Methylmalonic acid cobalamin metabolism

Rollman N and Sjostrom G (1946) The behavior of some propionic acid bacteria strains against NaCl, NaN03, and heating. Svenska Mejerit 38(19) 199-201 (20) 209-212 Romanskaya NN, Diment GS and Vorobjeva LI (1985) Method of production of dairy beverages. Avt svidet No 1184506 Bull No 38 Rosenberg LE (1983) Disorders of propionate, methylmalonate and cobalamin metabolism. 

Patients typically present by 6-12 months with severe developmental retardation, convulsions, microcephaly and homocysteinemia (=50pmol/l) with hypomethioninemia (<20 pmol/1). A few individuals have had psychiatric disturbances. The blood concentration of vitamin B12 is normal, and, unlike individuals with defects of cobalamin metabolism, these patients manifest neither anemia nor methylmalonic aciduria. The blood folic acid level is usually low. 

Methylmalonyl-CoA mutase is a cobalamin-linked enzyme of mitochondria that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. A reduction of this enzyme due to vitamin B12 deficiency will result in a metabolic block with the urinary excretion of methylmalonic acid, and the measurement of this metabolite has been used to confirm a deficiency of vitamin B12. The test has also been useful in investigating rare abnormalities of this enzyme that result in the excretion of methylmalonic acid in the presence of adequate vitamin B12. Given an oral loading dose of valine or isoleucine will increase the urinary excretion of methylmalonic acid in patients with a vitamin B12 deficiency (G4). However, Chanarin and his colleagues (CIO) found that one-quarter of their patients with pernicious anemia excreted a normal concentration of methylmalonic acid even after a loading dose of valine. Normal subjects excrete up to 15 mg of methylmalonic acid in their urine over a 24-hour period (Cll). 

Major vitamin Bi2-dependent metabolic processes include the formation of methionine from homocysteine, and the formation of succinyl coenzyme A from methylmalonyl coenzyme A. Thus, apart from directly determining vitamin B12 concentration in serum, elevated levels of both methylmalonic acid and homocysteine may indicate a vitamin B12 deficiency. Serum cobalamine concentration is often determined by automated immunoassays using an intrinsic factor as binding agent. These assays have mainly replaced the microbiological methods. Literature data about vitamin B12 concentration in serum varies. Values <110-150pmoll are considered to reflect deficiency, whereas values >150-200pmoll represents an adequate status. 

Figure 7.3. Scheme of the enzymatic synthesis of cobamides in the cell. AdoCbl and MeCbl are formed from the common precursor OHCbl via two reductive steps catalyzed by separate enzymes. Metabolic disorders due to enzyme defects may occur at the two reductions and additions of adenosyl or methyl residues. High urinary levels of methylmalonic acid (methylmalonic aciduria) indicate an impaired synthesis of AdoCbl, whereas high levels of urinary homocysteine (homocystinuria) indicate an impaired MeCbl synthesis. In patients with high urinary levels of both methylmalonic acid and homocysteine a defective reduction of cobalamin is likely (Rosenberg, 1983). 

The methylmalonic acidemias [14, 15] are a family of disorders in the metaboUsm of branched-chain amino acids in which the activity of methyl-malonyl-CoA mutase is defective. They may be divided into mutase apoen-zyme defects and defects in cofactor synthesis or cobalamin metabolism. 

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