Rearrangement methylmalonyl—succinyl

A Bi9-Catalyzed Rearrangement Yields Succinyl-CoA from L-Methylmalonyl-CoA... 

Odd-chain fatty acids are an exception. While they are relatively rare in the diet, odd-chain-length fatty acids end up at propionyl-CoA (C3). Propionyl-CoA is carboxylated by propionyl-CoA carboxylase to give methylmalonyl-CoA. Methylmalonyl-CoA is rearranged to succinyl-CoA by the enzyme methylmalonyl-CoA mutase, a vitamin-B12-requiring enzyme. 

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. 

Darbre T, Keese R, Siljegovic V, WollebGygi A. Model studies for the coenzyme-B-12-catalyzed methylmalonyl-succinyl rearrangement. The importance of hydrophobic peripheral associations. Helv. Chim. Acta. 1996 79 2100-2113. 

Wolleb-Gygi A, Darbre T, SUjegovic V, Keese R (1994) The importance of praipheral association for vitamin B12 catalysed methylmalonyl-succinyl-rearrangement. Chem Commun 7 835—836... 

The ratio of propionic to acetic acid is influenced by the redox potential of the cheese, and in the presence of nitrates, for example, the ratio is lower. Propionic acid fermentation is shown in Fig. 10.27. The crucial step is the reversible rearrangement of succinyl-CoA into methylmalonyl-CoA ... 

Methylmalonyl CoA is formed as an intermediate in the catabolism of valine and by the carboxylation of propionyl CoA arising in the catabolism of isoleucine, cholesterol and (rare) fatty acids with an odd number of carbon atoms. As shown in Figure 11.18, it normally undergoes vitamin B dependent rearrangement to succinyl CoA, catalysed by methylmalonyl CoA mutase. The activity of this enzyme is greatly reduced in vitamin B deficiency, leading to an accumulation of methylmalonyl CoA, some of which is hydrolysed to yield methylmalonic acid, which is excreted in the urine urinary... 

The biochemistry catalyzed by enzymes that use coenzyme B12 is particularly interesting. As an example, methylmalonyl CoA (15) can reversibly rearrange to succinyl CoA (16). Many other reactions are of this type, in which a hydrogen atom and another group change places along an ethano system. There is as yet no chemical process by which one can duplicate such reactions, regardless of rate. Thus in this case an enzyme mimic is needed not just to come up to the rate and selectivity of an enzyme, but indeed even to perform the chemical transformation itself. 

A recent study has indicated that the skeletal rearrangement step in the B12-catalysed isomerization of methylmalonyl-CoA to succinyl-CoA occurs not by a radical pathway but by an anionic or organocobalt pathway. A computational study of the isomerization of allyl alcohol into homoallyl alcohol by lithium amide has pointed to a process proceeding via a transition state in which the proton is half transferred between carbon and nitrogen in a hetero-dimer. l,l-Dilithio-2,2-diphenylethene... 

In rearrangements (isomerizations, not shown), groups are shifted within one and the same molecule. Examples of this in biochemistry include the isomerization of sugar phosphates (see p.36) and of methylmalonyl-CoA to succinyl CoA (see p. 166). 

Adenosylcobalamin (coenzyme 812) carries a covalently bound adenosyl residue at the metal atom. This is a coenzyme of various isomerases, which catalyze rearrangements following a radical mechanism. The radical arises here through homolytic cleavage of the bond between the metal and the adenosyl group. The most important reaction of this type in animal metabolism is the rearrangement of methylmalonyl-CoAto form succinyl-CoA, which completes the breakdown of odd-numbered fatty acids and of the branched amino acids valine and isoleucine (see pp. 166 and 414). 

Vitamin Bjj (8.50, cobalamin) is an extremely complex molecule consisting of a corrin ring system similar to heme. The central metal atom is cobalt, coordinated with a ribofuranosyl-dimethylbenzimidazole. Vitamin Bjj occurs in liver, but is also produced by many bacteria and is therefore obtained commercially by fermentation. The vitamin is a catalyst for the rearrangement of methylmalonyl-CoA to the succinyl derivative in the degradation of some amino acids and the oxidation of fatty acids with an odd number of carbon atoms. It is also necessary for the methylation of homocysteine to methionine. 

