Transamination metabolic role

The second nitrogen of biotin is incorporated by transamination of keto-aminopelargonic acid, with S-adenosyfinethionine - an apparently unique metabolic role for thus amino acid derivative that is normally a methyl donor. The immediate product of the deamination of S-adenosylmethionine, S-adenosyl-2-oxo-4-methylthiobutyric acid, is unstable and decomposes non-enzymicaUy to 2-oxo-3-butenoic acid and 5 -methyl tbioadenosine. 

Thus a thiamine derivative plays a metabolic role as cocarboxylase, which has been found to be inactivated by a specific phosphatase of yeast (122,123). The inactivation was inhibited by thiamine itself and to a lesser degree by thiamine monophosphate and the pyrimidine constituent of the thiamine molecule. Synthesis and breakdown of thiamine by Phycomyces species have also been studied (9,45,98). Pyridoxine derivatives are now known to catalyze two t3T)cs of bacterial reactions, involving transamination and decarboxylation of amino acids (4,32,35,59). Interconversion between members of the group of substances of natural occurrence which are related to pyridoxine has been observed in microorganisms and appears likely to afford a series of changes comparable to those observed in nicotinic acid dreivatives. Production of folic acid from chemically defined precursors by bacterial suspensions has also been observed (110,111). 

Be Pyridoxine, pyridoxal, pyridoxamine Coenzyme in transamination and decarboxylation of amino acids and glycogen phosphorylase role in steroid hormone action Disorders of amino acid metabolism, convulsions... 

The physiological relevance together with chnical importance of transamination and deamination is wide-ranging. As an aid to understanding the somewhat complex nature of amino acid metabolism, it can be considered (or imagined) as a metabolic box (represented in Figure 8.13). Some pathways feed oxoacids into the box whereas others remove oxoacids and the ammonia that is released is removed to form urea. The box illustrates the role of transdeamination as central to a considerable amount of the overall metabolism in the liver cell (i.e. protein, carbohydrate and fat metabohsm, see below). 

The terminology vitamin Bg covers a number of structurally related compounds, including pyridoxal and pyridoxamine and their 5 -phosphates. Pyridoxal 5 -phosphate (PLP), in particular, acts as a coenzyme for a large number of important enzymic reactions, especially those involved in amino acid metabolism. We shall meet some of these in more detail later, e.g. transamination (see Section 15.6) and amino acid decarboxylation (see Section 15.7), but it is worth noting at this point that the biological role of PLP is absolutely dependent upon imine formation and hydrolysis. Vitamin Bg deficiency may lead to anaemia, weakness, eye, mouth, and nose lesions, and neurological changes. 

Pyridoxal phosphate (4) is the most important coenzyme in amino acid metabolism. Its role in transamination reactions is discussed in detail on p. 178. Pyridoxal phosphate is also involved in other reactions involving amino acids, such as decarboxylations and dehydrations. The aldehyde form of pyridoxal phosphate shown here (left) is not generally found in free form. In the absence of substrates, the aldehyde group is covalently bound to the e-amino group of a lysine residue as aldimine ( Schiffs base ). Pyridoxamine phosphate (right) is an intermediate of transamination reactions. It reverts to the aldehyde form by reacting with 2-oxoacids (see p. 178). 

Vitamins, cofactors, and metals have the potential to broaden the scope of antibody catalysis considerably. In addition to hydrolytic and redox reactions, they facilitate many complex functional group interconversions in natural enzymes.131 Pyridoxal, for example, plays a central role in amino acid metabolism. Among the reactions it makes possible are transaminations, decarboxylations, racemizations, and (3,y-eliminations. It is also essential for ethylene biosynthesis. Not surprisingly, then, several groups have sought to incorporate pyridoxal derivatives into antibody combining sites. 

