Genetic and genomic systems to study methylmalonic acidemia

Abstract

Methylmalonic acidemia (MMAemia) is the biochemical hallmark of a group of genetic metabolic disorders that share a common defect in the ability to convert methylmalonyl-CoA into succinyl-CoA. This disorder is due to either a mutant methylmalonyl-CoA mutase apoenzyme or impaired synthesis of adenosylcobalamin, the cofactor for this enzyme. In this article, we will provide an overview of the pathways disrupted in these disorders, discuss the known metabolic blocks with a particular focus on molecular genetics, and review the use of selected model organisms to study features of methylmalonic acidemia.

Figure 1

Major pathway of the conversion of propionyl-CoA into succinyl-CoA. The precursors are indicated with their approximated contribution to whole body propionate metabolism. The biotin-dependent enzyme, propionyl-CoA carboxylase, converts propionyl-CoA into D-methylmalonyl-CoA that is then racemized into L-methylmalonyl-CoA and isomerized into succinyl-CoA, a Krebs cycle intermediate. The location of the D-methylmalonyl-CoA hydrolase is indicated as are minor pathways of propionyl-CoA metabolism, such as the glycine conjugation pathway and 2-methylcitrate formation. The L-methylmalonyl-CoA mutase reaction requires adenosylcobalamin, an activated form of vitamin B12. The formation of adenosylcobalamin requires intracellular metabolism as outlined in the next figure.

Figure 2

Pathway of cellular processing of cobalamin (OH-Cbl). The class and genes associated with isolated methylmalonic acidemia are cblA (MMAA), cblB (MMAB), cblD variant 2 (unknown gene), cblH (unknown gene) and MCM. Question marks indicate unknown genes or poorly defined cellular processes. The position of the MMAA gene product reflects the probable role that this protein has in the protection of MCM [22]. A mitochondrial isoform of the methionine synthase reductase gene may protect or interact with the product of the MMAB gene [25] and is shown with a dashed line.