succinylCoA

Succinyl-CoA is a thioester formed by coenzyme A and succinic acid. It is a central metabolic intermediate in the mitochondria, linking the tricarboxylic acid (TCA) cycle to multiple biosynthetic pathways.

In the TCA cycle, succinyl-CoA is produced from α-ketoglutarate by the α-ketoglutarate dehydrogenase complex, releasing CO2 and generating NADH. Succinyl-CoA is then converted to succinate by succinyl-CoA synthetase (also called succinyl-CoA thiokinase), a step that also yields GTP or ATP via substrate-level phosphorylation and releases CoA.

Succinyl-CoA can also arise from propionyl-CoA, which is generated during the catabolism of certain amino acids (valine, isoleucine, methionine, threonine) and odd-chain fatty acids. Propionyl-CoA is carboxylated to D- and L-m methylmalonyl-CoA and, via methylmalonyl-CoA mutase (requiring vitamin B12), is rearranged to succinyl-CoA, which then feeds into the TCA cycle or heme biosynthesis.

A notable biosynthetic role of succinyl-CoA is in heme formation. In mitochondria, glycine and succinyl-CoA are condensed by ALA synthase to produce δ-aminolevulinic acid (ALA), the first step of the porphyrin/heme pathway. In plants, a similar connection exists for chlorophyll precursors.

Regulation and clinical relevance: flux through succinyl-CoA–related pathways is influenced by cellular energy status and redox state. Defects in propionyl-CoA metabolism (e.g., methylmalonyl-CoA mutase deficiency) can lead to methylmalonic acidemia, reflecting disruptions in succinyl-CoA production from propionyl-CoA.