Amino acid, decarboxylation side-chain reactions

Some breakdown, as well as cyclisation reactions, can be expected for most of the coded amino acids when they are held at temperatures around and above 200 °C. These processes lead to decarboxylation, side-chain loss to form glycine and formation of amines, furans, pyrroles and pyridines, typically. Higher temperatures (850-1000 °C) cause all the common amino acids to decompose to HCN as the major pyrolysis product, together with C02 and the hydrocarbon derived from the side-chain. 

The biologically active form of vitamin Bg is pyridoxal-5-phosphate (PEP), a coenzyme that exists under physiological conditions in two tautomeric forms (Figure 18.25). PLP participates in the catalysis of a wide variety of reactions involving amino acids, including transaminations, a- and /3-decarboxylations, /3- and ") eliminations, racemizations, and aldol reactions (Figure 18.26). Note that these reactions include cleavage of any of the bonds to the amino acid alpha carbon, as well as several bonds in the side chain. The remarkably versatile chemistry of PLP is due to its ability to... 

The dibasic side chain at position 7 can be alternatively provided by a substituted amino alkyl pyrrolidine. Preparation of that diamine in chiral form starts with the extension of the ester function in pyrrolidone (46-1) by aldol condensation with ethyl acetate (46-2). Acid hydrolysis of the (3-ketoester leads to the free acid that then decarboxylates to form an acetyl group (46-3). The carbonyl group is next converted to an amine by sequential reaction with hydroxylamine to form the oxime, followed by catalytic hydrogenation. The desired isomer (46-4) is then separated... 

A third amino acid synthesis begins with diethyl a-bromomalonate. First the Br is replaced by a protected amino group using the Gabriel synthesis (see Section 10.6). Then the side chain of the amino acid is added by an alkylation reaction that resembles the malonic ester synthesis (see Section 20.4). Hydrolysis of the ester and amide bonds followed by decarboxylation of the diacid produces the amino acid. An example that shows the use of this method to prepare aspartic acid is shown in the following sequence ... 

The quinone ring is derived from isochorismic acid, formed by isomerization of chorismic acid, an intermediate in the shikirnic acid pathway for synthesis of the aromatic amino acids. The first intermediate unique to menaquinone formation is o-succinyl benzoate, which is formed by a thiamin pyrophosphate-dependent condensation between 2-oxoglutarate and chorismic acid. The reaction catalyzed by o-succinylbenzoate synthetase is a complex one, involving initially the formation of the succinic semialdehyde-thiamin diphosphate complex by decarboxylation of 2-oxoglutarate, then addition of the succinyl moiety to isochorismate, followed by removal of the pyruvoyl side chain and the hydroxyl group of isochorismate. 

To date, four main types of catalytic activity have been reported in detail for thermal polyamino acids. These are (with the most studied substrates in parentheses) hydrolyses (p-nitrophenyl acetate, p-nitro-phenyl phosphate, ATP), decarboxylations (OAA, glucuronic acid, pyruvic acid), and aminations (a-ketoglutaric acid, OAA, pyruvic acid, phenylpyruvic acid). The fourth type is a deamination reaction yielding a-ketoglutaric acid (51). For some of the actions of the thermal polymers the products are identified quantitatively, and the kinds of amino acid side chain necessary for activity in the polymer elucidated. In others, products have yet to be fully identified. The activities of thermal polyamino acids are manifest on substrates which range from chemically labile to relatively stable. 

Transamination reactions require the coenzyme pyridoxal-5 -phosphate (PLP), which is derived from pyridoxine (vitamin B6). PLP is also required in numerous other reactions of amino acids. Examples include racemizations, decarboxylations, and several side chain modifications. (Racemizations are reactions in which mixtures of l- and D-amino acids are formed.) The structures of the vitamin and its coenzyme form are illustrated in Figure 14.2. 

Doubts over the orientation of compounds such as those above can frequently be resolved by oxidation of the side chain, decarboxylation of the resulting carboxylic acid, iV-methylation, and comparison with the N-methyl oxo compounds 50 and 51. These compounds have been prepared unambiguously from methylamino aminopyridines by reaction with diethyl mesoxalate (Et02CC0C02Et), " followed by hydrolysis and decarboxylation. Thus 2-amino-3-methylaminopyridine (49) gave the... 

The most versatile of the coenzymes is perhaps pyridoxal phosphate (PEP). The PEP containing enzymes catalyze a wide variety of reactions such as racemization, transamination, [3- and a-decarboxylation, and interconversion of side chains. The first step of all these reactions is the transition between an internal aldimine intermediate to an external aldimine intermediate, which involves the condensation of PEP with an external amino acid substrate to form a Schiff base. The internal aldimine intermediate can then either undergo a-decarboxylation to convert the amino acid substrate into amines and aldehydes, or lose the a-hydrogen... 

If the PLP-catalyzed reaction is a decarboxylation, the carboxyl group is removed from the a-carbon of the amino acid. Electron rearrangement and protonation of the a-carbon of the decarboxylated intermediate by a protonated amino group of a lysine side chain or by some other acid group then reestablishes the aromaticity of the pyridine ring. The last step in all PLP-requiring enzymes is a transimination reaction with a lysine side chain, in order to release the product of the enzyme-catalyzed reaction and regenerate enzyme-bound PLP. 

Cephalosporin C is supplied directly to the enzymatic stage. The side chain of the molecule is oxidatively deaminated by a D-amino acid oxidase (obtained from yeast). Oxygen is consumed, and ketoadipinyl-7-ACS, ammonia, and hydrogen peroxide are formed. Under these reaction conditions, oxidative decarboxylation to form glutaryl-7-ACS occurs spontaneously. 

Kynurenic acid and xanthurenic acid, side products of the reaction, are the products of the transamination of the a-amino group of kynurenine and 3-hydroxy-kynurenine to a-ketoglutaric acid in the presence of pyridoxal phosphate and an enzyme found in mammalian liver and kidney, kynurenine transaminase. The keto acid resulting from the transamination reaction condenses spontaneously. Liver homogenate also decarboxylates 3-hydroxykynurenine to yield 4,8-de-hydroxyquinoline. Kynurenase may catalyze the cleavage of the side chain of kynurenine or 8-hydroxy-kynurenine and lead to the formation of alanine and... 

The participation of reactive groups at the active site provides specificity not only for the substrates that will bind, but also for the reaction that will be catalysed. For example, in a non-enzymic model system, an amino acid may undergo (X-decarboxylation to yield an amine, transfer of the a-amino group and replacement with an oxo-group (section 9.3.1.2), isomerization between the d- and L-isomers, or a variety of reactions involving elimination or replacement of the side-chain. In an enzyme-catalysed reaction only one of the possible reactions will be catalysed by any given enzyme. 

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