Frequent sequence variants of human glycine N-acyltransferase (GLYAT) and inborn errors of metabolism

Functional Characterisation of Three Glycine N-Acyltransferase Variants and the Effect on Glycine Conjugation to Benzoyl–CoA

“…This indicates how important it is to characterise haplotypes rather than SNPs, especially in the field of pharmacokinetics and pharmacogenomics. The most recent study [34] which compared the enzyme activity of the 61Gln > Leu variant with that of the wild-type, found that the 61Gln > Leu variant showed a decrease in specific activity when compared to the wild-type. It is important to note that the 61Gln > Leu mutation has only been identified in two haplotypes in the South African Afrikaner population that is, 61Gln > Leu,156Asn > Ser and 17Ser > Thr, 61Gln > Leu,156Asn > Ser [27], and therefore, the activity might be affected by the other SNPs in these haplotypes.…”

“…Overall, both the maximal activity and the affinity parameters agreed well with published literature, with our reported values falling in the ranges reported in previous studies (Table 4). It should be noted that two studies [30,34] reported in Table 4 might contain calculation errors as explained in the footnote. Importantly, though, the differences in the kinetic mechanism for the different haplotypes (Table 3) have not been reported previously.…”

“…It is extremely difficult to obtain fresh human liver samples in order to study the catalytic mechanism of GLYAT using a purified enzyme [14]. Previously determined GLYAT kinetic parameters, using either mitochondrial lysate preparations from liver tissue or purified recombinantly expressed GLYAT enzyme, vary considerably [28,[30][31][32][33][34], with only three studies determining the K m value for glycine [28,32,33]. These studies also assumed that GLYAT followed a Michaelis-Menten reaction mechanism and, as a consequence, reported a sequential two-substrate mechanism.…”

“…Most of the studies also did not report on whether the wildtype GLYAT or a variant was used in the analyses. This is important in order to compare the different studies as it has been shown that single nucleotide polymorphisms (SNPs) can alter the kinetic parameters of GLYAT [31,34].…”

Structure of glycine N-acyltransferase clarifies its catalytic mechanism

“…Due to its physiological relevance, human GLYAT has recently received considerable attention. Many groups have reported genetic polymorphisms in the GLYAT gene, and in vitro studies of the prevalent variants showed some of the mutations affect enzymatic activity [8][9][10][11] (Supplementary Table 2). Without a representative GLYAT structure, previous analyses were based on homology models generated using low identity templates (<12 %) 8 , which could introduce severe bias.…”