Keto acid decarboxylases

Schellenberger, A. Structure and mechanism of action of the active centre of yeast pyruvate decarboxylase. Angew. Chem. Int. Ed. Engl. 6, 1024-1035 (1967) 

Ullrich, J., Ostrovsky, Y. M., Eyzaguirre, J., Holzer, H. Thiamine pyrophosphate-catalyzed enzymatic decarboxylation of oc-oxo acids. Vitam. Horm. 25, 365-398 (1971) 

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As the name implies, the odor of urine in maple syrup urine disease (brancbed-chain ketonuria) suggests maple symp or burnt sugar. The biochemical defect involves the a-keto acid decarboxylase complex (reaction 2, Figure 30-19). Plasma and urinary levels of leucine, isoleucine, valine, a-keto acids, and a-hydroxy acids (reduced a-keto acids) are elevated. The mechanism of toxicity is unknown. Early diagnosis, especially prior to 1 week of age, employs enzymatic analysis. Prompt replacement of dietary protein by an amino acid mixture that lacks leucine, isoleucine, and valine averts brain damage and early mortality. 

Mutation of the dihydrolipoate reductase component impairs decarboxylation of branched-chain a-keto acids, of pyruvate, and of a-ketoglutarate. In intermittent branched-chain ketonuria, the a-keto acid decarboxylase retains some activity, and symptoms occur later in life. The impaired enzyme in isovaleric acidemia is isovaleryl-CoA dehydrogenase (reaction 3, Figure 30-19). Vomiting, acidosis, and coma follow ingestion of excess protein. Accumulated... 

This enzyme complex [EC 1.2.4.4], also known as 3-methyl-2-oxobutanoate dehydrogenase (lipoamide) and 2-oxoisovalerate dehydrogenase, catalyzes the reaction of 3-methyl-2-oxobutanoate with lipoamide to produce S-(2-methylpropanoyl)dihydrolipoamide and carbon dioxide. Thiamin pyrophosphate is a required cofactor. The complex also can utilize (5)-3-methyl-2-oxopenta-noate and 4-methyl-2-oxopentanoate as substrates. The complex contains branched-cham a-keto acid decarboxylase, dihydrolipoyl acyltransferase, and dihydrolipoa-mide dehydrogenase [EC 1.8.1.4]. 

H. Iding, P. Siegert, K. Mesch, M. Pohl, Application of alpha-keto acid decarboxylases in biotransformations. Biochim. Biophys. Acta 1998, 1385, 307-322. 

Various thiamine diphosphate (ThDP)-dependent a-keto acid decarboxylases have been described as catalyzing C-C bond formation and/or cleavage [48]. Extensive work has already been conducted on transketolase (TK) and pyruvate decarboxylase (PDC) from different sources [49]. Here attention should be drawn to some concepts based on the investigation of reactions catalyzed by the enzymes... 

The a-keto acid decarboxylases such as pyruvate (E.C. 4.1.1.1) and benzoyl formate (E.C. 4.1.1.7) decarboxylases are a thiamine pyrophosphate (TPP)-dependent group of enzymes, which in addition to nonoxidatively decarboxylating their substrates, catalyze a carboligation reaction forming a C-C bond leading to the formation of a-hydroxy ketones.269-270 The hydroxy ketone (R)-phenylacetylcarbinol (55), a precursor to L-ephedrine (56), has been synthesized with pyruvate decarboxylase (Scheme 19.35). BASF scientists have made mutations in the pyruvate decarboxylase from Zymomonas mobilis to make the enzyme more resistant than the wild-type enzyme to inactivation by acetaldehyde for the preparation of chiral phenylacetylcarbinols.271... 

V. Enzyme-Catalyzed Aldol- and Claisen-Type Condensations /3-Keto Acid Decarboxylases Stereochemistry versus Stability of Reaction Intermediates... 

Enzymes involved in aldol- and Claisen-type condensations and /3-keto acid decarboxylases catalyze electrophilic substitution reactions at the a-carbon of carbonyl substrates involving either retention or inversion of configuration at C [Eq. (29)] ... 

Keto acid decarboxylases catalyze the irreversible decarboxylation of j8-keto acids that are either used directly as substrates or are produced as initial reaction intermediates during the oxidative decarboxylation of j3-hydroxy acids [Eq. (37)] (Table VIII) (215-223). 

Keto Acid Decarboxylases Involve Both Net Retention and Inversion of Configuration... 

Whatever the explanation, the stereochemistry of the acetoacetate decarboxylase reaction is controlled by factors not common to the other /3-keto acid decarboxylases. 

OMP decarboxylase (ODCase) catalyzes the decarboxylation of OMP to UMP, a decarboxylation that must necessarily be mechanistically different from the groups of decarboxylations that occur throughout metabolism [1]. The structure of the substrate does not lend itself to decarboxylation mechanisms involving pyridoxal phosphate (typical of amino acid decarboxylases [2]), thiamine pyrophosphate (typical of a-keto acid decarboxylases [3]), or metal ions (typical of /3-keto acid decarboxylases [4]) although the presence of ions has been detected in some preparations of ODCase [5, 6], the enzyme clearly does not require for catalytic activity [7]. 

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). 

Forms of lipoic acid in oi-keto acid decarboxylase-dehydrogenase... 

Thiamine diphosphate is of significance as the coenzyme of x-keto acid decarboxylases (C 4) and transketolases. Thiamine is a vitamin for animals and human beings (vitamin E 2.1). 

Thiamine derivatives Thiamine diphosphate (D 10.4.5) Coenzyme of [Pg.492]

Pathways 8-10 are all thermodynamically favorable and produce 1 mol of ATP. Malonyl-CoA and malonic-semialdehyde can be derived from oxaloacetate by employing novel enzymes, with CoA-dependent oxaloacetate dehydrogenase and 2-keto acid decarboxylase activity, respectively. Malate can be converted to 3-HP using a novel enzyme with malate decarboxylase activity (Figure 14.4). These enzymes do not exist in nature and, because of this, it has been proposed that malate decarboxylase activity can be created by enzyme engineering in order to increase their specificity toward oxaloacetate and ability to produce the metabolic intermediates [33]. 

Figure 14.2. Example of some metabolic pathways adopted by Lactobacillus plantarum during fermentation of vegetable and fruit juices. He, isoleucine Leu, leucine Val, valine His, histidine Glu, glutamic acid BcAT, branched-chain aminotransferase KDC, a-keto acid decarboxylase ADH, alcohol dehydrogenase MLE, malol-actlc enzyme HDC, histidine decarboxylase (Adapted from Filannino etal. 2014)...

Flavor-related activities of LAB depend on the species, with some specific activities found only in a small number of species. The branched-chain a-keto acid decarboxylase activity involved in the formation of malty branched-chain aldehydes from branched-chain AA, for example, has been found only in L lactis and not in the Lactobacillus and Leuconostoc strains tested (Fernandez De Palencia et al. 2006). Most LAB, however, display a great strain-to-strain variability, on the genomic level and/or at the phenotypic level. Table 19.3 gives some examples of intra- and interspecies variability of flavor-related LAB properties, such as proteolytic activities, AA-converting enzymatic activities, ester synthesis, and autolysis. 

Leu aminotransferase activity detected in the 4 LAB genera tested Lactococcus, Lactobacillus, Streptococcus, leuconostoc) highly strain-dependent BC keto acid decarboxylase activity only detected in 1 genus Lactococcus out of the 5 LAB genera tested highly strain-dependent. 

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