Succinyl from methyl malonyl

In Rhodococcus ruber and Nocardia corallina the polymers composed of 3-hydroxybutyryl and 3-hydroxyvaleryl residues are synthesized from sugars by methyl-malonyl-CoA. Succinyl-CoA is decarboxylated via methyl-malonyl-CoA to propionyl-CoA as the precursor of 3-hydroxyvaleryl-CoA [40]. 

Propionyl CoA is the product from the catabolism of valine, isoleucine, methionine, and odd-numbered fatty acids. The carboxylation reaction, found in the mitochondria, produces methyl malonyl CoA. The latter undergoes a cobalamin (vitamin Bj2)-catalyzed rearrangement, forming succinyl CoA, which is metabolized further in the Krebs cycle. 

The pathway from propionyl CoA to succinyl CoA is especially interesting because it entails a rearrangement that requires vitamin (also known as cobalamin). Propionyl CoA is carboxylated at the expense ot the hydrolysis of a molecule of ATP to yield the D isomer of methyl-malonyl CoA (Figure 22.12). This carboxylation reaction is catalyzed by... 

One form of methionine synthase common in bacteria uses lV -methyltetrahydrofolate as a methyl donor. Another form of the enzyme present in some bacteria and mammals uses A/ -methyltetrahydro-folate, but the methyl group is first transferred to cobalamin, derived from coenzyme B12, to form methylcobalamin as the methyl donor in methionine formation. This reaction and the rearrangement of L-methyl-malonyl-CoA to succinyl-CoA (see Box 17-2, Fig. la) are the only known coenzyme Bi2-dependent reactions in mammals. In cases of vitamin B12 deficiency, some symptoms can be alleviated by administering not only vitamin B12 but folate. As noted above, the methyl group of methylcobalamin is derived from W -methyltetrahy-drofolate. Because the reaction converting the methylene form to the 7V -methyl form of tetrahydrofo-... 

In humans, methylmalonyl-CoA mutase is required for the metabolism of proprionate, derived from branched-chain amino acids, odd-chain fatty acids and cholesterol, into succinyl-CoA (Banerjee 1997 Pett et at. 2002). Methylmalonyl-CoA mutase requires AdoCbl as a cofactor. The mechanism involves the homolytic cleavage of the Co-C bond, forming cob(II)alamin and a 5 -deoxyadenosyl radical (Pett et at. 2002). The homolytic cleavage of the Co-C bond is increased 10 -fold in the presence of the enzyme. The 5 -deox-yadenosyl radical first abstracts a hydrogen atom from the substrate methyl-malonyl-CoA, which donates after a rearrangement reaction back to form succinyl-CoA (Pett et at. 2002). In humans, deficiency in methylmalonyl-CoA mutase causes an inherited metabolic disorder and is one of causes of methylmalonylacidemia. According to the severity of methylmalonyl-CoA mutase reduced activity, the deficiency is characterized as muf (detectable... 

In vitamin Bj2 deficiency, methylmalonic acid is excreted in the urine [103]. However, there also exists methylmalonic acidaemia as an inborn error of metabolism, distinct from vitamin B12 deficiency, with higher concentrations of methylmalonic acid in blood and urine [99, 104]. The blood and urine contain excess glycine—up to 12 mg per 100 ml blood and up to 4,000 mg per g creatinine in urine [99, 104-107]. The site of the metabolic block is reaction 4, methylmalonic acidaemia is caused by lack or inactivity of methylmalonyl-CoA mutase [108, 109]. Although there is no deficiency of vitamin Bi2, giving large doses causes a decrease in methylmalonic acid excretion in some cases (Bi2 i esponsive) [110]. Liver biopsy specimens from Bi2 i esponsive patients converted methyl-malonyl-CoA to succinyl-CoA at 10% of the normal rate, rising to normal with added Bj2 cofactor specimens from Bi2-unresponsive patients did not convert any methyl-malonyl-CoA to succinyl-CoA with or without added Bj2 cofactor [111]. 

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