Methylmalonyl coenzyme

Fatty acids derived from animal and vegetable sources generally contain an even number of carbon atoms siace they are biochemically derived by condensation of two carbon units through acetyl or malonyl coenzyme A. However, odd-numbered and branched fatty acid chains are observed ia small concentrations ia natural triglycerides, particularly mminant animal fats through propionyl and methylmalonyl coenzyme respectively. The glycerol backbone is derived by biospeciftc reduction of dihydroxyacetone. 

There is one exception to the rule that requires bulky hydrophobic residues to fill the interior of eight-stranded a/p barrels in order to form a tightly packed hydrophobic core. The coenzyme Biz-dependent enzyme methylmalonyl-coenzyme A mutase, the x-ray structure of which was determined by Phil Evans and colleagues at the MRC Laboratory of Molecular... 

Figure 4.4 Schematic diagram of the structure of the a/p-barrel domain of the enzyme methylmalonyl-coenzyme A mutase. Alpha helices are red, and p strands are blue. The inside of the barrel is lined by small hydrophilic side chains (serine and threonine) from the p strands, which creates a hole in the middle where one of the substrate molecules, coenzyme A (green), binds along the axis of the barrel from one end to the other. (Adapted from a computer-generated diagram provided by P. Evans.)...

Succinyl-coenzyme A H -COSR COOH L-Methylmalonyl coenzyme ... 

Table 9.1 Test data methylmalonyl-coenzyme A epimerase from Propionibacterium shermanii...

McCarthy, A. A., Baker, H. M., Shewry S. C., Patchett, M. L. and Baker, E. N. (2001). Crystal structure of methylmalonyl-coenzyme A epimerase from P. sher-manii a novel enzymatic function on an ancient metal binding scaffold. Structure 9,637-646. 

Cobalamin compounds Tight Cobalamin (B12) Transfer of methyl group to homocysteine during synthesis of methionine metabolism of methylmalonyl coenzyme A... 

The formation of succinyl coenzyme A from methylmalonyl coenzyme A, part of the metabolism of odd-chain fatty acids, cholesterol, and the amino acids valine, isoleucine, threonine, and methionine... 

Vitamin B12 is a biologically active corrinoid, a group of cobalt-containing compounds with macrocyclic pyrrol rings. Vitamin B12 functions as a cofactor for two enzymes, methionine synthase and L-methylmalonyl coenzyme A (CoA) mutase. Methionine synthase requires methylcobalamin for the methyl transfer from methyltetrahydrofolate to homocysteine to form methionine tetrahy-drofolate. L-methylmalonyl-CoA mutase requires adenosylcobalamin to convert L-methylmalonyl-CoA to succinyl-CoA in an isomerization reaction. An inadequate supply of vitamin B12 results in neuropathy, megaloblastic anemia, and gastrointestinal symptoms (Baik and Russell, 1999). 

Dong, S. L., Padmakumar, R., Maiti, N., Baneqee, R., and Spiro, T. G., 1998, Resonance raman spectra show that coenzyme B12 binding to methylmalonyl-coenzyme A mutase changes the corrin ring conformation but leaves the C06C bond essentially unaffected. J. Am. Chem. Soc. 120 994799948. 

Miller, W. W., and Richards, J. H., 1969, Mechanism of action of coenzyme B12. Hydrogen transfer in the isomerization of methylmalonyl coenzyme A to succinyl coenzyme A, J. Am. Chem. Soc. 91 1458nl507. 

The answer is d. (Murray, pp 238-249. Scriver, pp 2165-2194. Sack, pp 121-144. Wilson, pp 287-324.) Propionic acidemia (232000) results from a block in propionyl CoA carboxylase (PCC), which converts propionic to methylmalonic acid. Excess propionic acid in the blood produces metabolic acidosis with a decreased bicarbonate and increased anion gap (the serum cations sodium plus potassium minus the serum anions chloride plus bicarbonate). The usual values of sodium (-HO meq/L) plus potassium ( 4 meq/T) minus those for chloride (-105 meq/L) plus bicarbonate (—20 meq/L) thus yield a normal anion gap of -20 meq/L. A low bicarbonate of 6 to 8 meq/L yields an elevated gap of 32 to 34 meq/L, a gap of negative charge that is supplied by the hidden anion (propionate in propionic acidemia). Biotin is a cofactor for PCC and its deficiency causes some types of propionic acidemia. Vitamin B deficiency can cause methylmalonic aciduria because vitamin Bn is a cofactor for methylmalonyl coenzyme A mutase. Glycine is secondarily elevated in propionic acidemia, but no defect of glycine catabolism is present. 

Vitamin B12 (2 a) participates in the aqueous-phase biosynthesis of purine and pyrimidine bases, the reduction of ribonucleotide triphosphates, the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A, the biosynthesis of methionine from homocysteine, and the formation of myelin sheath in the nervous systems. 

The catalytic action of vitamin B12 coenzyme in the enzymatic conversion of methylmalonyl-coenzyme A to succinyl-coeiizyme A and of related mutases is as yet unexplained and poses fascinating problems (Equations 2- 5). 

Vrilbloed JW, Zerbe-Brnkhardt K, Ratnatilleke A, Grubelnik-Leiser A, Robinson JA (1999) Insertional inactivation of methylmalonyl coenzyme A (CoA) mutase and isobutyryl-CoA mutase genes in Streptomyces cinnamonensis-. influence on polyketide antibiotic biosynthesis. J Bacteriol 181 5600 - 5605... 

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. 

Cardinale, G.J., Carty, T. J., and Abeles, R. H., 1970, Effect of methylmalonyl coenzyme A, a metabolite which accumulates in vitamin Bj2 deficiency, on fatty acid synthesis, J. Biol. Chem. 245 3771. 

---