Malonyl Coenzyme decarboxylation

The four carbon atoms of the butanoyl group originate m two molecules of acetyl coenzyme A Carbon dioxide assists the reaction but is not incorporated into the prod uct The same carbon dioxide that is used to convert one molecule of acetyl coenzyme A to malonyl coenzyme A is regenerated m the decarboxylation step that accompanies carbon-carbon bond formation... 

JEZ, J.M., FERRER, J.-L., BOWMAN, M.E., DIXON, R.A., NOEL, J.P., Dissection of malonyl-coenzyme A decarboxylation from polyketide formation in the reaction mechanism of a plant polyketide synthase, Biochemistry, 2000, 39, 890-902. 

Serine hydroxymethyl transferase catalyzes the decarboxylation reaction of a-amino-a-methylmalonic acid to give (J )-a-aminopropionic acid with retention of configuration [1]. The reaction of methylmalonyl-CoA catalyzed by malonyl-coenzyme A decarboxylase also proceeds with perfect retention of configuration, but the notation of the absolute configuration is reversed in accordance with the CIP-priority rule [2]. Of course, water is a good proton source and, if it comes in contact with these reactants, the product of decarboxylation should be a one-to-one mixture of the two enantiomers. Thus, the stereoselectivity of the reaction indicates that the reaction environment is highly hydro-phobic, so that no free water molecule attacks the intermediate. Even if some water molecules are present in the active site of the enzyme, they are entirely under the control of the enzyme. If this type of reaction can be realized using synthetic substrates, a new method will be developed for the preparation of optically active carboxylic acids that have a chiral center at the a-position. 

The )9-ketoacyl-synthases/acyltransferases (KS/ AT) in each module effect the chain elongation by methyl-malonyl-coenzyme A units catalyzing a Claisen e.ster condensation followed by decarboxylation (Scheme 2). Subsequent domains are module-specific ketoreductases (KR), dehydratases (DH) or enoyl-reductases (ER), which regulate the functionalization of the newly prepared fi-oxoesters. The stepwise growing chain is picked up by an acyl-carrier protein (ACP). 

Fatty acids have predominantly even numbers of carbon atoms because they are effectively formed from acetyl (C2) units, which are derived from glucose in the presence of various enzymes, coenzymes and carrier proteins. An overall scheme for saturated fatty acid biosynthesis is presented in Fig. 2.13, in which it can be seen that the first step is the formation of acetyl coenzyme A (often abbreviated to acetyl-CoA). One molecule ofacetyl-CoA undergoes addition of CO, to form malonyl-CoA, while the acetyl group on another molecule is transferred to an enzyme (fatty acid synthase). The malonyl unit (C3) is added to the enzyme-bound acetyl unit, which produces a butyryl group following loss of C02, dehydration and reduction. Six further steps of combined malonyl addition, decarboxylation, dehydration and reduction occur to yield palmitate (C16). Higher acids are built from palmitate in a similar... 

Although some synthetic applications of enols are known, their main role is as reactive intermediates. Enols are intermediates in the hydration of alkynes (Section 9.12) and the decarboxylation of (3-keto acids and malonic acid derivatives (Section 18.16), for example. They are intermediates in a number of biochemical processes including glucose metabolism and malonyl coenzyme A biosynthesis. 

Biochemical reactions include several types of decarboxylation reactions as shown in Eqs. (1)-(5), because the final product of aerobic metabolism is carbon dioxide. Amino acids result in amines, pyruvic acid and other a-keto acids form the corresponding aldehydes and carboxylic acids, depending on the cooperating coenzymes. Malonyl-CoA and its derivatives are decarboxylated to acyl-CoA. -Keto carboxylic acids, and their precursors (for example, the corresponding hydroxy acids) also liberate carbon dioxide under mild reaction conditions. 

The energy for the carbon-to-carbon condensations in fatty acid synthesis is supplied by the process of carboxylation and then decarboxylation of acetyl groups in the cytosol. The carboxylation of acetyl CcA to form malonyl CoA is catalyzed by acetyl CoA carboxylase (Figure 16.7), and requires HC03 )and ATP. The coenzyme is the vitamin, biotin, which is covalently bound to a lysyl residue of the carboxylase. 

It may seem surprising that a coenzyme is needed for these carboxylation reactions. However, unless the cleavage of ATP were coupled to the reactions, the equilibria would lie far in the direction of decarboxylation. For example, the measured apparent equilibrium constant K for conversion of propionyl-CoA to S methyl-malonyl-CoA at pH 8.1 and 28°C51 is given by Eq. 14-4. 

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. 

