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Ketoacid-dependent Enzymes

The a-ketoacid-dependent enzymes are distinguished from other non-haem iron enzymes by their absolute requirement for an a-ketoacid cofactor as well as Fe(II) and O2 for activity. They catalyse two types of reaction (Table 2.3), hydroxyla-tion and oxidation. In both, the a-ketoglutarate is decarboxylated and one oxygen atom introduced into the succinate formed in the hydroxylases, the other oxygen atom is introduced into the substrate, while in the oxidases it is found in water, together with the cyclized product. In general these enzymes require one equivalent of Fe(II) an a-ketoacid, usually a-ketoglutarate and ascorbate. Examples of these enzymes include proline 4-hydroxylase, prolyl and lysyl hydroxylase, which... [Pg.84]

Coenzyme M was shown to function as the central cofactor of aliphatic epoxide carboxylation in Xanthobacter strain Py2, an aerobe from the Bacteria domain (AUen et al. 1999). The organism metabolizes short-chain aliphatic alkenes via oxidation to epoxyalkanes, followed by carboxylation to p-ketoacids. An enzyme in the pathway catalyzes the addition of coenzyme M to epoxypropane to form 2-(2-hydroxypropylthio)ethanesulfonate. This intermediate is oxidized to 2-(2-ketopropylthio)ethanesulfonate, followed by a NADPH-dependent cleavage and carboxylation of the P-ketothioether to form acetoacetate and coenzyme M. This is the only known function for coenzyme M outside the methanoarchaea. [Pg.145]

D-Amino acid oxidase D-Amino acids (see p. 5) are found in plants and in the cell walls of microorganisms, but are not used in the synthesis of mammalian proteins. D-Amino acids are, hew ever, present in the diet, and are efficiently metabolized by 1he liver. D-Amino acid oxidase is an FAD-dependent enzyme that catalyzes the oxidative deamination of these amino acid isomers. The resulting a-ketoacids can enter the general pathways of amino acid metabolism, and be reaminated to L-isomers, or cafe balized for energy. [Pg.250]

TDP-dependent enzymes include transketolase, an enzyme component of the pentose shunt pathway, pyruvate dehydrogenase complex, and aKGDH a tricarboxylic acid cycle enzyme (Fig. 3). Branched-chain ketoacid dehydrogenases are also TDP-dependent. [Pg.106]

Aspartate aminotransferase is the prototype of a large family of PLP-dependent enzymes. Comparisons of amino acid sequences as well as several three-dimensional structures reveal that almost all transaminases having roles in amino acid biosynthesis are related to aspartate aminotransferase by divergent evolution. An examination of the aligned amino acid sequences reveals that two residues are completely conserved. These residues are the lysine residue that forms the Schiff base with the pyridoxal phosphate cofactor (lysine 258 in aspartate aminotransferase) and an arginine residue that interacts with the a-carboxylate group of the ketoacid (see Figure 23.11). [Pg.995]

An elegant work is reported concerning the oxidation of 2-alkyl and 2-benzylthia-zolium salts, in the presence of a base, with the scope of finding a structural relationship for the thiamine-bound intermediate which intervene in the oxidative decarboxylation of a-ketoacids catalysed by thiamin diphosphate-dependent enzymes. 2-Alkyl and 2-benzylthiazolium salts, which are not electroactive, can be transformed into electroactive species by treatment with the base (trimethylsilyl)amide. Subsequent anodic oxidation affords the corresponding symmetrical dimers, by an EC mechanism (Scheme 72). As expected, the stabilizing effect of the substituents R, R at the a-carbon on the radical cation follows the order H < Me < OMe. When R is aryl, electron-donating p-substituents again enhance the enamine oxidation. [Pg.955]

In these reactions, the C2-atom of ThDP must be deprotonated to allo v this atom to attack the carbonyl carbon of the different substrates. In all ThDP-dependent enzymes this nucleophilic attack of the deprotonated C2-atom of the coenzyme on the substrates results in the formation of a covalent adduct at the C2-atom of the thiazolium ring of the cofactor (Ila and Ilb in Scheme 16.1). This reaction requires protonation of the carbonyl oxygen of the substrate and sterical orientation of the substituents. In the next step during catalysis either CO2, as in the case of decarboxylating enzymes, or an aldo sugar, as in the case of transketo-lase, is eliminated, accompanied by the formation of an a-carbanion/enamine intermediate (Ilia and Illb in Scheme 16.1). Dependent on the enzyme this intermediate reacts either by elimination of an aldehyde, such as in pyruvate decarboxylase, or with a second substrate, such as in transketolase and acetohydroxyacid synthase. In these reaction steps proton transfer reactions are involved. Furthermore, the a-carbanion/enamine intermediate (Ilia in Scheme 16.1) can be oxidized in enzymes containing a second cofactor, such as in the a-ketoacid dehydrogenases and pyruvate oxidases. In principal, this oxidation reaction corresponds to a hydride transfer reaction. [Pg.1419]

