Bile acids amino acid conjugates

Bile acids are also conjugated with amino acids in a similar manner, but different enzymes are involved. 

The bile acids are usually conjugated to the amino acids, glycine or taurine, as shown for the formation of glycocholate in figure 20.21. It is in this form that the bile acids are secreted via the gallbladder into the intestine where they are critically important for the solubilization of dietary lipids. At pH 7, these acids exist as the sodium salts and are often referred to as bile salts. Of course in the acidic environment of the small intestine, they occur largely in their acidic form. 

Bile acids are also conjugated by a similar sequence of reactions involving a microsomal bile acid CoA ligase and a soluble bile acid A-acyl-transferase. The latter has been extensively purified, and differences in acceptor amino acids, of which taurine is the most common, have been related to the evolutionary history of the species. 

Additional reactions of glycine include its ability to become conjugated with bile acids to form conjugated bile salts (see Chapter 19), formation of heme (Chapter 7), formation of purine nucleotides (Chapter 10), formation of creatine (see later), and the formation of hippuric acid from benzoic acid. In the last case, an amide linkage is formed between the carboxyl group of benzoic acid and the amino group of glycine. 

A mechanism for hepatic formation of amino acid conjugates of bile acids developed from early investigations of Siperstein and Murray [37], Bremer [38], and Elliott [39] is summarized as follows ... 

Bile acids are usually conjugated in amide linkage with the amino acid glycine or taurine, giving bile salts. The cholic acid conjugates with glycine and taurine are called glycocholate and taurocholate, respectively. 

These amino acid conjugates are usually less toxic than their precursor acids and hence, are excreted readily into the urine and bile. 

Pagels, P., Starke, D., Kramer, W., Hepatobiliary transport of bile add amino add, bile add peptide, and bile acid oligonucleotide conjugates in rats, Hepatology 1999, 30, 1257-1268. 

Cholic acid and chenodeoxycholic acid, known as the primary bile acids, are quantitatively the most important metabolites of cholesterol. After being biosynthesized, they are mostly activated with coenzyme A and then conjugated with glycine or the non-pro-teinogenic amino acid taurine (see p. 62). The acid amides formed in this way are known as conjugated bile acids or bile salts. They are even more amphipathic than the primary products. 

Before leaving the liver, a large proportion of the bile acids are activated with CoA and then conjugated with the amino acids g/ycine or taurine (2 cf A). In this way, cholic acid gives rise to glycocholic acid and taurocholic acid. The liver bile secreted by the liver becomes denser in the gallbladder as a result of the removal of water (bladder bile 3). 

Receptor-mediated transporters are excipients that serve as substrates to exploit specific receptors present on cell membranes. Examples of various receptors that have been explored for permeation enhancement include bile acids (45), vitamin Bi2 (46), amino acids (47), and folic acid (48). Most of the work in receptor-mediated transporters is conducted via the use of prodrugs. For example, a prodrug of acyclovir conjugated to bile acids was seen to have higher permeability as compared to the original drug, because of receptor-mediated transport of the prodrug via bile acid transporters (49). 

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. 

Before the bile acids leave the liver, they are conjugated to I molecule of either glycine or taurine (an end-product of cystene metabolism) by an amide bond between the carboxyl group of tit J bile acid and the amino group of the added compound. These netfl... 

The taurine residue can also be found as an amide derivative of the 26-carboxylic acid function in the 3p,5a,6p,15a-polyhydroxylated steroids 328 and 329, which were obtained from the starfish Myxoderma platyacanthum [245]. The structures of both compounds were determined from spectral data and chemical correlations. The bile of the sunfish Mola mola has been shown to contain a new bile acid conjugated with taurine (330) together with sodium taurocholate. Compound 330 was identified as sodium 2-[3a,7a, 11 a-trihydroxy-24-oxo-5P-cholan-24-yl]amino]ethane-sulfonate on the basis of its physicochemical data and chemical transformations [246]. 

As already pointed out, cysteine may be metabolized to pyruvate, or it can be oxidized to cystine. It can also be converted to taurine, NH3+-CH2-CH2-S03. Taurine is obtained by oxidizing the -SH group of cysteine and losing the carboxyl group of decarboxylation. Taurine is quite abundant in most tissues and is said to be the most abundant "amino acid" of the human organism. One of its functions is to conjugate primary bile acids (Chapter 19). 

Taurine was discovered in 1827 in ox hUe, where it is conjugated with the bile acids. It was later shown to be a major excretory product of the sulfur amino acids methionine and cysteine. Until about 1976, it was assumed that it was a metabolic end-product whose only function was the conjugation of bile acids. In the rat, taurine synthesis accounts for 70% to 85% of total cysteine catabolism. 

Biosynthesis of the two primary bile acids is followed by conjugation of their carboxylic group with the amino group of either glycine or taurine, mediated by a cytoplasmic enzyme. By means of this conjugation, the primary bile acids, which initially are barely water-soluble, become anions and are thus rendered hydrophilic. In this way four conjugated bile acids are formed ... 

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