GSS

GSS Full Name

glutathione synthetase

GSS Introduction

GSS encodes glutathione synthetase, the second and final enzyme in the de novo glutathione biosynthesis pathway, which catalyzes the ATP-dependent condensation of gamma-glutamylcysteine and glycine to produce glutathione (GSH), the most abundant intracellular non-protein thiol. Glutathione serves as a critical antioxidant, detoxifying reactive oxygen species, maintaining redox homeostasis, and participating in phase II drug metabolism through conjugation reactions catalyzed by glutathione S-transferases. GSS is a homodimeric enzyme localized predominantly in the cytosol, with its highest expression in the liver, kidney, and erythrocytes — tissues with elevated oxidative metabolism. The enzyme operates downstream of gamma-glutamylcysteine ligase (GCL), the rate-limiting first enzyme in glutathione biosynthesis, and its activity is essential for maintaining the cellular GSH pool that protects against oxidative damage, xenobiotic toxicity, and inflammatory injury.

Figure 1. Synthesis of GSH. (Source: Bradauskienė V, et al. 2026)

Mutations in GSS cause glutathione synthetase deficiency (GSSD), a rare autosomal recessive inborn error of metabolism with fewer than 100 cases reported worldwide. GSSD is biochemically characterized by severe depletion of cellular glutathione and massive urinary excretion of 5-oxoproline (pyroglutamic acid), a byproduct of the interrupted gamma-glutamyl cycle that accumulates when gamma-glutamylcysteine cannot be converted to GSH. Clinically, GSSD presents across a severity spectrum: mild forms manifest primarily as chronic hemolytic anemia; moderate forms additionally feature metabolic acidosis and 5-oxoprolinuria; and severe forms include progressive neurological impairment, intellectual disability, seizures, ataxia, and recurrent infections due to impaired immune cell function. The severe phenotype reflects the heightened vulnerability of the central nervous system to oxidative stress when glutathione-dependent neuroprotection is compromised. Management includes lifelong oral supplementation with GSH precursors such as N-acetylcysteine, sodium bicarbonate for metabolic acidosis correction, vitamin C and vitamin E as adjunctive antioxidants, and strict avoidance of known oxidative stress triggers. Early diagnosis through newborn screening and prompt initiation of therapy can significantly improve developmental outcomes, though no treatment fully reverses established neurological damage.

Alternate Names for GSS

GSS; glutathione synthetase; GSHS; HEL-S-64p; HEL-S-88n; GSH-S; GSH synthetase; glutathione synthase; epididymis secretory sperm binding protein Li 64p; epididymis secretory sperm binding protein Li 88n;

• 1. Bradauskienė V, et al. Glutathione in Our Diet and Its Role in the Body: From Disease Prevention to Anti-Aging. Nutrients. 2026 May 21;18(10):1640.
  2. Wu X, et al. Case report: A Chinese patient with glutathione synthetase deficiency and a novel glutathione synthase mutation. Front Pediatr. 2023 Jul 27;11:1212405.