Dog bites man or man bites dog? The enigma of the amino acid conjugations

Abstract

The proposition posed is that the value of amino acid conjugation to the organism is not, as in the traditional view, to use amino acids for the detoxication of aromatic acids. Rather, the converse is more likely, to use aromatic acids that originate from the diet and gut microbiota to assist in the regulation of body stores of amino acids, such as glycine, glutamate, and, in certain invertebrates, arginine, that are key neurotransmitters in the CNS. As such, the amino acid conjugations are not so much detoxication reactions, rather they are homeostatic and neuroregulatory processes. Experimental data have been culled in support of this hypothesis from a broad range of scientific and clinical literature. Such data include the low detoxication value of amino acid conjugations and the Janus nature of certain amino acids that are both neurotransmitters and apparent conjugating agents. Amino acid scavenging mechanisms in blood deplete brain amino acids. Amino acids glutamate and glycine when trafficked from brain are metabolized to conjugates of aromatic acids in hepatic mitochondria and then irreversibly excreted into urine. This process is used clinically to deplete excess nitrogen in cases of urea cycle enzymopathies through excretion of glycine or glutamine as their aromatic acid conjugates. Untoward effects of high-dose phenylacetic acid surround CNS toxicity. There appears to be a relationship between extent of glycine scavenging by benzoic acid and psychomotor function. Glycine and glutamine scavenging by conjugation with aromatic acids may have important psychosomatic consequences that link diet to health, wellbeing, and disease.

The glycine deportation system and its pharmacological consequences

“…Various lines of evidence have been presented in support of this theory (Beyoğlu et al, 2011), and can be summarized as follows: Compared with glucuronic acid conjugation, for example, amino acid conjugation does not render aromatic acids significantly more water soluble. In many cases, the converse is true.…”

“…We have recently proposed that the principal means of GLY removal from its systemic pool is not by metabolic degradation but by scavenging by benzoic acid (BA), mainly in the liver, but to some extent in the kidney (Beyoğlu et al, 2011). This reaction, in contradistinction to the mitochondrial degradation by the glycine cleavage system and SHMT, is irreversible.…”

“…We have recently argued that the conjugation of aromatic acids with the amino acids GLY, glutamine/glutamate, and taurine is not as hitherto believed a detoxication reaction for certain aromatic acids, such as BA and phenylacetic acid, but rather a homeostatic neuroregulatory mechanism for these same amino acids, that are CNS neurotransmitters (Beyoğlu et al, 2011). What follows from this is that benzoic acid should be viewed as a means of regulating GLY pools and not GLY a means of accelerating the excretion of benzoic acid.…”

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

“…Traditionally, glycine conjugation became part of the paradigm of detoxification, with the critical role of glycine conjugation for aromatic acids [7]. More recently, new views were proposed, shifting the focus to glycine homeostasis to assist in the regulation of body stores of glycine and other amino acids which are key neurotransmitters in the central nervous system (CNS) [8] or to serve as a molecular escort in the glycine deportation system to excrete excess glycine into urine as hippuric acid [9]. …”

A Novel Anti-Hepatitis C Virus and Antiproliferative Agent Alters Metabolic Networks in HepG2 and Hep3B Cells

“…It has also been proposed that glycine may protect the cell by conjugating potentially toxic acids and making them available for deportation [23,24]. The presence of reactive oxygen species (ROS) depletes GSH, oxidizing it to its dimer GSSG, which can be reduced back to GSH by the action of glutathione reductase (GR).…”