Propionyl-CoA is first carboxylated to form the d stereoisomer of methylmalonyl-CoA (Pig. 17—11) by propionyl-CoA carboxylase, which contains the cofactor biotin. In this enzymatic reaction, as in the pyruvate carboxylase reaction (see Pig. 16-16), C02 (or its hydrated ion, HCO ) is activated by attachment to biotin before its transfer to the substrate, in this case the propionate moiety. Formation of the carboxybiotin intermediate requires energy, which is provided by the cleavage of ATP to ADP and Pi- The D-methylmalonyl-CoA thus formed is enzymatically epimerized to its l stereoisomer by methylmalonyl-CoA epimerase (Pig. 17-11). The L-methylmal onyl -CoA then undergoes an intramolecular rearrangement to form succinyl-CoA, which can enter the citric acid cycle. This rearrangement is catalyzed by methylmalonyl-CoA mutase, which requires as its coenzyme 5 -deoxyadenosyl-cobalamin, or coenzyme Bi2, which is derived from vitamin B12 (cobalamin). Box 17—2 describes the role of coenzyme B12 in this remarkable exchange reaction. 

The catabolism of certain amino acids (e.g., valine, isoleucine, methionine) and odd-chain fatty acids (17 0) produces propionyl-CoA. Propionyl-CoA enters the TCA (citric acid) cycle following conversion to succinyl-CoA, as shown in Fig. 28-7. Propionyl-CoA is first carboxylated to produce D-methylmalonyl-CoA, which in turn is then racemized to L-methylmalonyl-CoA. In an intramolecular rearrangement reaction catalyzed by L-methylmalonyl-CoA mutase, a vitamin B12-... 

Dowd, P., Wilk, B., and Wilk, B. K., 1992, 1st Hydrogen abstraction rearrangement model for the coenzyme B12-dependent methylmalonyl-CoA to succinyl-CoA carbon skeleton rearrangement reaction. J. Am. Chem. Soc. 114 794997951. 

ATP to yield the d isomer of methylmalonyl CoA (Figure 22.11). This carboxylation reaction is catalyzed by propionyl CoA carboxylase, a biotin enzyme that is homologous to and has a catalytic mechanism like that of pyruvate carboxylase (Section 16.3.2). The d isomer of methylmalonyl CoA is racemized to the 1 isomer, the substrate for a mutase that converts it into succinyl CoA by an intramolecular rearrangement. The -CO-S-CoA group migrates from C-2 to C-3 in exchange for a hydrogen atom. This very unusual isomerization is catalyzed by methylmalonyl CoA mutase, which contains a derivative of vitamin Bj2, cobalamin, as its coenzyme. 

Cobalamin enzymes, which are present in most organisms, catalyze three types of reactions (1) intramolecular rearrangements (2) methylations, as in the synthesis of methionine (Section 24.2.7) and (3) reduction of ribonucleotides to deoxyribonucleotides (Section 25.3). In mammals, the conversion of 1-methylmalonyl CoA into succinyl CoA and the formation of methionine by methylation of homocysteine are the only reactions that are known to require coenzyme Bj2. The latter reaction is especially important because methionine is required for the generation of coenzymes that participate in the synthesis of purines and thymine, which are needed for nucleic acid synthesis. 

Figure 22.15. Formation of Succinyl CoA by a Rearrangement Reaction. A free radical abstracts a hydrogen atom in the rearrangement of methylmalonyl CoA to succinyl CoA.

The coenzyme that mediates this transfer of a methyl group is methylcobalamin, derived from vitamin Bj2- In fact, this reaction and the rearrangement of 1-methylmalonyl CoA to succinyl CoA (Section 23.5.4), catalyzed by a homologous enzyme, are the only two Bj2-dependent reactions known to take place in mammals. Another enzyme that converts homocysteine into methionine without vitamin Bj2 also is present in many organisms. 

Four amino acids are converted to propionyl CoA, which is car-boxylated in a biotin-requiring reaction to form methylmalonyl CoA, o which is rearranged to form succinyl CoA in a reaction that requires... 

Mechanism Methylmalonyl CoA Mutase Catalyzes a Rearrangement to Form Succinyl CoA... 

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