Succinylation is a reversible post-translational modification (PTM) where a succinyl group is added to a protein. This modification primarily occurs on lysine residues, which are amino acids with a positively charged side chain. The addition of this large chemical group alters a protein’s structure, activity, and interactions. Succinylation impacts cellular processes.
The Molecular Mechanism of Succinylation
Succinylation involves the transfer of a succinyl group, derived from succinyl-CoA, to a lysine residue on a target protein. This transfer can occur through enzymatic or non-enzymatic pathways. The succinyl group is a four-carbon, negatively charged moiety.
Enzymes that add the succinyl group are succinyltransferases, such as KAT2A and CPT1A. Desuccinylases are enzymes that remove the succinyl group, making the modification reversible. Sirtuin 5 (SIRT5) is a desuccinylase found in mitochondria and other cellular compartments.
Adding the succinyl group to a lysine residue changes its charge from positive to negative. This charge reversal, along with the bulkiness of the succinyl group, induces changes in the protein’s three-dimensional structure. These structural alterations impact the protein’s ability to interact with other molecules, its overall stability, and its enzymatic activity.
Diverse Roles in Cellular Function
Succinylation plays a regulatory role across various cellular processes, often linking metabolic states to protein function. Its influence is notable in energy metabolism, where it modulates the activity of enzymes. This modification is highly dynamic, responding to changes in nutrient availability and cellular redox status.
The modification is found in the mitochondria, where it affects enzymes involved in the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase and isocitrate dehydrogenase, and fatty acid oxidation. For instance, succinylation of succinate dehydrogenase inhibits its activity, affecting mitochondrial respiration. Succinylation also impacts glucose metabolism by influencing enzymes like pyruvate dehydrogenase complex (PDHC) and glyceraldehyde-3-phosphate dehydrogenase, regulating glucose breakdown and energy production.
Beyond metabolism, succinylation influences gene regulation. It modifies histones, which package DNA, altering chromatin structure and affecting gene expression. This modification also impacts transcription factors, which control the expression of specific genes. Furthermore, succinylation affects protein stability and cellular localization, influencing how long a protein exists in the cell and where it performs its function.
Succinylation and Human Health
Dysregulation of succinylation is linked to various human diseases. Its connection to cellular metabolism makes it relevant to metabolic disorders. For example, altered succinylation patterns are observed in conditions like obesity, type 2 diabetes, and non-alcoholic fatty liver disease.
In cancer, abnormal succinylation patterns contribute to tumor growth, altered metabolism, and metastasis. Hyper-succinylation, an elevated level of succinylation, is associated with accelerated glycolysis and promoted tumor growth in several cancer types, including lung, liver, and gastric cancers. This dysregulation also affects the stability and activity of proteins involved in cancer progression.
Succinylation also connects to neurodegenerative diseases such as Alzheimer’s and Parkinson’s. In Alzheimer’s, increased succinylation of proteins like amyloid precursor protein and tau disrupts their normal processing and promotes their aggregation, contributing to plaque and tangle formation. Succinylation plays a role in inflammatory responses, with elevated succinate levels influencing pro-inflammatory signaling pathways.