Alternative titles; symbols
HGNC Approved Gene Symbol: CHAC2
Cytogenetic location: 2p16.2 Genomic coordinates (GRCh38): 2:53,767,783-53,775,196 (from NCBI)
CHAC2 belongs to the ChaC family of gamma-glutamylcyclotransferases, which degrade glutathione into 5-oxoproline and cys-gly. CHAC2 appears to be involved in continuous, basal turnover of cytosolic glutathione (Kaur et al., 2017).
Kaur et al. (2017) cloned human CHAC2, which encodes a deduced 184-amino acid protein. Human CHAC2 shares 50% amino acid identity with CHAC1 (614587) and 94% identity with its mouse ortholog. Human and mouse CHAC2 had apparent molecular masses of 22 and 21 kD, respectively, by SDS-PAGE. Phylogenetic analysis revealed CHAC2 orthologs in various mammals, zebrafish, fruit fly, plants, yeast, and bacteria. Immunofluorescence analysis showed that endogenous CHAC2 localized to cytoplasm in human embryonic kidney (HEK) cells.
Kaur et al. (2017) found that expression of human CHAC2 in yeast deficient in glutathione usage made them able to use glutathione, but not gamma-glutamyl amino acids, as a substrate. In vitro assays with purified recombinant human and mouse CHAC2 confirmed the substrate specificity for glutathione. Human and mouse CHAC2 exhibited comparable kinetic parameters in in vitro enzyme assays, but human CHAC2 showed 10- to 20-fold lower catalytic efficiency than human CHAC1. In HEK cells, endoplasmic reticulum stress and sulfur starvation significantly upregulated expression of CHAC1, but not CHAC2, suggesting that CHAC2 functions as a housekeeper of glutathione degradation. The single E. coli ChaC enzyme exhibited similar in vitro catalytic efficiency to human and mouse CHAC2, indicating that E. coli ChaC is functionally orthologous to CHAC2 rather than CHAC1. The authors suggested that CHAC2, which continuously turns over glutathione, may be the ancestral ChaC family enzyme. Kaur et al. (2017) concluded that CHAC2 mediates continuous, basal turnover of cytosolic glutathione.
Kaur et al. (2017) determined the crystal structure of yeast Gcg1, an ortholog of human CHAC2, at 1.34-angstrom resolution. The structure revealed the presence of a gamma-glutamylcyclotransferase-like fold, as well as the likely catalytic site. The overall structure consists mainly of 7 antiparallel beta strands and 6 alpha helices.
Gross (2017) mapped the CHAC2 gene to chromosome 2p16.2 based on an alignment of the CHAC2 sequence (GenBank BC017941) with the genomic sequence (GRCh38).
Gross, M. B. Personal Communication. Baltimore, Md. 4/20/2017.
Kaur, A., Gautam, R., Srivastava, R., Chandel, A., Kumar, A., Karthikeyan, S., Bachhawat, A. K. ChaC2, an enzyme for slow turnover of cytosolic glutathione. J. Biol. Chem. 292: 638-651, 2017. [PubMed: 27913623] [Full Text: https://doi.org/10.1074/jbc.M116.727479]