Interconversion of amino acids

The citric acid cycle is the final common pathway for the aerobic oxidation of carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA or intermediates of the cycle. It also has a central role in gluconeogenesis, lipogenesis, and interconversion of amino acids. Many of these processes occur in most tissues, but the hver is the only tissue in which all occur to a significant extent. The repercussions are therefore profound when, for example, large numbers of hepatic cells are damaged as in acute hepatitis or replaced by connective tissue (as in cirrhosis). Very few, if any, genetic abnormalities of citric acid cycle enzymes have been reported such ab-normahties would be incompatible with life or normal development. 

The citric acid cycle is amphibolic, since in addition to oxidation it is important in the provision of carbon skeletons for gluconeogenesis, fatty acid synthesis, and interconversion of amino acids. 

Fig. 6.4 Reversible interconversion of amino acid and keto acid. Conjugation of the imine bond in the aldimine with the electron sink of the pyridine ring plus protonation of the pyridine nitrogen as well as the metal ion - all this results in weakening of the C-H bond of the amino acid residue. Thus, also catalyzed is a-proton exchange, racemization of a chiral center at the a-carbon atom and decarboxylation of the appropriate amino acid. ...

Figure 6.8 Interconversion of amino acids occurs through transamination reactions catalysed by aminotransferases.

Rich in both phase I (principally the cytochromes P450, catalyzing hydrolysis, reduction, and oxidation reactions) and phase II (catalyzing conjugation of xenobiotic molecules with hydrophilic moieties) biotransforming enzymes, the liver is the metabolic center of the body. In fact, most of the field of biochemistry is concerned with its metabolic reactions. The liver essentially converts ingested food into a balanced cell culture medium via metabolic interconversion of amino acids, carbohydrates, and lipids and synthesizes many substances that are subsequently exported for use in other areas of... 

Protein Metabolism The most important functions of the liver in protein metabolism are (1) deamination of amino acids for use as energy or conversion into fats and carbohydrates, (2) synthesis and interconversion of amino acids and other metabolically important compounds, (3) formation of urea for excretion of ammonia, and (4) formation of plasma proteins. 

The aminotransferases constitute a group of enzymes that catalyze the interconversion of amino acids to 2-oxo-acids by transfer of amino groups. Aspartate aminotransferase (EC 2.6.1.1 L-aspartate 2-oxoglutarate aminotransferase AST) and alanine aminotransferase (EC 2.6.1.2 L-alanine 2-oxoglutarate aminotransferase ALT) are examples of aminotransferases that are of clinical interest. 

Pyridoxine (pyridoxol), pyridoxamine, and pyridoxal are the three natural forms of vitamin Bg. They are converted to pyridoxal phosphate, which is required for the synthesis, catabohsm, and interconversion of amino acids. 

Some general reactions that involve degradation or interconversion of amino acids provide for the synthesis of nonessential amino acids from a-keto acid precursors derived from carbohydrate intermediates. 

The general arguments about the antiquity of cofactors apply to PLP. The nonenzymatic synthesis of pyridoxal under prebiotic conditions is considered possible, whereas the presence of a 5 phosphate group could hint to an ancestral attachment of the cofactor to RNA molecules. " Furthermore, there are specific grounds to assume that PLP arrived on the evolutionary scene before the emergence of proteins. In fact, in current metabolism, PLP-dependent enzymes play a central role in the synthesis and interconversion of amino acids, and thus they are closely related to protein biosynthesis. In an early phase of biotic evolution, free PLP could have played many of the roles now fulfilled by PLP-dependent enzymes, since the cofactor by itself can catalyze (albeit at a low rate) reactions such as amino acid transaminations, racemizations, decarboxylations, and eliminations. " This suggests that the appearance of PLP may have preceded (and somehow eased) the transition from primitive RNA-based life forms to more modern organisms dependent on proteins. 

Fig. 3.2 Classification of "metabolism ESTs. Tentative unique genes (TUGs) from each species that clustered into the metabolism category (see Fig. 3.1J were further subdivided. Here, carbohydrate incorporates all glycoside hydrolases, lipid includes lipases, B-oxidation and steroid metabolizing enzymes, protein includes predominantly proteases and their precursors, and amino acid includes all enzymes involved in the interconversion of amino acids. Esterase includes those esterase-like enzymes with unknown substrates, and other contains those TUGs that do not sort into other categories. These include predominantly oxidoreductases and purine/pyrimidine metabolizing enzymes.

Racemization, the interconversion of amino acid enantiomers, occurs slowly in biological and geological systems. The rate increases with extreme pH values, high temperature, and high-ionic strength. Rates also vary between amino acids At 25°C, the racemization half-life of serine is about 400 yr, while that of isoleucine is 40,000 yr. Enantiomer analysis is used to confirm bioactivity of synthetic peptides and for geological dating. ... 

The term deracemization covers reactions in which two enantiomers are inter-converted by a stereoinversion process such that a racemate can be transformed to a non-racemic mixture without any net change in the composition of the molecule. Deracemization reactions usually involve a redox process, for example, the interconversion of chiral secondary alcohols via the ketone or alternatively the interconversion of amino acids/amines via the corresponding imine (Scheme 4.37). 

Amino acids are absorbed by the mammary gland in quantities sufficient to account for the protein synthesised within it. Considerable interconversion of amino acids occurs before synthesis, and certain amino acids are important as sources of others. Thus, ornithine, which does not appear in milk protein, is absorbed and retained in large quantities by the mammary gland and has been shown to be a precursor of proline, glutamate and aspartate. Synthesis of the carbohydrate moieties of the proteins takes place in the mammary gland, as does phosphorylation of serine and threonine before their incorporation into the caseins. 

Biochemists know these two forms of butenedioic acid by different (non-systematic) names. Fumaric acid (trans-butenedioic acid) is an intermediate in the Krebs cycle, an essential part of aerobic respiration for energy release in cells (Chapter 15, and Chapter 23 on the accompanying website). Maleic acid (cis-butenedioic acid) is an inhibitor of reactions involved in the interconversion of amino acids in the liver. These different biological roles are a consequence of the molecules different shapes and their interactions with the enzymes involved in metabolic pathways. 

Imines play pivotal roles in the biological transformations of 2-aminocarboxylic acids (amino acids), the building blocks of proteins (Chapter 26). Pyridoxal and p5Tidoxamine, two derivatives of vitamin Bg (pyridoxine), mediate the interconversion of amino acids and 2-oxocarboxylic acids (ketoacids). Imines are the key intermediates in this transformation, by which amino acids are broken down biologically (a process called catabolism). 

Folic acid (pteroyhnonoglutamic acid or PGA) exists in different forms in nature. These forms are changed to at least five active coenzymes critically important for the formation of purines and pyrimidines needed for the synthesis of DNA and RNA, the formation of hanoglobin, the interconversion of amino acids such as homocysteine to methionine, and the synthesis of choline from ethanolamine. Vitamins B,2, Bg, and C are essential as coenzymes for the activity of folacin in many metabolic processes. In practical terms, folic acid is required for cell division and reproduction, and prevents neural tube defects in newborns and cardiovascular diseases in adults. The cardiovascular protective role is because folacin and vitamin Bjj lower levels of homocysteine. 

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