Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation

  title={Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation},
  author={Christoffel P. S. Badenhorst and Rencia van der Sluis and Elardus Erasmus and Alberdina Aike van Dijk},
  journal={Expert Opinion on Drug Metabolism \& Toxicology},
  pages={1139 - 1153}
Introduction: Glycine conjugation of mitochondrial acyl-CoAs, catalyzed by glycine N-acyltransferase (GLYAT, E.C., is an important metabolic pathway responsible for maintaining adequate levels of free coenzyme A (CoASH). However, because of the small number of pharmaceutical drugs that are conjugated to glycine, the pathway has not yet been characterized in detail. Here, we review the causes and possible consequences of interindividual variation in the glycine conjugation pathway… 

A new perspective on the importance of glycine conjugation in the metabolism of aromatic acids

It will be argued that the major role of glycine conjugation is to dispose of the end products of phenylpropionate metabolism, and it will be explained that the glycine Conjugation of benzoate, a commonly used preservative, exacerbates the dietary deficiency of Glycine in humans.

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

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, indicating that individuals with this haplotype might have a decreased ability to metabolise benzoate when compared to individuals with the 156AsN > Ser variant.

Sequencing and molecular characterization of variations in the glycine N-acyltransferase gene

It was found that participant 17 may have multiple copies of parts of the 3-terminal end of the gene (exons five and six), which might have an effect on GLYAT activity, but no correlation could be made between the variations identified during this study and the cohort’s detoxification ability.

Glycine Metabolism and Its Alterations in Obesity and Metabolic Diseases

The present review aims at synthesizing the recent advances in glycine metabolism, pinpointing its main metabolic pathways, identifying the causes leading to glycine deficiency—especially in obesity and associated metabolic disorders— and evaluating the potential benefits of increasing glycine availability to curb the progression of obesity and obesity-related metabolic disturbances.

The Use of p‐Aminobenzoic Acid as a Probe Substance for the Targeted Profiling of Glycine Conjugation

Glycine conjugation facilitates the metabolism of toxic aromatic acids, capable of disrupting mitochondrial integrity. Owing to the high exposure to toxic substrates, characterization of individual

Analyses of the genetic diversity and protein expression variation of the acyl: CoA medium-chain ligases, ACSM2A and ACSM2B.

The allelic variation, haplotype diversity, Tajima's D values, and phylogenetic analyses indicated that AC SM2A and ACSM2B are highly conserved and essential for life as it maintains the CoA and glycine homeostasis in the liver mitochondria.

New insights into the catalytic mechanism of human glycine N‐acyltransferase

The hippuric acid concentrations produced by the GLYAT enzyme reaction were analyzed using the allosteric sigmoidal enzyme kinetic module and showed mechanistic kinetic cooperativity as described by the Ferdinand enzyme mechanism rather than the previously assumed Michaelis–Menten reaction mechanism.

Cytosolic 10-formyltetrahydrofolate dehydrogenase regulates glycine metabolism in mouse liver

It is indicated that in the absence of ALDH1L1 enzyme, 10-formyl-THF cannot be efficiently metabolized in the liver, which leads to the decrease in THF causing reduced generation of glycine from serine and impaired histidine degradation, two pathways strictly dependent on THF.

Contribution towards a Metabolite Profile of the Detoxification of Benzoic Acid through Glycine Conjugation: An Intervention Study

It is disclosed that detoxification of benzoic acid through glycine conjugation to hippuric acid does not indicate glycine depletion, but is supplemented by ample glycine regeneration, indicating that time-dependent metabolomics investigations, using designed interventions, provide a way of interpreting the variation induced by the different factors of a designed experiment.



Amino acid conjugation: contribution to the metabolism and toxicity of xenobiotic carboxylic acids

Evidence is presented that in the absence of glycine conjugation substrates that form acyl-CoA thioesters perturb mitochondrial function, and the concept that xenobiotic substrate selectivity provides a barrier to protect the metabolic integrity of the mitochondria is presented.

Hereditary and acquired diseases of acyl-coenzyme A metabolism.

Enzymatic Characterization and Elucidation of the Catalytic Mechanism of a Recombinant Bovine Glycine N-Acyltransferase

The recombinant bovine GLYAT enzyme, combined with this new understanding of its active site and reaction mechanism, could be a powerful tool to investigate the functional significance ofGLYAT sequence variations.

The utilization of alanine, glutamic acid, and serine as amino acid substrates for glycine N‐acyltransferase

The conjugation of benzoyl‐CoA with the aliphatic and acidic amino acids by glycine N‐acyltransferase, as well as the amides of the latter group, was investigated and may prove to have a useful contribution to detoxification of elevated acyl‐CoAs.

The effects of ions on the conjugation of xenobiotics by the aralkyl-CoA and arylacetyl-CoA N-acyltransferases from bovine liver mitochondria.

The data suggest that the increase in Kglym is due to bound K+ forcing reorientation of salicylyl-CoA at the active site so that it impinges on the glycine binding site, which accounts for its slow rate of metabolism.

Role of mitochondrial and cytoplasmic serine hydroxymethyltransferase isozymes in de novo purine synthesis in Saccharomyces cerevisiae.

Growth and 13C NMR experiments indicate that the two isozymes function in different directions, depending on the nutritional conditions of the cell, and suggest the existence of at least two sites of de novo purine biosynthesis in growing yeast cells, each being fed by distinct pools of precursors.

Genetic polymorphisms of Glycine N-acyltransferase (GLYAT) in a French Caucasian population

A comprehensive investigation of GLYAT genetic polymorphisms in DNA samples from 55 subjects of French Caucasian origin, using polymerase chain reaction–single-strand conformation polymorphism and sequencing strategies suggests that these variants might have a potential role on theGLYAT protein activity.

Effect of valproic acid on glycine conjugation of benzoic acid.

VPA minimally influenced the capacity of glycine conjugation of benzoic acid in normal rats, but decreased it markedly in glycine-loaded rats.