Methylmalonyl coenzyme A isomerase

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). 

Oxidation of unsaturated fatty acids requires two additional enzymes enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase. Odd-number fatty acids are oxidized by the /3-oxidation pathway to yield acetyl-CoA and a molecule of propionyl-CoA This is carboxylated to methylmalonyl-CoA, which is isomerized to succinyl-CoA in a reaction catalyzed by methylmalonyl-CoA mutase, an enzyme requiring coenzyme B12. 

Isomerases that are dependent on coenzyme B12 constitute the largest subfamily of Bi2 enzymes and are components of a number of fermentative pathways in microbes [10, 11]. A single member of this group of enzymes, methylmalonyl-CoA mutase, is found in both bacteria and in mammals where it is a mitochondrial enzyme involved in the catabolism of odd-chain fatty acids, branched chain amino... 

The propionyl CoA carboxylation is another reaction in which the energy required to synthesize a car-bon-to-carbon bond is provided by ATP. Thus, the free energy of the pyrophosphate bond is transferred to CO2, which forms an N-carboxy bond with the biotin enzyme complex. Some of the molecular details of the propionyl carboxylation reaction are presented in Fig. 1-27. The isomerization of methylmalonyl CoA to succinyl CoA also involves vitamin B12. At first it was demonstrated that the activity of the isomerase was considerably decreased in the liver of vitamin B 12-deficient rats. Later the stimulating effect of 5,6-dimethylbenzimidazole carbamide coenzyme was demonstrated with partially purified preparations of the liver enzyme. The methylmalonate CoA-isomerase complex purified from sheep liver has been divided into two different protein fractions, one with isomerase and the other racemase activity. The isomerase acts on only one of the enantiomorphs of methylmalonyl CoA, but the absolute formula of the enantiomorph that serves as substrate for the isomerase is unknown. A racemase catalyzes the conversion of the alternate enantiomorph to the substrate of the isomerase. 

The metabolic role of many minerals and vitamins is as prosthetic groups or coenzymes in different enzyme systems. Consequently, mineral and vitamin deficiencies can cause a breakdown of the processing system and precipitate metabolic disease. For example, methylmalonyl-CoA isomerase (see p. 203) is an important vitamin Bi2-dependent enzyme in the gluconeogenic pathway. A deficiency of vitamin B12 (or cobalt) may reduce enzyme activity, decrease the efficiency of glucose synthesis and predispose the animal to ketosis. Similarly, ceruloplasmin is a copper-dependent enzyme responsible for releasing iron from cells into blood plasma. A copper deficiency may reduce ceruloplasmin activity, decrease the efficiency of iron utilisation for haemoglobin synthesis and predispose the animal to anaemia. 

Finally, it should be noted that coenzyme B g would probably have been discovered by Beck et during their studies of the conversion of methylmalonyl-CoA to succinyl-CoA by the sheep kidney mutase (isomerase) were it not for the fact that this enzyme binds the coenzyme very tightly in such a way that it is not susceptible to inactivation by light. Because of these properties they were unable to obtain a coenzyme-free mutase and so concluded that the reaction probably has no cofactor requirement. 

It has recently been established that a vitamin Bn derivative is the coenzyme of methylmalonyl isomerase (105a, 106). 

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