Kynurenine aminotransferase (EC 2.6.1.7) is a PLP-dependent enzyme that converts kynurenine to the corresponding a-ketoacid, employing a-ketoglutarate as an electron acceptor. A rapid cyclisation of the reaction product leads to kynurenic acid. By the same way, HK is converted to xanthurenic acid. In the brain, two forms of kynurenine aminotransferase have been found, somewhat differing as regards substrate specificity, affinity, and inhibition. The mechanism of the enzymic transamination of kynurenine and HK has drawn little attention, even if its irreversible character should be an interesting feature. [Pg.970]

The broad synthetic potential ThDP-dependent enzymes for asymmetric C-C bond formation is by far not fully exploited with the acyloin- and benzoin-condensations discussed above. On the one hand, novel branched-chain a-keto-acid decarboxylases favorably extend the limited substrate tolerance of traditirnial enzymes, such as PDC, by accepting sterically hindered a-ketoacids as dcmors [1511], On the other hand, the acceptor range may be significantly widened by using carlxMiyl compounds other than aldehydes Thus, ketones, a-ketoacids and even CO2 lead to novel types of products (Scheme 2.203). [Pg.231]

Thiamine-dependent enzymes consist of pyruvate dehydrogenase complex, a-ketoglutarate dehydrogenase complex (fCGDHC), branched-chain a-ketoacid dehydrogenase complex and transketolase. [Pg.580]

Stetter and Lorenz reported in 1985 that a thiazolylidine catalyst could promote the addition of a-ketoacid derivatives (17) to activated olefins (18) with loss of CO2 to give 1,4-diketones (19)7 The reaction has been called biomimetic because of its resemblance to the family of biochemical transformations effected by thiamine diphosphate-dependent enzymes acting on pyruvate While the original report was limited to alkyl vinyl ketones, more recent work by Scheldt and co-workers has greatly expanded the scope of this reaction by employing a, 3-unsaturated 2-acylimidazoles as the activated olefin component. ... [Pg.579]

Use of aminotransferases Aminotransferases are pyridoxal 5 -phosphate-dependent enzymes that catalyze the reversible transfer of an amino group from an a-amino acid to an a-ketoacid in a two-step process. Of the many transaminases, aspartate aminotransferase (EC 2.6.1.1) is synthetically most useful since spontaneous decarboxylation of the generated oxaloacetate to pyruvate shifts the equilibrium to the product side. [Pg.612]

Exceptionally, in Escherichia coli acireductone dioxygenase (enediol dioxygenase) carries out two enzymatic activities that are responsible for the salvage of methionine, but are encoded by the same gene. Whereas one enzyme is dependent on Fe and produces the ketoacid and formate (Figure 3.34a), the other that is nickel-dependent produces the carboxylic acid, formate, and CO (Figure 3.34b) (Dai et al. 1999). [Pg.182]

A number of factors complicate the aerobic metabolism of amino acids—different enzymes may be used even for the same amino acid the enzymes may be inducible or constitutive depending on their function a-ketoacids may be produced by deamination or amines by decarboxylation. [Pg.312]

Among the mononuclear non-haem iron enzymes catalysing hydroxylation reactions (Table 2.3) we can distinguish between intramolecular dioxygenases and external mononoxygenases. The former can be divided into those which are pterin-dependent and those which use a-ketoacids such as a-keto glutarate as obligatory... [Pg.83]

The configuration of 3-hydroxyacid esters obtained by yeast reduction of 3-ketoprecursors depends on the chain length of the acids (.18. >1.9). Zhou et al. (20)demonstrated that the structure of the alcohol esterified in 3-ketoacid esters also influences the configuration of the 3-hydroxycompounds that are formed. The fact, that the optical purity of the products depends on the concentration of the 3-ketocompounds (21) indicates the presence of competing enzymes leading to opposite enantiomers at different rates. [Pg.51]

