Pyridoxal Phosphate in Amino Acid Metabolism

The various reactions of pyridoxal phosphate in amino acid metabolism shown in Table 9.1 all depend on the same chemical principle - the ability to stabilize amino acid carbanions and to labilize bonds about the a-carbon, by 

The ring nitrogen of pyridoxeil phosphate exerts a strong electron withdrawing effect on the aldimine, and this leads to weakening of all three bonds about the a-carbon of the substrate. In nonenzymic reactions, all the possible pyridoxeil-catalyzed reactions are observed - a-decEU boxylation, aminotrans-fer, racemization and side-chain elimination, eind replacement reactions. By contrast, enzymes show specificity for the reaction pathway followed which bond is cleaved will depend on the orientation of the Schiff base relative to reactive groups of the catalytic site. As discussed in Section 9.3.1.5, reaction specificity is not complete, eind a number of deceu boxyltises tdso undergo transamination. 

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The Role of Pyridoxal Phosphate in Amino Acid Metabolism... 

A subclass of lyases, involved in amino acid metabolism, utilizes pyridoxal 5-phosphate (PLP, 3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]-4-pyridinecarbaldehyde) as a cofactor for imine/ enamine-type activation. These enzymes are not only an alternative to standard fermentation technology, but also offer a potential entry to nonnatural amino acids. Serine hydroxymethyl-tansferase (SHMT EC 2.1.2.1.) combines glycine as the donor with (tetrahydrofolate activated) formaldehyde to L-serine in an economic yield40, but will also accept a range of other aldehydes to provide /i-hydroxy-a-amino acids with a high degree of both absolute and relative stereochemical control in favor of the L-erythro isomers41. 

Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially in transamination and decarboxylation. It is also the cofactor of glycogen phosphorylase, where the phosphate group is catalytically important. In addition, vitamin Bg is important in steroid hormone action where it removes the hormone-receptor complex from DNA binding, terminating the action of the hormones. In vitamin Bg deficiency, this results in increased sensitivity to the actions of low concentrations of estrogens, androgens, cortisol, and vitamin D. 

If a vitamin or cofactor is involved in amino acid metabolism, it s most likely pyridoxal phosphate (B6), unless it involves serine, and then it s B6 and folic acid. 

The vitamin Be family of molecules are metabolic precursors to pyridoxal phosphate, an essential coenzyme for multiple enzymes involved in amino acid metabolism. 

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). 

Pyridoxal phosphate is an essential cofactor in the glycogen phosphorylase reaction its phosphate group acts as a general acid catalyst, promoting attack by Pj on the glycosidic bond. (This is an unusual role for this cofactor its more typical role is as a cofactor in amino acid metabolism see Fig. 18-6.)... 

Vitamin B6 (pyridoxine, pyridoxamine, and pyridoxal) has the active form, pyridoxal phosphate. It functions as a cofactor for enzymes, particularly in amino acid metabolism. Deficiency of this vitamin is rare, but causes glossitis and neuropathy. The deficiency can be induced by isoniazid, which causes sensory neuropathy at high doses. 

Unlike other pyridoxal phosphate-dependent enzymes, in which it is the carbonyl group that is essential for catalysis, the internal Schiff base between pyridoxal phosphate and lysine in glycogen phosphorylase can be reduced with sodium borohydride without affecting catalytic activity. Thus, while pyridoxal phosphate is essential for phosphorylase activity, it does not act by the same kind of mechanism as in amino acid metabolism. 

Pyridoxal 5 -phosphate dependent enzymes constitute an important class of proteins involved predominately in amino acid metabolism. The PLP-cofactor is capable of catalyzing a variety of reactions at the a-, [3-, and/or y-carbons of amino acid substrates. These reactions include tranamination, racemization, decarboxylation, and aldoyltic cleavage reactions at the a-carbon and elimina-tion/substitution reactions at either the 3-, or y-position of the amino acid substrate (67-74) The chemical properties of the cofactor (67-71) are responsible for the great diversity of reactions catalyzed by PLP, while reaction specificity is ultimately determined by the active site environment imposed by the surrounding apo-protein to which the cofactor is covalendy bound (69). 

The term vitamin Bg broadly refers to six compounds named pyridoxal (PL 1), pyridoxine (PN 2), pyridox-amine (PM 3) and their 5 -phosphorylated counterparts (PLP 4, PNP 5, and PMP 6, respectively (Scheme 1)). Pyridoxal 5 -phosphate (PLP) is typically recognized as the active form of vitamin Bg and participates in a remarkable number of biochemical transformations mostly in amino acid metabolism, but also in some reactions in carbohydrate metabolism as well as in the modification of a variety of amine-containing molecules. ... 

Several types of enzyme involved in amino-acid metabolism (including aminotransferases and decarboxylases) require pyridoxal phosphate (7, PLP) as co-factor. It has been postulated that all such reactions involve the formation of a Schiff-base intermediate between the amino-acid and (7) as the first step. Simple systems containing metal ion, amino-acid, and... 

