title: Conservation of the coding regions of the glycine N-acyltransferase gene further suggests that glycine conjugation is an essential detoxification pathway.
abstract: Thorough investigation of the glycine conjugation pathway has been neglected. No defect of the glycine conjugation pathway has been reported and this could reflect the essential role of glycine conjugation in hepatic metabolism. Therefore, we hypothesised that genetic variation in the open reading frame (ORF) of the GLYAT gene should be low and that deleterious alleles would be found at low frequencies. This hypothesis was investigated by analysing the genetic variation of the human GLYAT ORF using data available in public databases. We also sequenced the GLYAT ORF of a small cohort of South African Afrikaner Caucasian individuals. In total, data from 1537 individuals was analysed. The two most prominent GLYAT haplotypes in all populations analysed, were S156 (70%) and T17S156 (20%). The S156C199 and S156H131 haplotypes, which have a negative effect on the enzyme activity of a recombinant human GLYAT, were detected at very low frequencies. In the Afrikaner Caucasian cohort a novel Q61L SNP occurring at a high frequency (12%) was detected. The results of this study indicated that the GLYAT ORF is highly conserved and supported the hypothesis that the glycine conjugation pathway is an essential detoxification pathway. These findings emphasise the importance of future investigations to determine the in vivo capacity of the glycine conjugation pathway for the detoxification of benzoate and other xenobiotics.
authors.affiliation: Centre for Human Metabonomics, Biochemistry Division, North-West University, Potchefstroom 2520, South Africa.
authors.forename: Rencia
authors.initials: R
authors.lastname: van der Sluis
authors.affiliation: Centre for Human Metabonomics, Biochemistry Division, North-West University, Potchefstroom 2520, South Africa.
authors.forename: Christoffel P S
authors.initials: CP
authors.lastname: Badenhorst
authors.affiliation: Centre for Human Metabonomics, Biochemistry Division, North-West University, Potchefstroom 2520, South Africa.
authors.forename: Elardus
authors.initials: E
authors.lastname: Erasmus
authors.affiliation: Centre for Human Metabonomics, Biochemistry Division, North-West University, Potchefstroom 2520, South Africa.
authors.forename: Etresia
authors.initials: E
authors.lastname: van Dyk
authors.affiliation: Centre for Human Metabonomics, Biochemistry Division, North-West University, Potchefstroom 2520, South Africa.
authors.forename: Francois H
authors.initials: FH
authors.lastname: van der Westhuizen
authors.affiliation: Centre for Human Metabonomics, Biochemistry Division, North-West University, Potchefstroom 2520, South Africa. Electronic address: albie.vandijk@nwu.ac.za.
authors.forename: Alberdina A
authors.initials: AA
authors.lastname: van Dijk
mesh_terms: D000217:Acyltransferases / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D001565:Benzoates / Q000378:metabolism; D044383:Black People / Q000235:genetics; D015331:Cohort Studies; D017124:Conserved Sequence / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D005998:Glycine / Q000378:metabolism*; D006239:Haplotypes; D006626:Hippurates / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics*; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013019:South Africa; D044465:White People / Q000208:ethnology / Q000235:genetics; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D001565:Benzoates; D006626:Hippurates; D015262:Xenobiotics; D000217:Acyltransferases; C020680:glycine acyltransferase; C030514:hippuric acid; D005998:Glycine
keywords: Afrikaner Caucasian; Benzoate; GLYAT SNPs; GLYAT haplotypes; Salicylate; Xenobiotic detoxification