The liver also plays an essential role in dietary amino acid metabolism. The liver absorbs the majority of amino acids, leaving some in the blood for peripheral tissues. The priority use of amino acids is for protein synthesis rather than catabolism. By what means are amino acids directed to protein synthesis in preference to use as a fuel The K jyj value for the aminoacyl-tRNA synthetases is lower than that of the enzymes taking part in amino acid catabolism. Thus, amino acids are used to synthesize aminoacyl-tRNAs before they are catabolized. When catabolism does take place, the first step is the removal of nitrogen, which is subsequently processed to urea. The liver secretes from 20 to 30 g of urea a day. The a-ketoacids are then used for gluconeogenesis or fatty acid synthesis. Interestingly, the liver cannot remove nitrogen from the branch-chain amino acids (leucine, isoleucine, and valine). Transamination takes place in the muscle. 

Although the mitochondria are the primary site of oxidation for dietary and storage fats, the peroxisomal oxidation pathway is responsible for the oxidation of very long-chain fatty acids, jS-methyl branched fatty acids, and bile acid precursors. The peroxisomal pathway also plays a role in the oxidation of dicarboxylic acids. In addition, it plays a role in isoprenoid biosynthesis and amino acid metabolism. Peroxisomes are also involved in bile acid biosynthesis, a part of plasmalogen synthesis and glyoxylate transamination. Furthermore, the literature indicates that peroxisomes participate in cholesterol biosynthesis, hydrogen peroxide-based cellular respiration, purine, fatty acid, long-chain... 

Two types of reactions play prominent roles in amino acid metabolism. In transamination reactions, new amino acids are produced when a-amino groups are transferred from donor a-amino acids to acceptor a-keto acids. Because transamination reactions are reversible, they play an important role in both amino acid synthesis and degradation. Ammonium ions or the amide nitrogen of glutamine can also be directly incorporated into amino acids and eventually other metabolites. 

Glutamate is a central amino acid in general amino-acid metabolism. It plays a major role in transamination, ammonia production, formation of ornithine, proline, glutamine, and g-amino butyric acid (GABA). 

Alanine is the simplest L-amino acid found in protein. It has a simple metabolism, but complex physiological roles and functions. Alanine can transaminate reversibly with a-ketoglutarate, forming pyruvate and glutamate. This transamination occurs in many tissues, including liver and muscle. This is the only metabolic fate of pyruvate, other than protein synthesis. Therefore, alanine is glucogenic and is not required in the diet. 

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. 

O-Ketoglutaric Acid. 2-Oxopentanedioic acid 2-oxoglutaric acid 2-oxo-l,5-pentanedioic acid. CsH40 mol wt 146.10. C 41.10%, H 4.14%, O 54.76%. HOOC. CH.CHjCOCOOH. Plays an important role in amino add metabolism (transamination) see Severo Ochoa, "Enzymic Mechanisms in the Citric Acid Cycle in Advances fn Enzy-mology 15, 183-270 (1954). Prepn Friedman, Kosower, Org. Syn. cell. vol. Ill, 510 (1955) Bottorff. Moore, ibid. Coll. vol. V, 687 (1973). Microbial synthesis using a strain of Pseudomonas Lockwood et al. U.S. pat. 2,443,919 (1948) Berger, Witt, U.S. pat. 2,841,616 (1958). 

Alanine is an allosteric inhibitor of glutamine synthetase, an enzyme with a central role in nitrogen metabolism in the cell. Alanine participates in transamination reactions and in the glucose-alanine cycle. 

Studies of the carbohydrate metabolism of T. cruzi (21) have shown that phos-phoenolpyruvate serves as the acceptor of the primary COj-fixation reaction. This resulted in the formation of oxaloacetate and malate and the excretion of succinate. The central role of PEPCK in energy metabolism in insect-stage trypanosomatids has been illustrated in the case of T. cruzi epimastigotes, using 3-mercaptopicolinic aeid, a powerful inhibitor of this enzyme (22). Inhibition led to a twofold reduction in the anaerobic production of succinate and a similar decrease in glucose consumption, while the production of alanine, via the transamination of pyruvate, increased threefold. 

---