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Mutase reactions, coenzyme dependent

Concerning the Mechanism of Coenzyme B12 Dependent Mutase Reactions... [Pg.18]

Leutbecher, U., Albracht, S. P. J., and Buckel, W., 1992, Identification of a paramagnetic species as an early intermediate in the coenzyme B]2 -dependent glutamate mutase reaction a cob(II)amide , FEBS Lett. 307(2) 144nl46. [Pg.400]

Wollowitz, S., and Halpem, J., 1984, Free-radical rearrangement involving the 1,2-migration of a thioester groupoModel for the coenzyme-B12 dependent methylmalonyl-CoA mutase reaction, J. Am. Chem. Soc. 106 831998321. [Pg.403]

Zhao, Y., Such, P., and REtey, J., 1992, Radical intermediates in the coenzyme B12 dependent methylmalonyl-CoA mutase reaction shown by EPR spectroscopy, Angew. Chem. Int. Ed. Engl. 31 2159216. [Pg.403]

Table I is a summary of all of the reactions known to date which require vitamin B12 coenzyme (i). The reaction catalyzed by glutamate mutase, the first reaction in which vitamin B12 was known to be involved, was discovered by Barker and his coworkers. The second reaction is the only one of these which also occurs in mammals all other reactions occur in bacteria. Much of the experimental data described here will be derived from the enzyme called dioldehydrase. An additional reaction which is not shown is the conversion of nucleotides to deoxynucleotides. The conversion of —CHOH— to — CH2— is in some way very similar to the reaction catalyzed by dioldehydrase. Vitamin B12 coenzyme-depend-... Table I is a summary of all of the reactions known to date which require vitamin B12 coenzyme (i). The reaction catalyzed by glutamate mutase, the first reaction in which vitamin B12 was known to be involved, was discovered by Barker and his coworkers. The second reaction is the only one of these which also occurs in mammals all other reactions occur in bacteria. Much of the experimental data described here will be derived from the enzyme called dioldehydrase. An additional reaction which is not shown is the conversion of nucleotides to deoxynucleotides. The conversion of —CHOH— to — CH2— is in some way very similar to the reaction catalyzed by dioldehydrase. Vitamin B12 coenzyme-depend-...
Of possible biological interest is the report, based on a model reaction study with hydroxocobalamine, that the coenzyme-B, 2-dependent methyl-malonyl-CoA mutase reaction could involve intramolecular addition of a primary radical to a thioester group. The cyclopropyloxy radical so formed in a Cy3/Cy4 case would open to the carbethoxy-substituted and hence stabilized radical to give the rearranged product. ... [Pg.209]

Various coenzymes are involved in these reactions. The carboxylase [3] requires biotin, and the mutase [4] is dependent on coenzyme Bj2 (5 -deoxyadenosyl cobalamin see p. 108). Succinyl-CoA is an intermediate in the tricar-... [Pg.166]

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. [Pg.42]

Vitamin B12 is required by only two enzymes in human metabolism methionine synthetase and L-methylmalonyl-CoA mutase. Methionine synthetase has an absolute requirement for methylcobalamin and catalyzes the conversion of homocysteine to methionine (Fig. 28-5). 5-Methyltetrahydrofolate is converted to tetrahydrofolate (THF) in this reaction. This vitamin B12-catalyzed reaction is the only means by which THF can be regenerated from 5-methyltetrahydrofolate in humans. Therefore, in vitamin B12 deficiency, folic acid can become trapped in the 5-methyltetrahydrofolate form, and THF is then unavailable for conversion to other coenzyme forms required for purine, pyrimidine, and amino acid synthesis (Fig. 28-6). All folate-dependent reactions are impaired in vitamin B12 deficiency, resulting in indistinguishable hematological abnormalities in both folate and vitamin B12 deficiencies. [Pg.308]

In mammals, there are only three vitamin B12 -dependent enzymes methionine synthetase, methylmalonyl CoA mutase, and leucine aminomutase. The enzymes use different coenzymes methionine synthetase uses methylcobal-amin, and cobalt undergoes oxidation during the reaction methylmalonyl CoA mutase and leucine aminomutase use adenosylcobalamin and catalyze the formation of a 5 -deoxyadenosyl radical as the catalytic intermediate. [Pg.304]

Glutamate mutase was discovered by Barker, who showed that the enzyme catalyzes the equilibration of (i j-glutamate with (25,36 )-3-methylaspaitate (Entry 1, Table 1 AG° = + 6.3 kJ mol K = 0.095) (for a review of glutamate mutase see Reference 7). This reaction is one of three distinct methods that nature uses to ferment glutamate to butyrate (5). Surprisingly, they all proceed through intermediate radicals. The coenzyme B 12-dependent fermentation is the only one of the three that... [Pg.67]

