Amino acid derivatives acyl-CoAs

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. 

Flavoproteins Yeast fatty acyl-CoA oxidase Porcine liver fatty acyl-CoA dehydrogenase Yeast glutathione reductase Egg-white flavoprotein Old yellow enzyme D-amino acid oxidase NADPH-cytochrome P-450 reductase Flavin Type of bonding between flavin and protein. Chemistry of charge-transfer complexes involving flavin and second ligand (e.g. phenolor amino-acid derivative )... 

Biochemical reactions include several types of decarboxylation reactions as shown in Eqs. (1)-(5), because the final product of aerobic metabolism is carbon dioxide. Amino acids result in amines, pyruvic acid and other a-keto acids form the corresponding aldehydes and carboxylic acids, depending on the cooperating coenzymes. Malonyl-CoA and its derivatives are decarboxylated to acyl-CoA. -Keto carboxylic acids, and their precursors (for example, the corresponding hydroxy acids) also liberate carbon dioxide under mild reaction conditions. 

The S-CoA derivative then acylates the amino group of the particular amino acid in an analogous way to the acetylation of amine groups described above, yielding a peptide conjugate. This is catalyzed by an amino acid N-acyltransferase, which is located in the mitochondria. Two such enzymes have been purified, each using a different group of CoA derivatives. 

Fig. 1. Structure of CoA, composed of three parts a nucleotide pan derived from 3 -adenosine-5 -pbosphate, forming a phosphodiester bond with a 4-phospho derivative of pantothenic acid, and a third pan derived horn the amino acid, cysteine. The side chain SH group of the latter is ftee in this compound and is readily acylated, and thus able to act as a carrier for acyl groups in biochemical reactions in which it transfers that group between two substrates...

Amino Acid Conjugation. In the second type of acylation reaction, exogenous carboxylic acids are activated to form S-CoA derivative in a reaction involving ATP and CoA. These CoA derivatives then acylate the amino group of a variety of amino acids. Glycine and glutamate appear to be the most common acceptor of amino acids in mammals in other organisms, other amino acids are involved. These include ornithine in reptiles and birds and taurine in fish. 

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 reactions are catalyzed by acyl-CoA amino acid A-acyltransferase, of which two distinct A-acyltransferases exist in mammalian mitochondria. The predominant transferase conjugates medium-chained fatty acyl CoA and substituted benzoic acid derivatives with glycine and is termed an aralkyl-CoA glycine A-acyltransferase, while the other enzyme conjugates arylacetic acid derivatives with glycine, glutamine, or arginine and is an arylacetyl-CoA amino acid A-transferase. 

Conversion of the carboxylic acid to its CoA ester derivative is the rate-limiting step. The enzyme that catalyzes the final reaction, acyl-CoA amino acid N-acyltransferase, is localized in the mitochondria of the kidney and liver. The amino acid substrate selectivity, which varies from species to species, resides in the specific N-acyltransferase that... 

The a,-dehydrogenation is catalyzed by an FAD protein and is analogous to the dehydrogenation of straight-chain acyl-CoA thioesters in jd-oxidation of fatty acids (Chapter 18). Methylenecyclopropylacetyl-CoA derived from the plant toxin hypoglycin (Chapters 15 and 18), which inhibits this step in )S-oxidation, also inhibits it in the catabolism of branched-chain amino acids. 

Short chain acyl-CoA substrates utilized by the R1128 initiation module are derived mainly dvough amino acid catabolism. The catabolic pathways involve... 

Isoleucine is a good example of branched-chain amino acids for a semi-in-depth examination. Unique aspects of the metabolism of valine and leucine are highlighted. After transamination and oxidative decarboxylation to form the branched-chain fatty-acyl CoA, a double bond is formed between a and b carbons utilizing FAD then water is added to form a b hydroxy derivative (Fig. 18.4). Then a NAD+-dependent dehydrogenase produces a keto derivative of the branched-chain fatty-acyl CoA. The similarity to straight-chain fatty-acid oxidation should be noted. This keto fragment is cleaved with participation of coenzyme A to form acetyl CoA, which ei-... 

Rifamycin B, produced by Amycolatopsis mediterranei, is one of the most notable members of the ansamycin family [36, 37, 64, 65] (Fig. 14). It has been used clinically in a synthetically modified form called rifampicin and it is still one of the first-line therapies effective in the treatment of tuberculosis and other mycobacterial infections. The starter unit for rifamycin polyketide assembly is part of the chromophore and is derived from 3-amino-5-hydroxybenzoic acid. Five polyketide synthases are involved in the formation of rifamycin chromophore and the first polyketide synthase contains at the N terminus the loading domain for 3-amino-5-hydroxybenzoic acid, which consists of an acyl-CoA ligase linked to ACP, and module 1-3. The rifamycin polyketide synthase lacks a TE domain at the C terminus. The release of polyketide chain from polyketide synthase and the formation of amide to generate the macrocyclic lactam will be catalyzed by RifF, which is very similar to arylamine A-acetyltransferase. 

Most coenzymes, such as functional groups on the enzyme amino acids, are regenerated during the course of the reaction. However, CoASH and a few of the oxidation-reduction coenzymes are transformed during the reaction into products that dissociate from the enzyme at the end of the reaction (e.g., CoASH is converted to an acyl CoA derivative, and NAD+ is reduced to NADH). These dissociating coenzymes are nonetheless classified as coenzymes rather than substrates because they are common to so many reactions, the original form is regenerated by subsequent reactions in a metabolic pathway, they are synthesized from vitamins, and the amount of coenzyme in the cell is nearly constant. 

Many important reactions are driven to completion by formation of pyrophosphate in the reaction ATP —> AMP + PPj followed by PPj —> 2 Pj. Examples would include DNA polymerase (Section 5.3.1, p. 127), attachment of amino acids to transfer RNA (Section 29.2.1, p. 818), synthesis of NAD+ (p. 709), synthesis of acyl CoA derivatives (p. 606), and many other reactions. Yet in Table 14.1 on page 380, the standard free energy of hydrolysis of pyrophosphate is given as -4.6 kcal/mol, a rather low value. Why should a reaction with such a small standard hee energy change be utilized in such critically important processes ... 

Isoleucine can give its amino group to a-ketoglutarate in a transamination reaction and then be oxidatively decarboxylated and dehydrogenated to form the corresponding (a,(3)-unsaturated acyl-CoA derivative. Further reactions (see the figure on p. 424) then are identical to fatty acid oxidation until the carbon skeleton is split into acetyl-S-CoA and propionyl-S-CoA. The three subsequent steps for the conversion of the (odd-chain) propionyl-S-CoA to succinyl-S-CoA have been discussed for the oxidation of odd-chain fatty acids (see Chapter 22). 

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