Correction

Michael Emmett. Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid): A Tale of Two Cycles, One an ATP-Depleting Futile Cycle and the Other a Useful Cycle. Clin J Am Soc Nephrol 9: 191–200, 2014.

Due to author error, the direction of the ATP to ADP+P reaction was inadvertently reversed in Figure 4 and Figure 5 of the article. The corrected figures are included below.

Figure 4.

γ-Glutamyl cysteine synthetase: a two-step reaction sequence. (A) Two synthetic reactions first combine glutamic acid and cysteine to form γ-glutamylcysteine and then add glycine to form glutathione. (These two reactions were also shown in Figure 1.) Note the interrupted blue arrow, which represents inhibition of the enzyme γ-glutamylcysteine synthetase (also called γ-glutamylcysteine ligase) by physiologic concentrations of glutathione. (B) The γ-glutamylcysteine synthetase reaction, which combines glutamate and cysteine, occurs in two discrete steps. (Step 1) Glutamate enters the active site of the enzyme and is then “activated” by the addition of phosphate from ATP to form γ-glutamyl phosphate. This high energy intermediate molecule remains within the active site of γ-glutamyl cysteine synthetase until step 2, when it combines with cysteine to form γ-glutamyl cysteine. The γ-glutamyl cysteine is then released from the active site of the enzyme. However, if cysteine is deficient, then γ-glutamyl phosphate will autocyclize to form 5-oxoproline. The black dotted lines are part of an ATP-depleting 5-oxoproline futile cycle.

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.