Search Results (3)

Clear cell renal cell carcinoma (KIRC) is the most common subtype of renal cell carcinoma (RCC). This form of cancer is characterized by resistance to traditional therapies and an increased likelihood of metastasis. A major factor contributing to the pathogenesis of KIRC is the alteration of metabolic pathways. As kidney cancer is increasingly considered a metabolic disease, there is a growing need to understand the enzymes involved in the regulation of metabolism in tumorigenic cells. In this context, our research focused on glycine N-acyltransferase (GLYAT), an enzyme known to play a role in various metabolic diseases and cancer. Here, through a bioinformatic analysis of public databases, we performed a characterization of GLYAT expression levels in KIRC cases. Our goal is to evaluate whether GLYAT could serve as a compelling candidate for an in-depth study, given its pivotal role in metabolic regulation and previously established links to other malignancies. The analysis showed a marked decrease in GLYAT expression in all stages and grades of KIRC, regardless of mutation rates, suggesting an alternative mechanism of regulation along the tumor development. Additionally, we observed a hypomethylation in the GLYAT promoter region and a negative correlation between the expression of the GLYAT and the levels of cancer-associated fibroblasts. Finally, the data show a correlation between higher levels of GLYAT expression and better patient prognosis. In conclusion, this article underscores the potential of GLYAT as a diagnostic and prognostic marker in KIRC. Full article

The glycine conjugation pathway in humans is involved in the metabolism of natural substrates and the detoxification of xenobiotics. The interactions between the various substrates in this pathway and their competition for the pathway enzymes are currently unknown. The pathway consists of a mitochondrial xenobiotic/medium-chain fatty acid: coenzyme A (CoA) ligase (ACSM2B) and glycine N-acyltransferase (GLYAT). The catalytic mechanism and substrate specificity of both of these enzymes have not been thoroughly characterised. In this study, the level of evolutionary conservation of GLYAT missense variants and haplotypes were analysed. From these data, haplotype variants were selected (156Asn > Ser, [17Ser > Thr,156Asn > Ser] and [156Asn > Ser,199Arg > Cys]) in order to characterise the kinetic mechanism of the enzyme over a wide range of substrate concentrations. The 156Asn > Ser haplotype has the highest frequency and the highest relative enzyme activity in all populations studied, and hence was used as the reference in this study. Cooperative substrate binding was observed, and the kinetic data were fitted to a two-substrate Hill equation. The coding region of the GLYAT gene was found to be highly conserved and the rare 156Asn > Ser,199Arg > Cys variant negatively affected the relative enzyme activity. Even though the 156Asn > Ser,199Arg > Cys variant had a higher affinity for benzoyl-CoA (s_0.5,benz = 61.2 µM), k_cat was reduced to 9.8% of the most abundant haplotype 156Asn > Ser (s_0.5,benz = 96.6 µM), while the activity of 17Ser > Thr,156Asn > Ser (s_0.5,benz = 118 µM) was 73% of 156Asn > Ser. The in vitro kinetic analyses of the effect of the 156Asn > Ser,199Arg > Cys variant on human GLYAT enzyme activity indicated that individuals with this haplotype might have a decreased ability to metabolise benzoate when compared to individuals with the 156Asn > Ser variant. Furthermore, the accumulation of acyl-CoA intermediates can inhibit ACSM2B leading to a reduction in mitochondrial energy production. Full article

The glycine-N-acyltransferase (GLYAT) is well known to be involved in thedetoxification of endogenous and exogenous xenobiotic acyl-CoA's in mammals.Unfortunately, the knowledge about the gene encoding GLYAT is very limited. Here wereport a novel gene encoding a GLYAT member, designated as GLYATL1, which was1546 base pairs in length and contained an open reading frame (ORF) encoding apolypeptide of 302 amino acids. GLYATL1 was a split gene that was consisted of 7 exonsand 6 introns and mapped to chromosome 11q12.1. The expression of GLYATL1 could befound in liver, kidney, pancreas, testis, ovary and stomach among 18 human tissues by RT-PCR analysis. Subcellular localization of myc-tagged GLYATL1 fusion protein revealedthat GLYATL1 was distributed primarily in the cytoplasm of COS-7 cells. Furthermore,through the pathway profiling assay, the GLYATL1 protein was found to activate HSEsignaling pathway in a dose-dependent manner when overexpressed in HEK293T cells. Full article