Pyridoxal-5 -phosphate reactions involving

The unusual amino acid, 1-aminocyclopropanecarboxylic acid, a precursor of the phytohormone ethylene, is biosynthesized in plants from S-adenosylmethionine. By using dideuterated S-adenosylmethionine, the reaction, under the influence of a pyridoxal phosphate dependent synthase, involves an inversion at the x-carbon center (a feature rarely observed for pyridoxal phosphate reactions), leading to (5)-l-amino-2,2-dideuterocyclopropanecarboxylic acid4. 

Although pyridoxal phosphate is involved in a wide variety of reactions the processes are all related mechanistically by the electron withdrawal toward the cationic or hydrogen-bonded imine nitrogen and into the electron sink of the pyridine/pyridinium ring. 

F. 393. Pyridoxal phosphate covalently attached to an amino acid substrate. The arrows indicate which bonds are broken for the various typies of reactions in which pyridoxal phosphate is involved. The X and Y represent leaving groups that may be present on the amino acid (such as the hydroxyl group on serine or threonine). 

The fact that pyridoxal phosphate is involved in so many different metabolic pathways presents a major difficulty in correlating the metabolic effects of the vitamin with the clinical manifestations of the deficiency. The use of inhibitors has been of little help in that respect because their effect is seldom restricted to a single reaction. 

Serine and Glycine. Serine can be converted to glycine by the loss of an active formaldehyde. This reaction is one of the most important suppliers of the Ci fragment. Two coenzymes are necessary, tetrahydrofolate (Chapt. VI-5), and pyridoxal phosphate. The elimination of the /3-C atom is a pyridoxal-catalyzed reaction involving the resonance structure mentioned before in Section 4. While this is taking place, the serine is also bound to tetrahydrofolate. The reaction is reversible Serine is also formed from glycine and active formaldehyde. 

Fig. 2. Biosynthetic pathway for epinephrine, norepinephrine, and dopamine. The enzymes cataly2ing the reaction are (1) tyrosine hydroxylase (TH), tetrahydrobiopterin and O2 are also involved (2) dopa decarboxylase (DDC) with pyridoxal phosphate (3) dopamine-P-oxidase (DBH) with ascorbate, O2 in the adrenal medulla, brain, and peripheral nerves and (4) phenethanolamine A/-methyltransferase (PNMT) with. Cadenosylmethionine in the adrenal...

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... 

It has been said that God created an organism especially adapted to help the biologist find an answer to every question about the physiology of living systems if this is so it must be concluded that pyridoxal phosphate was created to provide satisfaction and enlightenment to those enzymologists and chemists who enjoy pushing electrons, for no other coenzyme is involved in such a wide variety of reactions, in both enzyme and model systems, which can be reasonably interpreted in terms of the chemical properties of the coenzyme. Most of... 

Pyridoxal phosphate, a close relative of vitamin B6, is involved in a large number of metabolic reactions. TeJl the hybridization, and predict the bond angles for each nonterminal atom. 

Most amino acids lose their nitrogen atom by a transamination reaction in which the -NH2 group of the amino acid changes places with the keto group of ct-ketoglutarate. The products are a new a-keto acid plus glutamate. The overall process occurs in two parts, is catalyzed by aminotransferase enzymes, and involves participation of the coenzyme pyridoxal phosphate (PLP), a derivative of pyridoxine (vitamin UJ. Different aminotransferases differ in their specificity for amino acids, but the mechanism remains the same. 

The metabolism of P-hydroxy-a-amino adds involves pyridoxal phosphate-dependent enzymes, dassified as serine hydroxymethyltransferase (SHMT) (EC 2.1.2.1) or threonine aldolases (ThrA L-threonine selective = EC 4.1.2.5, L-aHo-threonine selective = EC 4.1.2.6). Both enzymes catalyze reversible aldol-type deavage reactions yielding glycine (120) and an aldehyde (Eigure 10.45) [192]. 

The role of Schiff bases formed between pyridoxal phosphate and amino acid residues as intermediate products in many enzymatic reactions is well known and documented. NMR is an excellent tool for studies of the enzymatic processes involving Schiff bases formation. 

These enzymes invariably involve a cofactor, pyridoxal phosphate (vitamin B6). In addition, pyridoxal phosphate is also required for most decarboxylations, racemizations, or elimination reactions in which an amino acid is a substrate. Pyridoxal phosphate is not involved in decarboxylations in which the substrate is not an amino acid. So if a question... 

Group-transfer reactions often involve vitamins3, which humans need to have in then-diet, since we are incapable of realizing their synthesis. These include nicotinamide (derived from the vitamin nicotinic acid) and riboflavin (vitamin B2) derivatives, required for electron transfer reactions, biotin for the transfer of C02, pantothenate for acyl group transfer, thiamine (vitamin as thiamine pyrophosphate) for transfer of aldehyde groups and folic acid (as tetrahydrofolate) for exchange of one-carbon fragments. Lipoic acid (not a vitamin) is both an acyl and an electron carrier. In addition, vitamins such as pyridoxine (vitamin B6, as pyridoxal phosphate), vitamin B12 and vitamin C (ascorbic acid) participate as cofactors in an important number of metabolic reactions. 

Pyridoxal phosphate is a required coenzyme for many enzyme-catalyzed reactions. Most of these reactions are associated with the metabolism of amino acids, including the decarboxylation reactions involved in the synthesis of the neurotransmitters dopamine and serotonin. In addition, pyridoxal phosphate is required for a key step in the synthesis of porphyrins, including the heme group that is an essential player in the transport of molecular oxygen by hemoglobin. Finally, pyridoxal phosphate-dependent reactions link amino acid metabolism to the citric acid cycle (chapter 16). 

