Alternative titles; symbolsTSC510CAMELLO, XENOPUS, HOMOLOG OF, 1; CML1HGNC Approved Gene Symbol: NAT8Cytogenetic location: 2p13.1 Genomic coordinates (GRCh38...
Alternative titles; symbols
HGNC Approved Gene Symbol: NAT8
Cytogenetic location: 2p13.1 Genomic coordinates (GRCh38): 2:73,640,722-73,642,421 (from NCBI)
Mercapturic acid synthesis allows detoxification and excretion of cysteinyl conjugates under the form of mercapturic acids. NAT8 catalyzes the last step of mercapturic acid formation by acetylating cysteine S-conjugates to mercapturic acids (Veiga-da-Cunha et al., 2010).
▼ Cloning and Expression
Using primers identified with the differential display method, Ozaki et al. (1998) isolated a NAT8 cDNA, which they designated TSC510, from a human kidney cDNA library. The cDNA encodes a deduced 227-amino acid protein with a molecular mass of 25.6 kD and structural similarity to several bacterial acetyltransferases. Northern blot analysis detected abundant and specific expression of a 1-kb NAT8 transcript in liver and kidney.
By searching an EST database for sequences similar to the Xenopus camello protein, Popsueva et al. (2001) identified NAT8, which they designated CML1. The deduced 227-amino acid protein shares significant similarity with other camello proteins, including a conserved N-terminal hydrophobic domain and C-terminal consensus motifs of GCN5 (see 602301)-related N-acetyltransferases.
Using immunohistochemical analysis, Veiga-da-Cunha et al. (2010) found that epitope-tagged human NAT8 was expressed in the endoplasmic reticulum of transfected Chinese hamster ovary cells.
▼ Gene Function
Based on the expression pattern and structure of NAT8, Ozaki et al. (1998) suggested that the gene plays an important role in the development and maintenance of normal kidney and liver structure and function.
Popsueva et al. (2001) found that overexpression of Xenopus Cml in Xenopus dorsal blastomeres disrupted mesodermal cell movements and loosened cell contacts. Deletion of part of the N-acetyltransferase domain abolished the effects of overexpression. Injection of in vitro-synthesized human NAT8 produced similar developmental defects.
Veiga-da-Cunha et al. (2010) found that lysates of HEK293T cells overexpressing NAT8 had increased activity in N-acetylation of S-benzyl-L-cysteine in the presence of acetyl-CoA, with the formation of free CoA-SH. NAT8 was not active against other L-amino acids examined. About 100-fold lower activity was found with leukotriene E4 as substrate. Mutation analysis revealed that conserved arg149 was required for activity. Overexpression of wildtype or catalytically inactive NAT8 caused cell death in HEK293T cells, suggesting that toxicity is not linked to NAT8 catalytic activity.
▼ Gene Structure
Veiga-da-Cunha et al. (2010) determined that exon 2 of the NAT8 gene contains the complete reading frame.
By radiation hybrid analysis, Ozaki et al. (1998) mapped the NAT8 gene to chromosome 2p13.1-p12.
▼ Molecular Genetics
Associations Pending Confirmation
Suhre et al. (2011) reported a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with nontargeted metabolomics. They identified 37 genetic loci associated with blood metabolite concentrations, of which 25 showed effect sizes that were unusually high for GWAS and accounted for 10 to 60% differences in metabolite levels per allele copy. These associations provided new functional insights for many disease-related associations that had been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism, and Crohn disease. Suhre et al. (2011) identified an association between rs13391552 in the NAT8 gene and N-acetylornithine levels with a p value of 5.4 x 10(-252). The N-acetyltransferase function of NAT8 matches the associating metabolite N-acetylornithine, and Suhre et al. (2011) found association with glomerular filtration rate (GFR) and chronic kidney disease, represented by association of N-acetylornithine with estimated GFR, in this study.