Enzyme-mediated decarboxylation reactions

Ohta, H., Sugai, T. Enzyme-mediated decarboxylation reactions in organic S5mthesis. In Stereoselective Biocatalysis (ed. Patel, R.N.), 2000, Marcel Dekker, New York, 487-526. 

H. Ohta, T. Sugai, Enzyme-mediated decarboxylation reactions in organic synthesis, in R. N. Patel (Ed.) Stereoselective Biocatalysis, Marcel Dekker, Inc., New York, 2000, pp. 467-526. 

Enzyme-Mediated Decarboxylation Reactions in Organic Synthesis... 

This decarboxylation reaction serves as the tool for enzyme-mediated organic synthesis. " As shown in Fig. 18, the addition of thiazolium intermediate derived... 

It is appropriate here to look at the structure of oxaloacetic acid, a critical intermediate in the Krebs cycle, and to discover that it too is a P-ketoacid. In contrast to oxalosuccinic acid, it does not suffer decarboxylation in this enzyme-mediated cycle, but is used as the electrophile for an aldol reaction with acetyl-CoA (see Box 10.4). 

Biotin enzymes are believed to function primarily in reversible carboxvlahon-decarboxylation reactions. For example, a biotin enzyme mediates the carboxylation of propionic acid to methylmalonic add, which is subsequently converted to succinic acid, a dtric acid cycle intermediate. A vitamin Bl2 coenzyme and coenzyme A are also essential to this overall reaction, again pointing out the interdependence of the B vitamin coenzymes. Another biotin enzyme-mediated reaction is the formation of malonyl-CoA by carboxylation of acetyl-CoA ( active acetate ). Malonyl-CoA is believed lo be a key intermediate in fatly add synthesis. 

In 1966 Dunathan (18) proposed that, in PLP-mediated reactions, the bond to be broken in the substrate-cofactor compound should be perpendicular to the plane of the extended conjugated system so that there would be maximum a-n overlap between the breaking bond and the ring-imine n system. Thus 3a, 3b, and 3c represent the conformations of the imine 3 best suited to achieve transamination reactions, decarboxylation reactions, and retroaldol reactions, respectively. The enzyme will be responsible for the orientation of the amino acid-PLP complex and thus dictate the nature of the resultant reaction. An example of an enzyme catalyzing two distinct reactions was found for serine hydroxymethyltransferase (EC 2.1.2.1), which normally catalyzes the retroaldol process outlined in 3c when L-serine or L-threonine are substrates. When D-alanine was used as substrate, however, a slow transamination was observed (19). Comparison of the conformations of the amino acid-PLP complexes, 3c and 17, respectively, for the retroaldol and transamination reactions shows that both the proton removed from the... 

A brilliantly simple and largely satisfying solution [16] to the observations on lysine and cadaverine incorporation has been proposed. It is consistent in particular with the observed incorporation of lysine with distinction between C-2 and C-6, loss of nitrogen from C-2 but retention of the C-2 proton and it allows for normal incorporation of cadaverine 6.26). Central to the proposal is enzyme-catalysed decarboxylation of lysine (lysine decarboxylase) and oxidation of cadaverine (diamine oxidase) both involving pyridoxal phosphate as coenzyme. The proposed sequence involves orthodox pyridoxal-linked intermediates of which 625) and 6.27) are common to both enzyme-mediated reactions (Scheme 6.8). It is an important... 

All reactions mediating fixation of CO by reductive carboxylation are readily reversible. Their equilibrium constant is sUghtly in favor of carboxylation, but at the low tensions of CO prevailing in cells and biological fluids the reverse action, i.e., oxidative decarboxylation, is favored unless appropriate mechanisms are broi t into play to displace the equilibrium position in favor of carboxylation. The two primary processes in each of these reactions, oxidation and decarboxylation or carboxylation and reduction, are intiinately interconnected and appear to be catalyzed by the same enzyme protein. The reactions to be considered in this section are the reductive car-boxylations of pyruvate, a-ketoglutarate, and ribulose 5-phosphate to L-malate, d-isocitrate, and 6-phosphogluconate, respectively. 