The first step in the catabolism of most amino acids is the transfer of the o-amino group from the amino acid to a-ketoglutarate (tx-KG). This process is catalyzed by transaminase (aminotransferase) enzymes that require pyridoxal phosphate as a cofactor. The products of this reaction are glutamate (Glu) and the a-ketoacid analog of the amino acid destined for catabolic breakdown. For example, aspartate is converted to its a-keto analog, oxalo-acetate, by the action of aspartate transaminase (AST), which also produces Glu from a-KG. The transamination process is freely reversible, and the direction in which the reaction proceeds is dependent on the concentrations of the reactants and products. These reactions do not effect a net removal of amino nitrogen the amino group is only transferred from one amino acid to another. [Pg.341]

With such an extensive knowledge base, what is the present state of our understanding of the mechanisms of this disorder Not unexpectedly, initial studies, primarily in experimental animal models, focused on the known metabolic pathways which involve thiamine. Indeed, the classical studies of Peters in 1930 (Peters, 1969) showed lactate accumulation in the brainstem of thiamine deficient birds with normalization of this in vitro when thiamine was added to the tissue. This led to the concept of the biochemical lesion of the brain in thiamine deficiency. The enzymes which depend on thiamine are shown in Fig. 14.1. They are transketolase, pyruvate and a-ketoglutarate dehydrogenase. Transketolase is involved in the pentose phosphate pathway needed to form nucleic acids and membrane lipids, including myelin. The ketoacid dehydrogenases are key enzymes of the Krebs cycle needed for energy (ATP) synthesis and also to form acetylcholine via Acetyl CoA synthesis. Decrease in activity of this cycle would result in anaerobic metabolism and lead to lactate formation (i.e., tissue acidosis) (Fig. 14.1). [Pg.292]

Figure 6 Fatty-acid biosynthesis. Cytoplasmic acetyl-CoA (AcCoA) is the primary substrate for de novo fatty-acid synthesis. This two-carbon compound most commonly derives from the glycolytic degradation of glucose, and its formation is dependent upon several reactions in the mitochondria. The mitochondrial enzyme pyruvate carboxylase is found primarily in tissues that can synthesize fatty acids. AcCoA is converted to maionyl-CoA (MalCoA) by acetyl-CoA carboxylase. Using AcCoA as a primer, the fatty-acid synthase multienzyme complex carries out a series of reactions that elongate the growing fatty acid by two carbon atoms. In this process MalCoA condenses with AcCoA, yielding an enzyme-bound four-carbon /3-ketoacid that is reduced, dehydrated, and reduced again. The product is enzyme-bound 4 0. This process is repeated six more times, after which 16 0 is released from the complex. The reductive steps require NADPH, which is derived from enzyme reactions and pathways shown in grey. Enz refers to the fatty acid synthase multienzyme complex. Figure 6 Fatty-acid biosynthesis. Cytoplasmic acetyl-CoA (AcCoA) is the primary substrate for de novo fatty-acid synthesis. This two-carbon compound most commonly derives from the glycolytic degradation of glucose, and its formation is dependent upon several reactions in the mitochondria. The mitochondrial enzyme pyruvate carboxylase is found primarily in tissues that can synthesize fatty acids. AcCoA is converted to maionyl-CoA (MalCoA) by acetyl-CoA carboxylase. Using AcCoA as a primer, the fatty-acid synthase multienzyme complex carries out a series of reactions that elongate the growing fatty acid by two carbon atoms. In this process MalCoA condenses with AcCoA, yielding an enzyme-bound four-carbon /3-ketoacid that is reduced, dehydrated, and reduced again. The product is enzyme-bound 4 0. This process is repeated six more times, after which 16 0 is released from the complex. The reductive steps require NADPH, which is derived from enzyme reactions and pathways shown in grey. Enz refers to the fatty acid synthase multienzyme complex.

See other pages where Ketoacid-dependent Enzymes is mentioned: [Pg.84]    [Pg.84]    [Pg.330]    [Pg.955]    [Pg.109]    [Pg.1432]    [Pg.4]    [Pg.195]    [Pg.2856]    [Pg.502]    [Pg.116]    [Pg.499]    [Pg.1048]    [Pg.381]    [Pg.276]    [Pg.2855]    [Pg.593]    [Pg.330]    [Pg.334]    [Pg.250]    [Pg.192]    [Pg.845]   


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