Malonic semialdehyde

The final step in the metabolic degradation of uracil is the oxidation of malonic semialdehyde to give malonvl CoA. Propose a mechanism. 

P-Alanine, a metabolite of cysteine (Figure 34-9), is present in coenzyme A and as P-alanyl dipeptides, principally carnosine (see below). Mammalian tissues form P-alanine from cytosine (Figure 34-9), carnosine, and anserine (Figure 31-2). Mammalian tissues transami-nate P-alanine, forming malonate semialdehyde. Body fluid and tissue levels of P-alanine, taurine, and... 

Poelarends GJ, WH Johnson, AG Murzin, CP Whitman (2003) Mechanistic characterization of a bacterial malonate semialdehyde decarboxylase. J Biol Chem 278 48674-48683. 

The most obvious route of metabolism of propionyl-CoA is further (1 oxidation which leads to 3-hydroxypropionyl-CoA (Fig. 17-3, step a). This appears to be the major pathway in green plants.17 Continuation of the (1 oxidation via steps a-c of Fig. 17-3 produces the CoA derivative of malonic semialdehyde. The latter can, in turn, be oxidized to malonyl-CoA, a P-oxoacid which can be decarboxylated to acetyl-CoA. The necessary enzymes have been found in Clostridium kluyveri,70 but the pathway appears to be little used. 

Nevertheless, malonyl-CoA is a major metabolite. It is an intermediate in fatty acid synthesis (see Fig. 17-12) and is formed in the peroxisomal P oxidation of odd chain-length dicarboxylic acids.703 Excess malonyl-CoA is decarboxylated in peroxisomes, and lack of the decarboxylase enzyme in mammals causes the lethal malonic aciduria.703 Some propionyl-CoA may also be metabolized by this pathway. The modified P oxidation sequence indicated on the left side of Fig. 17-3 is used in green plants and in many microorganisms. 3-Hydroxypropionyl-CoA is hydrolyzed to free P-hydroxypropionate, which is then oxidized to malonic semialdehyde and converted to acetyl-CoA by reactions that have not been completely described. Another possible pathway of propionate metabolism is the direct conversion to pyruvate via a oxidation into lactate, a mechanism that may be employed by some bacteria. Another route to lactate is through addition of water to acrylyl-CoA, the product of step a of Fig. 17-3. Tire water molecule adds in the "wrong way," the OH ion going to the a carbon instead of the P (Eq. 17-8). An enzyme with an active site similar to that of histidine ammonia-lyase (Eq. 14-48) could... 

The product of acetyl-CoA carboxylase reaction, malonyl-CoA, is reduced via malonate semialdehyde to 3-hydroxypropionate, which is further reductively converted to propionyl-CoA. Propionyl-CoA is carboxylated to (S)-methylmalonyl-CoA by the same carboxylase. (S)-Methylmalonyl-CoA is isomerized to (R)-methylmal-onyl-CoA, followed by carbon rearrangement to succinyl-CoA by coenzyme B 12-dependent methylmalonyl-CoA mutase. Succinyl-CoA is further reduced to succinate semialdehyde and then to 4-hydroxybutyrate. The latter compound is converted into two acetyl-CoA molecules via 4-hydroxybutyryl-CoA dehydratase, a key enzyme of the pathway. 4-Hydroxybutyryl-CoA dehydratase is a [4Fe-4S] cluster and FAD-containing enzyme that catalyzes the elimination of water from 4-hydroxybutyryl-CoA by a ketyl radical mechanism to yield crotonyl-CoA [34]. Conversion of the latter into two molecules of acetyl-CoA proceeds via normal P-oxidation steps. Hence, the 3-hydroxypropionate/4-hydroxybutyrate cycle (as illustrated in Figure 3.5) can be divided into two parts. In the first part, acetyl-CoA and two bicarbonate molecules are transformed to succinyl-CoA, while in the second part succinyl-CoA is converted to two acetyl-CoA molecules. 

Fig. 8.12 Microbial production routes to 3-hydroxypropanoic acid. Compounds 3HPCoA, 3-hydroxypropanoyl coenzyme A ester 2KGA, 2-ketogluconic acid MSA, malonate semialdehyde. Enzymatic activities AAM, alanine-2,3-aminomutase TA, transaminase.

This reaction involves addition of a thiol residue of the enzyme to malonic semialdehyde, yielding a hemithioacetal. Oxidation by NAD+, followed by nucleophilic acyl substitution by CoA, gives malonyl CoA. 

Acetaldehyde from malonic semialdehyde a, 3-Diaminopropionic acid (DAP)... 

Acetaldehyde is formed by decarboxylation of malonic semialdehyde during subsequent acid hydrolysis. 

Interestingly, two enzymes have been described that catalyze the addition of water to alkynes, resulting in the formation of alkenols acetylene carboxylate hydratase from Pseudomonas (E.C. 4.2.1.71), which converts propynoic acid to 3-hydroxyprope-noate1201. The latter tautomerizes to malonic semialdehyde. Acetylene dicarboxylate hydratase (E. C. 4.2.1.72) converts acetylene dicarboxylic acid to 2-hydroxyethylenedi-carboxylic acid, which spontaneously decarboxylates to pyruvate[21]. 

The best-studied example of a CoA-dependent nonphosphorylating ALDH is the methylmalonate-semi-aldehyde dehydrogenase, which has been isolated from both mammalian and bacterial sources. This enzyme transforms malonate semialdehyde and methylmalonate semialdehyde into acetyl-CoA and propionyl-CoA, respectively, through an oxidation reaction as described above, followed by a decarboxylation reminiscent of other (3-keto acids. Mechanistic studies of the B. sukilis enzyme have shown that it is activated by NAD" " binding, that it exhibits half-of-sites reactivity (only two moles of NADH forms per tetrameric protein unit) and that the decarboxylation reaction occurs after formation of the acyl-enzyme intermediate. Acyl transfer from the enzyme to CoA completes the reaction. 

Tautomerase supertamily Malonate semialdehyde decarboxylase Decarboxylation of malonate Hydration of 2-oxo-3-pentynoate 113-117... 

CaaD is part of a pathway that is responsible for the degradation of the nematocide 1,3-dichloropropene in the soil bacterium Pseudomonas pavonaceae 170 (Figure l(b)). Its metabolic function is to convert trans-l>-chloroacrylate into malonate semialdehyde (4 at 3 s, 1.2 x lO moH Is ), which is probably the... 

Figure 11 Three possible mechanisms for the dehalogenation of frans-3-chloroacrylate. (a) Addition of water to the double bond, followed by enzyme-catalyzed or chemical decomposition of a short-lived halohydrin intermediate to afford malonate semialdehyde, (b) Conjugate addition reaction where the chlorine atom is displaced by a water-derived hydroxyl group, followed by tautomerization of the enol intermediate, (c) Conjugate addition reaction where the chlorine atom is displaced by an active site carboxylate group, followed by hydrolysis of the covalent ester intermediate, and tautomerization of the enol intermediate.

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