Like the related fatty acid synthases (FASs), polyketide synthases (PKSs) are multifunctional enzymes that catalyze the decarboxylative (Claisen) condensation of simple carboxylic acids, activated as their coenzyme A (CoA) thioesters. While FASs typically use acetyl-CoA as the starter unit and malonyl-CoA as the extender unit, PKSs often employ acetyl- or propionyl-CoA to initiate biosynthesis, and malonyl-, methylmalonyl-, and occasionally ethylmalonyl-CoA or pro-pylmalonyl-CoA as a source of chain-extension units. After each condensation, FASs catalyze the full reduction of the P-ketothioester to a methylene by way of ketoreduction, dehydration, and enoyl reduction (Fig. 3). In contrast, PKSs shortcut the FAS pathway in one of two ways (Fig. 4). The aromatic PKSs (Fig. 4a) leave the P-keto groups substantially intact to produce aromatic products, while the modular PKSs (Fig. 4b) catalyze a variable extent of reduction to yield the so-called complex polyketides. In the latter case, reduction may not occur, or there may be formation of a P-hydroxy, double-bond, or fully saturated methylene additionally, the outcome may vary between different cycles of chain extension (Fig. 4b). This inherent variability in keto reduction, the greater variety of... 

In the biosynthesis of compound 72 (Fig. 9) and other ansamycin antibiotics, 3-amino-5-hydroxyl-coenzyme A might act as a starter-molecule. To this seven-carbon amino unit the first propionate unit (via methylmalonyl-CoA), then an acetate unit via malonyl-CoA) and finally another propionate unit are added by condensation and decarboxylation. In the case of 72, the resulting aromatic triketide is then converted into the product P8/1-OG (72) by hydrogenation of the keto group at C-7 and enolization of the keto groups at C-3 and C-5. The CoA is then split off, possibly during the excretion of the product [118]. 

The malonic ester synthesis might seem like an arcane technique that only an organic chemist would use. Still, it is much like the method that cells use to synthesize the long-chain fatty acids found in fats, oils, waxes, and cell membranes. Figure 22-4 outlines the steps that take place in the lengthening of a fatty acid chain by two carbon atoms at a time. The growing acid derivative (acyl-CoA) is activated as its thioester with coenzyme A (structure on page 1027). A malonic ester acylation adds two of the three carbons of malonic acid (as malonyl-CoA), with the third carbon lost in the decarboxylation. A )8-ketoester results. Reduction of the ketone, followed by dehydration and reduction of... 

The biosynthesis of saphenic acid (27) and derivatives thereof is based on addition of a one-carbon unit to phenazine-1,6-carboxylic acid (Iq, Scheme 3). The transfer of a methyl group from C2 of acetate is a well-known biosynthetic transformation and occurs when the thioester of acetyl coenzyme A is converted by acetyl-CoA carboxylase to malonyl-CoA. Malonyl-CoA undergoes a decarboxylative Claisen condensation with a mono-CoA thioester of phenazine-1,6-... 

Fatty acid biosynthesis a process catalysed by fatty acid synthase, in which the fatty acid carbon chain is formed stepwise from 2-carbon units (derived from malonyl groups, with subsequent decarboxylation). The intermediates of F.a.b. are thioesters of Acyl carrier protein (see) (ACP) and not of coenzyme A as in fatty add degradation. 

A similar long arm is apparent in biotin (7.9), again enzyme bound through a lysine residue. The coenzyme (7.9) assists in the carboxylation of acetyl-CoA 1.8) with carbon dioxide yielding malonyl-CoA 1.14). Exchange of both acetyl-CoA and malonyl-CoA occurs with acyl carrier proteins (AGP) having free thiol groupings. Condensation then occurs between acetyl-S-ACP and malonyl-S-ACP with simultaneous decarboxylation the carboxylate anion is transferred into the new bond (Scheme 1.2) [6]. Subsequent steps involve reduction, dehydration and double-bond saturation. They... 

To clarify the characteristics of AMDase, the effects of additives were examined. The addition of ATP and coenzyme A (CoA) to the enzyme reaction mixture did not enhance the rate of decarboxylation. In the case of malonyl-CoA decarboxylase, ATP and substrate form a mixed anhydride, which in turn reacts with CoA to form a thiol ester of the substrate. In the case of AMDase, however, neither ATP nor CoA had any effect, so this mechanism is unlikely. It is well established that avidin is a potent inhibitor of biotin-enzyme complex formation [11,12]. In this case, addition of avidin had no influence on decarboxylase activity, indicating that AMDase is not a biotin-dependent decarboxylase. Thus, the cofactor requirements of AMDase are entirely different from known analogous enzymes, such as malonyl-CoA decarboxylases. 

Two important reactions involving coenzyme A are worthy of mention the first is the oxidative decarboxylation of pyruvate to acetyl-coenzyme A, which is catalyzed by the multienzyme complex, pyruvate dehydrogenase. This reaction involves a series of steps mediated by five coenzymes, during which a series of acid-base reactions and nucleophilic displacements take place, with pyruvate being oxidized and converted to acetyl-CoA. Another essential series of reactions involving acetyl-CoA is that of fatty acid synthesis. Here acetyl-CoA is converted to malonyl-CoA through condensation of the enzyme-bound thioester, with the occurrence of simultaneous decarboxylation. 

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