This enzyme s role in humans is to assist the detoxification of propionate derived from the degradation of the amino acids methionine, threonine, valine, and isoleucine. Propionyl-CoA is carboxylated to (5 )-methylmalonyl-CoA, which is epimerized to the (i )-isomer. Coenzyme Bi2-dependent methylmalonyl-CoA mutase isomerizes the latter to succinyl-CoA (Fig. 2), which enters the Krebs cycle. Methylmalonyl-CoA mutase was the first coenzyme B -dependent enzyme to be characterized crystallographically (by Philip Evans and Peter Leadlay). A mechanism for the catalytic reaction based on ab initio molecular orbital calculations invoked a partial protonation of the oxygen atom of the substrate thioester carbonyl group that facilitated formation of an oxycyclopropyl intermediate, which connects the substrate-derived and product-related radicals (14). The partial protonation was supposed to be provided by the hydrogen bonding of this carbonyl to His 244, which was inferred from the crystal structure of the protein. The ability of the substrate and product radicals to interconvert even in the absence of the enzyme was demonstrated by model studies (15). [Pg.69]

We chose this reaction since it has been proposed as a model for the rearrangement of 2-methyleneglutarate to 3-methylitaconate, catalyzed by the coenzyme-B,2-dependent enzyme, 2-methyleneglutarate mutase [16, 26, 57]. More specifically, equation 2 represents the second step in the addition-elimination pathway (reaction c. Scheme 4) for a 1,2-shift. Additionally, this reaction has been widely studied experimentally [58] and has been described as the most precisely calibrated radical reaction [59]. [Pg.191]

Enzymes catalyzing carbon skeleton rearrangements were the first to be recognized as coenzyme B 12-dependent. The first was glutamate mutase (GM), discovered in 1960, and the nature of the skeletal rearrangement in the reaction of GM inspired the identification of coenzyme B12 as the coenzyme for the apparently similar reaction of... [Pg.527]

Lysine 2,3-aminomutase is not coenzyme 832 dependent, but a further lysine mutase, -lysine mutase (EC 5.4.3.3), catalyzes the coenzyme 812-dependent rearrangement shown in Scheme 68, the product 3,5-diaminohe-xanoic acid 261 having been shown (265) to have the (35,55) configuration. When the reaction was conducted in the presence of [5 - H] coenzyme 8,2 and the )5-lysine 258a was degraded to succinic acid, assay with succinate dehydrogenase showed the latter to be (25)-[2- HJ succinate (266). Thus... [Pg.436]

The homolytic cleavage of the Co - C bond of the protein-boimd organo-metallic cofactor AdoCbl (2) is the initial step of the coenzyme Bi2-catalyzed enzymatic reactions. Halpern quoted that adenosyl cobamides can be considered as reversibly functioning sources for organic radicals [119]. A neutral aqueous solution of 2 is remarkably stable with a half-Ufe of 10 s (in the dark at room temperature), but decomposes, mainly with the homolysis of the Co-C bond, at higher temperatures [119,123]. The coenzyme B12-catalyzed enzyme reactions occur with maximal rates of approximately 100 s [173,239]. Rapid formation of Co(ll)corrins occurs only with addition of substrate to a solution of holoenzyme (or of apoenzymes and 2), as demonstrated in most of the known coenzyme Bi2-dependent enzymes, e.g., in methyl-malonyl-CoA mutase [121], glutamate mutase [202] and ribonucleotide reductase [239]. [Pg.42]

Heptamethylcob3rrinate cobester (13) and peripherically functionalized derivatives of 13 were used as catalysts to mimic the rearrangement catalyzed by the coenzyme Bi2-dependent enzyme methylmalonyl-CoA mutase (see Fig. 13) (45). In these studies, the reductive transformation of bromomethyl-malonates to succinates, catalyzed by 13, and similar rearrangement reactions were observed (45). [Pg.758]

The rearrangement described above by Barker using the coenzyme B12-dependent enzyme glutamate mutase is a most remarkable reaction. Until very recently, no analogous chemical reaction was known. In fact, elucidation of the structure of the coenzyme form of vitamin B12 did not clarify its mechanism. Beside this transformation, nine distinct enzymatic reactions requiring coenzyme B12 as cofactor are known. Most of which are without precedent in terms of organic reactions. They are listed in Fig. 6.11. In choosing vitamin B12 derivatives as coenzymes, enzymes appear to have reached a peak of chemical sophistication which would be difficult to mimic by the chemist. [Pg.371]


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