Glutathione Metabolism (gamma-Glutamyl Cycle)

1. 1

   L-Glutamate + L-cysteine + ATP -> gamma-glutamylcysteine + ADP + Pi

   gamma-Glutamylcysteine synthetase (GCL) 6.3.2.2 ST-0336 Irreversible rate-limiting ATP Mg2+
   In Glutamate Cysteine ATP

   Out gamma-Glutamylcysteine ADP Pi
   › Notes

   Rate-limiting step; feedback-inhibited by GSH. Cysteine availability is usually the limiting substrate.

2. 2

   gamma-Glutamylcysteine + glycine + ATP -> glutathione (GSH) + ADP + Pi

   Glutathione synthetase (GSS) 6.3.2.3 ST-0337 Irreversible/directional ATP
   In gamma-Glutamylcysteine Glycine ATP

   Out Glutathione (GSH) ADP Pi
   › Notes

   Deficiency causes 5-oxoprolinuria (pyroglutamic aciduria) with haemolytic anaemia.

3. 3

   2 GSH + H2O2 -> GSSG + 2 H2O

   Glutathione peroxidase (GPX) 1.11.1.9 ST-0338 Irreversible/directional Selenium
   In Glutathione (GSH) H2O2

   Out GSSG (oxidised glutathione) H2O
   › Notes

   Selenocysteine enzyme; the principal peroxide defence of the erythrocyte.

4. 4

   GSSG + NADPH + H+ -> 2 GSH + NADP+

   Glutathione reductase (GSR) 1.8.1.7 ST-0339 Irreversible/directional NADPH FAD
   In GSSG (oxidised glutathione) NADPH H+

   Out Glutathione (GSH) NADP+
   › Notes

   Links antioxidant defence to the pentose phosphate pathway; this is why G6PD deficiency causes oxidative haemolysis. Riboflavin (FAD) dependent.

5. 5

   Xenobiotic/electrophile + GSH -> GS-conjugate -> mercapturic acid

   Glutathione S-transferase (GST) 2.5.1.18 ST-0340 Irreversible/directional GSH
   In Xenobiotic/electrophile Glutathione (GSH)

   Out GS-conjugate
   › Notes

   Phase II conjugation; depletion of GSH by NAPQI underlies paracetamol (acetaminophen) hepatotoxicity, treated with N-acetylcysteine.

Showing all 5 steps.