Methylmalonyl CoA arises directly as an intermediate in the catabolism of valine, and is formed by the carboxylation of propionyl CoA arising in the catabolism of isoleucine, cholesterol, and fatty acids with an odd number of carbon atoms. Normally, as shown in Figure 10.13, it undergoes an adeno-sylcobalamin-dependentrearrangementto succinyl CoA, catalyzed by methylmalonyl CoA mutase. In vitamin B12 deficiency, the activity of this enzyme is greatly reduced, although there is induction of the apoenzyme to some 1.5- to 5-fold above that seen in control animals.
The sequence of the methylmalonyl CoA mutase reaction is as follows (Ludwig and Matthews, 1997; Frey, 2001):
1. Cleavage of the Co-C bond to the deoxyadenosyl group, with the probable formation of a 5'-deoxyadenosyl radical.
2. Removal of hydrogen from the substrate by the 5'-deoxyadenosyl radical, generating a substrate radical. It is not clear whether the dehydro-genation of the substrate occurs simultaneously with the cleavage of the Co-C bond or whether the 5'-deoxyadenosyl radical catalyzes this step.
3. Rearrangement of the substrate radical to give the product radical. It is not clear whether there is intermediate transfer of the carboxyl group of the substrate onto the cobalt of the coenzyme or direct carbon-to-carbon transfer in the substrate radical.
4. Removal of hydrogen from the deoxyadenosine by the product radical, forming the product and the 5'-deoxyadenosine radical.
5. Reformation of the C-Co bond of the intact coenzyme by reaction between the 5-deoxyadenosine radical and the central cobalt atom.
As a result of the reduced activity of the mutase in vitamin B12 deficiency, there is an accumulation of methylmalonyl CoA, some of which is hydrolyzed to yield methylmalonic acid, which is excreted in the urine. As discussed in Section 10.10.3, this can be exploited as a means of assessing vitamin B12 nutritional status. There may also be some general metabolic acidosis, which has been attributed to depletion of CoA because of the accumulation of methylmalonyl CoA. However, vitamin B12 deficiency seems to result in increased synthesis of CoA to maintain normal pools of metabolically useable coenzyme. Unlike coenzyme A and acetyl CoA, neither methylmalonyl CoA nor propionyl CoA (which also accumulates in vitamin B12 deficiency) inhibits pantothenate kinase (Section 12.2.1). Thus, as CoA is sequestered in these metabolic intermediates, there is relief of feedback inhibition of its de novo synthesis. At the same time, CoA may be spared by the formation of short-chain fatty acyl carnitine derivatives (Section 14.1.1), which are excreted in increased amounts in vitamin B12 deficiency. In vitamin B12-deficient rats, the urinary excretion of acyl carnitine increases from 10 to 11 nmol per day to 120 nmol per day (Brass etal., 1990).
Methylmalonyl CoA inhibits the synthesis of fatty acids from acetyl CoA at concentrations of the order of those found in tissues of vitamin B12-deficient animals. It is a substrate for fatty acid synthetase, leading to the formation of branched-chain and odd-carbon fatty acids.
Propionyl CoA inhibits N-acetylglutamate synthetase competitively with respect to acetyl CoA, forming N-propionylglutamate and reducing the synthesis of N-acetylglutamate. This is an obligatory activator of carbamyl phosphate synthetase, the first enzyme of urea synthesis. Vitamin B12 deficiency may result in some degree of protein intolerance and hyperammonemia.
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