Disorders of Propionate and Methylmalonate Metabolism

The final unique stage in the metabolism of L-isoleucine involves the cleavage of 2-methylacetoacetyl-CoA to acetyl-CoA and propionyl-CoA (Section 10.4). The propionyl-CoA is further metabolized to methylmalonyl-CoA by a biotin-dependent carboxylase and subsequently via succinyl-CoA into the tricarboxylic acid cycle. L-Valine is also metabolized ultimately to methylmalonyl-CoA (Section 10.4), and thus these two branched-chain amino acids form the major precursors of propionyl-CoA and methylmalonyl-CoA. Other precursors of propionyl-CoA include methionine, threonine, odd-carbon-number fatty acids and cholesterol. The methyhnalonyl-CoA produced by propionyl-CoA carboxylase occurs as the D(5)-enantiomer and is racemized to the L(/ )-enantiomer by methylmalonyl-CoA racemase. l(/ )-Methylmalonyl-CoA is then metabolized to succinyl-CoA by a vitamin B12-dependent mutase prior to introduction of the modified molecule into the tricarboxylic acid cycle. 

Disorders in the metabolism of propionyl-CoA and methylmalonyl-CoA have been recorded at every step of these pathways and are further augmented by disorders in the synthesis of the 5 -deoxyadenosylcobalamin cofactor required by methylmalonyl-CoA mutase and of propionyl-CoA holo-carboxylase due to deficient activity of holocarboxylase synthetase (Section 10.3.2). Collectively these disorders comprise probably the most commonly encountered abnormal organic acidurias and this chapter describes these diseases and their underlying biochemistry. 

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Fenton WA, Gravel RA, Rosenblatt DS. Disorders of propionate and methylmalonate metabolism. In Scriver CR, Beaudet AL, Valle D, Sly WS, Childs B, Kinzler KW, et al, eds. The metabolic molecular bases of inherited disease, 8th ed. New York McGraw-Hill, 2001 2165-93. 

This chapter is concerned with the known disorders in the metabolism of the branched-chain amino acids after the initial transamination step, that lead to abnormal organic aciduria. Disorders of propionate and methylmalonate metabolism are discussed separately in Chapter 11. 

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