A new role for α-ketoglutarate dehydrogenase complex: regulating metabolism through post-translational modification of other enzymes

Abstract

This Editorial highlights a study by Gibson et al. published in this issue of JNeurochem, in which the authors reveal a novel role for the α-ketoglutarate dehydrogenase complex (KGDHC) in post-translational modification of proteins. KGDHC may catalyze post-translational modification of itself as well as several other proteins by succinylation of lysine residues. The authors' report of an enzyme responsible for succinylation of key mitochondrial enzymes represents a major step toward our understanding of the complex functional metabolome. TCA, tricarboxylic acid; KG, α-ketoglutarate; KGDHC, α-ketoglutarate dehydrogenase complex; FUM, fumarase; MDH, malate dehydrogenase; ME, malic enzyme; GDH, glutamate dehydrogenase; AAT, aspartate aminotransferase; GS, glutamine synthetase; PAG, phosphate-activated glutaminase; SIRT3, silent information regulator 3; SIRT5, silent information regulator 5.

Figure 1

Schematic illustration of α-ketoglutarate dehydrogenase complex (KGDHC) mediated succinylation of enzymes described by Gibson et al. (Gibson et al. 2015) (this issue). Green arrows point to enzymes fumarase (FUM) and pyruvate dehydrogenase complex (PDH) that have increased activity after succinylation. Gibson et al. (Gibson et al. 2015) also found increased acetylation of PDHC in the presence of KGDHC. The red arrow points to isocitrate dehydrogenase which has decreased activity after succinylation. SIRT5 activity leads to de-succinylation of proteins, and SIRT3 activity leads to deacetylation of proteins. Abbreviations: TCA, tricarboxylic acid; KG, α-ketoglutarate; KGDHC, a-ketoglutarate dehydrogenase complex; FUM, fumarase; ME, MDH, malate dehydrogenase; malic enzyme; GDH, glutamate dehydrogenase; AAT, aspartate aminotransferase; GS, glutamine synthetase; PAG, phosphate activated glutaminase; SIRT3, silent information regulator 3; SIRT5, silent information regulator 5.