation was replaced by serine or, more recently, by tyrosine. In a parallel or successive evolutionary step, a serine residue replaced Cys in this activation role This residue is found in the Theta, Tau, Delta, Zeta, Epsilon, and Phi classes GSTs. the most recently evolved GSTs possess a tyrosine residue involved in GSH activation (e.g. Alpha, Pi, Mu, Sigma, Plasmodium falciparum GST, Onchocerca volvulus GST, and Schistosoma GSTs). When NO enters the cell or is produced inside the cell, a further spontaneous reaction occurs, involving endogenous thiols and labile iron, leading to the formation of dinitrosyl1⁄7iron complexes These compounds display paramagnetic properties (g ϭ 2.03) and can function as NO carriers by virtue of their relatively high stability (minutes) compared with free NO (seconds) [8]. The GSTs with the greatest affinity are localized in the perinuclear region suggesting that, beside key cytosolic enzymes, further targets of protection may be DNA or the transcription machinery localized inside the nucleus
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