Vitamin Be (pyridoxine) is widely distributed in cereal grains, yeast, liver, milk, etc. it is a constituent of a coenzyme (pyridoxal phosphate) involved in amino acid metabolism. Deficiency can cause anaemia, dermatitis, and fatigue. 

Decarboxylation and transamination proceed via the intermediacy of an amino acid-pyridoxal phosphate complex. Pyridoxal phosphate is related to vitamin Be and is of pivotal importance in amino acid metabolism. This cofactor occurs in two forms pyridoxal-5 -phosphate (aldehyde form) and pyridoxamine (amine form), which mediate a reversible interconversion of a-amino acid and a-keto acids via a Schiff-... 

Vitamin is pyridoxal (ll.lOSf), pyridoxine (ll.lOSg) or pyridoxamine (ll.lOSh), all of which exist as their phosphate esters. This vitamin was first isolated in 1936. Pyridoxyl phosphate (ll.lOSi) is a versatile coenzyme used by all living organisms which participates in transamination (11.111) and (11.112), decarboxylation (11.113) and racemisation (11.114) reactions. It is the essential cofactor in amino acid metabolism. Virtually all enzymes which catalyse reactions of 2-amino acids utilise pyridoxyl phosphate as the coenzyme (11.111) through (11.114). 

Pyridoxal phosphate is derived from vitamin which Is essential In amino acid metabolism in your body. Box 7-1 discussed the drawing of organic structures. 

Pyridoxal phosphate, PalP the coenzyme form of Vitamin Bj (see Vitamins for formula of PalP and related compounds). Af, of PalP 247.1. PalP is stable in aqueous solution when kept refrigerated and pro-teeted from light It is particidarly sensitive to photodecomposition in the solid state and in alkaline solution. PalP plays an important central role in amino acid metabolism, acting as the coenzyme in many different metabolic conversions of amino acids. It is formed from pyridoxal by a Mg -dependent kinase reaction pyridoxal + ATP -> pyridoxal 5-phosphate + ADP. With amines and amino acids, PalP forms SchifTs bases (azomethines). The substrate of a pyrid-... 

Since their discovery, first published by Needham et al, transaminases or aminotransferases (EC2.6.1.X) have received much attention as biocatalysts for the transformation of a keto acid to the corresponding amino acid/amine or vice versa [1]. Transaminases play an important role in amino acid metabolism and are ubiquitous in microbes and eukaryotic cells. They are pyridoxal-5 -phosphate (PLP)-dependent enzymes and are qualified as biocatalysts, due to their wide substrate scope, high enantio- and regioselectivity, high reaction rates, and stability [2]. As pictured in Scheme 29.1, the amino group of the amino donor is transferred to the carbonyl group of the amino acceptor. 

The transamination reaction is important biologically in amino acid metabolism. Simple aldehydes are rare in biological systems and are mostly masked as imines. Biochemists often refer to them as Schiff bases, which are a special class of aldehyde imine where the nitrogen atom is substituted by an alkyl or aryl group. The transamination reaction interconverts amino and carbonyl functionalities (Figure 14.32). The enzymes involved in the process are called transaminases, and they require pyridoxal phosphate as a cofactor. 

Pyridoxal phosphate mainly serves as coenzyme in the amino acid metabolism and is covalently bound to its enzyme via a Schiff base. In the enzymatic reaction, the amino group of the substrate and the aldehyde group of PLP form a Schiff base, too. The subsequent reactions can take place at the a-, (3-, or y-carbon of the respective substrate. Common types of reactions are decarboxylations (formation of biogenic amines), transaminations (transfer of the amino nitrogen of one amino acid to the keto analog of another amino acid), and eliminations. 

Pantothenic acid is present in coenzyme A and acyl carrier protein, which act as carriers for acyl groups in metabolic reactions. Pyridoxine, as pyridoxal phosphate, is the coenzyme for several enzymes of amino acid metabolism, including the aminotransferases, and of glycogen phosphorylase. Biotin is the coenzyme for several carboxylase enzymes. 

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). 

Among the NH2 transfer reactions, transaminations (1) are particularly important. They are catalyzed by transaminases, and occur in both catabolic and anabolic amino acid metabolism. During transamination, the amino group of an amino acid (amino acid 1) is transferred to a 2-oxoacid (oxoacid 2). From the amino acid, this produces a 2-oxo-acid (a), while from the original oxoacid, an amino acid is formed (b). The NH2 group is temporarily taken over by enzyme-bound pyridoxal phosphate (PLP see p. 106), which thus becomes pyridoxamine phosphate. 

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. 

It is involved as a coenzyme (pyridoxal phosphate) in metabolism of tryptophan, in several metabolic transformations of amino acids including transamination, decarboxylation and racemization. 

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). 

Vitamin B6 Pridoxine Pyridoxamine Pyridoxal Pyridoxal phosphate Cotacior for enzymes, particularly in 1 amino acid metabolism J. 

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