Protein succinylation (Ksucc)

Protein succinylation is a reversible post-translational modification (PTM) where a negatively charged four-carbon succinyl group is covalently attached to the lysine residues of a protein. This modification is chemically significant as it reverses the positive charge of lysine to a negative one, potentially triggering major conformational changes and altering the activity, stability, or localization of the target protein. It is predominantly regulated by Sirtuin 5 (SIRT5), which serves as the primary mitochondrial desuccinylase, while enzymes such as KAT2A and CPT1A act as succinyltransferases or 'writers'. Succinylation is a key regulator of cellular metabolism, particularly within the mitochondria where it modulates enzymes in the tricarboxylic acid (TCA) cycle, fatty acid oxidation, and the urea cycle. Dysregulation of protein succinylation has been implicated in a wide array of diseases, including various cancers where it supports metabolic reprogramming, cardiovascular conditions like heart failure, and neurodegenerative disorders such as Alzheimer's disease. While the modification process itself is not a discrete therapeutic target, the regulatory enzymes—most notably SIRT5—are being extensively researched as targets for drug development. Modulating these enzymes offers a potential strategy for treating metabolic and inflammatory diseases by restoring homeostatic protein function.

Other names

Lysine succinylationProtein lysine succinylationKsuc

Inhibition of desuccinylase enzymes (primarily Sirtuin 5) or modulation of the availability of the succinyl donor, succinyl-CoA.