Amino acid conjugation, xenobiotics

Although bile acid conjugates with amino acids are normally excreted into bile, amino acid conjugates of xenobiotics are usually excreted into urine. Conjugation with endogenous amino acids facilitates urinary excretion because of the organic anion transport systems located in the kidney tubules. 

The second type involves the activation of the xenobiotic to form an acyl CoA derivative, which then reacts with an amino acid to form an amino acid conjugate. 

The conjugation of carboxylic acid xenobiotics with amino acids occurs in both liver and kidney and is catalyzed by an enzyme system located in the mitochondria. Conjugation requires initial activation of the xenobiotic to a Co A derivative in a reaction catalyzed by acyl CoA ligase. The acyl CoA subsequently reacts with an amino acid, giving rise to acylated amino acid conjugate and CoA. 

Many xenobiotic carboxylic acids undergo conjugation with one of a variety of amino acids. In which the carboxyl group of the xenobiotic Is linked In an amide (peptide) bound with the alpha-amino group of the amino acid (78). The chemical classes of acid Involved In amino acid conjugation are relatively few In number, and the reactions are restricted to certain aliphatic, aromatic, heteroaromatic, cinnamic and arylacetlc acids (28). The occurrence of the reaction Is markedly dependent on the steric hindrance around the carboxyl group by substituents on the aryl moiety or the side chain bearing the acid function (79). 

In the past decade, several aspects of xenobiotic conjugation have been studied In aquatic animals. This paper will summarize and review recent findings, with particular emphasis on glycosylation, glutathione conjugation and mercapturlc acid biosynthesis, and amino acid conjugation. 

Xenobiotic carboxylic acids can be excreted as amino acid conjugates, where the COOH grot ) forms an amide bond with the -NHg group of an amino acid. In mammals, the aminn acid most commonly used for conjugation is glycine. This pathway has been studied in vitro and In vivo in several fish species and a marine Invertebrate. 

Although not studied in insects the mechanism of amino acid conjugation usually occurs in two stages (2j6). The first of these, requires ATP and coenzyme A and results in the activation of the xenobiotic acid, and the second involves condensation of the activated xenobiotic acid with the appropriate amino acid. 

Xenobiotics that contain a free or potential carboxyl group can be metabolized by amino acid conjugation in both plants and animals. This reaction is illustrated by the conjugation of 2,4-D with aspartic acid (Equation 31). In higher plants, amino acid conjugation is... 

The formation of an amide bond by organic chemical methods Is usually accomplished by reacting the acid halogenlde and the amino acid unless the acid substrate contains other reactive groups. The acid chloride Is prepared directly with thlonyl chloride (244) or Indirectly via the formation of a mixed anhydride by use of another acid halogenlde (245,246). Isotoplcally labeled [(2,4-Dlchlorophenoxy)acetyl]valine was synthesized by a DCC catalyzed reaction between the acid and valine (247). A few examples of synthetic amino acid conjugates of xenobiotics are shown In Table X. Several taurine conjugates of both alkanolc and benzylic acids have been synthesized and their physical properties determined by Idle et al. (2 ). 

The metabolism of xenobiotic carboxylic acids to amino acid conjugates involves a two-step enzymatic pathway in which the xenobiotic is first activated in an ATP-dependent reaction to the corresponding coenzyme A thioester. This in turn serves as the substrate for an N-acyltransferase that catalyzes the formation of the peptide bond... 

M. expansa, H. diminuta and F. hepatica failed to form hippurate, the glycine conjugate of benzoic acid (8), although small amounts of this product were detected in M. benedeni (60). Given that several other amino acids besides glycine can often serve as acyl acceptors particularly in invertebrate species (3), additional studies are needed before concluding that amino acid conjugation is not a pathway of parasite xenobiotic metabolism. 

Aceiyltransferases catalyze the addition of acetyl groups to xenobiotics containing amino or hydroxyl groups. Two types of acctyltransfera,ses arc involved. The first involves the addition of acetyl CoA to the xcnobiotic and the second involves the activation of a xcnobiotic to form an acyl CoA intermediate, which then reacts with an amino acid to form an amino acid conjugate. 

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