A new class of glutathione transferases has been discovered by analysis of the expressed sequence tag data base and sequence alignment. Glutathione S-transferases (GSTs) of the new class, named Omega, exist in several mammalian species and Caenorhabditis elegans. In humans, GSTO 1-1 is expressed in most tissues and exhibits glutathione-dependent thiol transferase and dehydroascorbate reductase activities characteristic of the glutaredoxins. The structure of GSTO 1-1 has been determined at 2.0-Å resolution and has a characteristic GST fold (Protein Data Bank entry code 1eem). The Omega class GSTs exhibit an unusual N-terminal extension that abuts the C terminus to form a novel structural unit. Unlike other mammalian GSTs, GSTO 1-1 appears to have an active site cysteine that can form a disulfide bond with glutathione.

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The hypothetical protein C7orf24 has been implicated as a cancer marker with a potential role in cell proliferation. We have identified C7orf24 as ␥-glutamyl cyclotransferase (GGCT) that catalyzes the formation of 5-oxoproline (pyroglutamic acid) from ␥-glutamyl dipeptides and potentially plays a significant role in glutathione homeostasis. In the present study we have identified the first cDNA clones encoding a ␥-glutamyl cyclotransferase. The GGCT gene is located on chromosome 7p14-15 and consists of four exons that span 8 kb. The primary sequence is 188 amino acids in length and is unlike any protein of known function. We crystallized functional recombinant ␥-glutamyl cyclotransferase and determined its structure at 1.7 Å resolution. The enzyme is a dimer of 20,994-Da subunits. The topology of GGCT is unrelated to other enzymes associated with cyclotransferase-like activity. The fold was originally classified as "BtrG-like," a small family that only includes structures of hypothetical proteins from Mus musculus, Escherichia coli, Pyrococcus horikoshii, and Arabidopsis thaliana. Since this is the first member of this family with a defined function, we propose to refer to this structure as the ␥-glutamyl cyclotransferase fold. We have identified a potential active site pocket that contains a highly conserved glutamic acid (Glu 98 ) and propose that it acts as a general acid/base in the reaction mechanism. Mutation of Glu 98 to Ala or Gln completely inactivates the enzyme without altering the overall fold.

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