The GCLC gene consists of 16 exons and encodes the 636 amino acid protein g-GCSc (g-glutamylcysteine synthetase heavy subunit), also designated g-L-glutamate-L-cysteine ligase catalytic subunit (GLCLC). g-GCSc is expressed in hemocytes, brain, liver and kidney. g-GCSc associates with a regulatory or modifier subunit, g-GCSm (g-glutamylcysteine synthetase light subunit), to form a heterodimer, g-GCS. g-GCS is the first enzyme involved and the rate determining step in glutathione biosynthesis. Oxidants, cadium and methyl mercury upregulate the transcription of g-GCS. H2O2 regulation depends on the Yap1 protein and the presence of glutamate, glutamine and lysine. Cadium regulates transcription through proteins Met-4, Met-31 and Met-32. Cbf1, a DNA binding protein, inhibits transcription of g-GCS. Chemopreventive compounds cause increased levels of g-GCSc in kidney tissues, which may protect against chemically induced carcinogenesis. A His370Leu amino acid change in g-GCSc causes deficiencies in activity which are responsible for hemolytic anemia and low red blood cell glutathione levels.