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). 

The active form of vitamin Be, pyridoxai phosphate, is the most important coenzyme in the amino acid metabolism (see p. 106). Almost all conversion reactions involving amino acids require pyridoxal phosphate, including transaminations, decarboxylations, dehydrogenations, etc. Glycogen phosphory-lase, the enzyme for glycogen degradation, also contains pyridoxal phosphate as a cofactor. Vitamin Be deficiency is rare. 

This enzyme [EC 4.3.1.9] catalyzes the following reaction involving pyridoxal phosphate as a cofactor D-glucosam-inate = 2-dehydro-3-deoxy-o-gluconate -f NH3. 

Non-pyridoxal Phosphate Dependent. Figure 2 depicts the postulated mechanism for a non-pyridoxal phosphate catal) zed decarboxylation of histidine to histamine involving a pyruvoyl residue instead of pyridoxal -5 - phosphate (20). Histidine decarboxylases from Lactobacillus 30a and a Micrococcus sp. have been shown to contain a covalently bound pyruvoyl residue on the active site. The pyruvoyl group is covalently bound to the amino group of a phenylalanine residue on the enzyme, and is derived from a serine residue (21) of an inactive proenzyme (22). The pyruvoyl residue acts in a manner similar to pyridoxal phosphate in the decarboxylation reaction. 

Tiburzy (22,31) obtained similar results by application of the PAL inhibitor aminooxyacetic acid (AOA). However, AOA does not specifically inhibit PAL (99), and PAL is not only involved in lignin biosynthesis (100). Thus, AOA and the related inhibitor aminooxyphenyl propionic acid (AOPP) (101,102) inhibit the biosynthesis of lignin (103,104), anthocyanins (105), other flavonoids (106), and conjugates of cinnamic acids (107) via PAL, as well as ethylene (108-110) via a pyridoxal phosphate dependent enzyme (110,111). In view of the possible function of phenolic compounds as phytoalexins (21,112,113) and the well documented role of ethylene in some resistance reactions (114-116), the above cited experiments with AOA (22,... 

Vitamin Bg is a mixture of six interrelated forms pyridoxine (or pyridoxol) (Figure 19.23), pyri-doxal, pyridoxamine, and their 5 -phosphates derivatives. Interconversion is possible between all forms. The active form of the vitamin is pyridoxal phosphate, which is a coenzyme correlated with the function of more than 60 enzymes involved in transamination, deamination, decarboxylation, or desulfuration reactions. 

Pyridoxal phosphate is the coenzyme for the enzymic processes of transamination, racemization and decarboxylation of amino-acids, and for several other processes, such as the dehydration of serine and the synthesis of tryptophan that involve amino-acids (Braunstein, 1960). Pyridoxal itself is one of the three active forms of vitamin B6 (Rosenberg, 1945), and its biochemistry was established by 1939, in considerable part by the work of A. E. Braunstein and coworkers in Moscow (Braunstein and Kritzmann, 1947a,b,c Konikova et al 1947). Further, the requirement for the coenzyme by many of the enzymes of amino-acid metabolism had been confirmed by 1945. In addition, at that time, E. E. Snell demonstrated a model reaction (1) for transamination between pyridoxal [1] and glutamic acid, work which certainly carried with it the implication of mechanism (Snell, 1945). 

Isoniazid reacts with pyridoxal phosphate to form a hydrazone (Fig. 7.42), which is a very potent inhibitor of pyridoxal phosphate kinase. The hydrazone has a much greater affinity for the enzyme (100—lOOOx) than the normal substratepyridoxal. The result of this is a depletion of tissue pyridoxal phosphate. This cofactor is of importance particularly in nervous tissue for reactions involving decarboxylation and transamination. The decarboxylation reactions are principally affected however, with the result that transamination reactions assume a greater importance. 

The amino acid and nucleotide biosynthetic pathways make repeated use of the biological cofactors pyridoxal phosphate, tetrahydrofolate, and A-adenosylmethionine. Pyridoxal phosphate is required for transamination reactions involving glutamate and for other amino acid transformations. One-carbon transfers require S-adenosyhnethionine and tetrahydrofolate. Glutamine amidotransferases catalyze reactions that incorporate nitrogen derived from glutamine. 

Vitamin B6 is a collective term for pyridoxine, pyridoxal, and pyridox amine, all derivatives of pyridine. They differ only in the nature of the functional group attached to the ring (Figure 28.10). Pyridoxine occurs primarily in plants, whereas pyridoxal and pyridoxamine are found in foods obtained from animals. All three compounds can serve as precur sors of the biologically active coenzyme, pyridoxal phosphate. Pyridoxal phosphate functions as a coenzyme for a large number of enzymes, par ticularly those that catalyze reactions involving amino acids. 

The principles of the above reactions form the basis of a series of important metabolic interconversions involving the coenzyme pyridoxal phosphate (structure 2.41). This condenses with amino acids to form a Schiff base (structure 2.42). The pyridine ring in the Schiff base acts as an electron sink which very effectively stabilizes a negative charge. 

Pyndoxal phosphate is also a cofactor for transamination reactions, In these reactions, an amino group is transferred from an amino acid to an or-keto acid, thus founing a new amino acid and a new or-keto acid, Transamination reactions are important for the synthesis of amino acids from non-protein metabolites and for the degradation of amino acids for energy production. Since pyridoxal phosphate is intimately involved ill amino add metabolism, the dietary requirement for vitamin B6 increases as the protein content of the diet increases. 

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