Inherently, the decarboxylation of p-keto acids and malonic acids (1) proceeds very smoothly, as the resulting product bearing anion adjacent to carbonyl group stabilizes as its enolate form (2) [Eq. (1)]. Enzyme-mediated reaction sometimes utilizes this facilitated decarboxylation. Indeed, isocitric acid (3) was oxidized to the corresponding keto acid, which subsequently decarboxylated to a-ketoglutaiic acid (4) by means of isocitrate dehydrogenase (EC 1.1.1.41) [Eq. (2)]. Another example is observed in the formation of acetoacetyl-CoA (5), which occupies the first step of fatty acid biosynthesis. A p-keto carboxylate 6, derived from the acetylation of malonyl-CoA with acetyl-CoA, decarbox-ylates to 5 by the action of 3-ketoacyl synthase [Eq. (3)]. 

This decarboxylation reaction serves as the tool for enzyme-mediated organic synthesis [136,137]. As seen in Eq. (27), the addition of thiazolium intermediate derived from hy-droxypyruvate proceeds via re face attack to afford the products (76) with stereochemically defined 2,3-erythro stereochemistry. The examples are summarized in Table 7. This method works very well for the synthesis of naturally occurring phosphorylated [126,134], nonphosphorylated ketoses [120,125], and deoxy sugars [115,124]. Moreover, 2,3-erythro-dio motif is exemplified in the chemoenzymatic synthesis of die L-series of aldoses (77-79) [122], aza sugars (80,81) [128-130] and ( )-gjco-brevicomin (69), an insect pheromone [131] (Tab e 8). The stereochemically controlled syntiiesis of aldehydes with d(2) config-... 

TPP-dependent enzymes catalyze either simple decarboxylation of a-keto acids to yield aldehydes (i.e. replacement of C02 with H+), or oxidative decarboxylation to yield acids or thioesters. The latter type of reaction requires a redox coenzyme as well (see below). The best known example of the former non-oxidative type of decarboxylation is the pyruvate decarboxylase-mediated conversion of pyruvate to acetaldehyde and C02. The accepted pathway for this reaction is shown in Scheme 10 (69MI11002, B-70MI11003, B-77MI11001>. 

Figure 7-2. Reactions of the pyruvate dehydrogenase (PDU) multienzyme complex (PDC). Pyruvate is decarboxylated by the PDH subunit (I ,) in the presence of thiamine pyrophosphate (TPP). The resulting hydroxyethyl-TPP complex reacts with oxidized lipoamide (LipS3), the prosthetic group of dehydrolipoamide transacetylase (Ii2), to form acetyl lipoamide. In turn, this intermediate reacts with coenzyme A (CoASH) to yield acetyl-CoA and reduced lipoamide [Lip(SH)2]. The cycle of reaction is completed when reduced lipoamide is reoxidized by the flavoprotein, dehydrolipoamide dehydrogenase (E3). Finally, the reduced flavoprotein is oxidized by NAD+ and transfers reducing equivalents to the respiratory chain via reduced NADH. PDC is regulated in part by reversible phosphorylation, in which the phosphorylated enzyme is inactive. Increases in the in-tramitochondrial ratios of NADH/NAD+ and acetyl-CoA/CoASH also stimulate kinase-mediated phosphorylation of PDC. The drug dichloroacetate (DCA) inhibits the kinase responsible for phosphorylating PDC, thus locking the enzyme in its unphosphory-lated, catalytically active state. Reprinted with permission from Stacpoole et al. (2003).

Protoporphyrinogen oxidase converts protoporphyrinogen IX to the fully desaturated porphyrin in a reaction that uses O2 as the terminal electron acceptor (Fig. 3). The crystal structure of the homodimeric enzyme shows it has one FAD per monomer, which presumably mediates the porphyrin oxidation reaction (19). Like the decarboxylation mediated by coproporphyrinogen oxidase, this reaction also occurs in the mitochondrion. Mutations in the protoporphyrinogen oxidase gene are responsible for variegate porphyria (21). Acute attacks of this disease can be effectively treated by intravenous administration of hematin. 

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