Figure 5.

The ATP-depleting futile 5-oxoproline cycle. Glutathione deficiency increases the activity of γ-glutamyl cysteine synthase, an ATP utilizing enzyme. However, if cysteine deficiency exists, then step 2 of this reaction sequence is blocked and γ-glutamyl cysteine cannot be generated. Instead, the γ-glutamyl phosphate synthesized by step 1 will autocyclize to form 5-oxoproline. The 5-oxoproline ring can then be broken open by 5-oxoprolinase to regenerate glutamate. This reaction also requires energy from ATP hydrolysis. This series of reactions creates a futile cycle that consumes two ATP molecules for each circuit. When ATP levels fall, the 5-oxoprolinase reaction is inhibited and this leads to the accumulation of 5-oxoproline.