Succinylation Links Metabolism to Protein Functions

Abstract

Post-translational modifications (PTMs) are important regulators of protein function, and integrate metabolism with physiological and pathological processes. Phosphorylation and acetylation are particularly well studied PTMs. A relatively recently discovered novel PTM is succinylation in which metabolically derived succinyl CoA modifies protein lysine groups. Succinylation causes a protein charge flip from positive to negative and a relatively large increase in mass compared to other PTMs. Hundreds of protein succinylation sites are present in proteins of multiple tissues and species, and the significance is being actively investigated. The few completed studies demonstrate that succinylation alters rates of enzymes and pathways, especially mitochondrial metabolic pathways. Thus, succinylation provides an elegant and efficient mechanism to coordinate metabolism and signaling by utilizing metabolic intermediates as sensors to regulate metabolism. Even though the brain is one of the most metabolically active organs, an understanding of the role succinylation in the nervous system is largely unknown. Data from other tissues and other PTMs suggest that succinylation provides a coupling between metabolism and protein function in the nervous system and in neurological diseases. This review provides a new insight into metabolism in neurological diseases and suggests that the drug development for these diseases requires a better understanding of succinylation and de-succinylation in the brain and other tissues.

Keywords: Metabolism; Mitochondria; Sirtuins; Succinlyation.

Figure 1.

Succinylation changes protein size and charge, and increases mass by 100 Da and changes charge from a single positive to a single negative

Figure 2.

Little is known about regulation of succinylation and desuccinylation

Figure 3.

Inhibition of KGDHC with CESP reduces succinylation in cultured neurons. Neurons were incubated with or without a KGHDC antibody, immuno-precipitated and then stained with antisuccinyl-lysine antibody

Figure 4.

Sources of succinyl CoA

Figure 5.

Regulation of PDHC