How to Decipher the Regulatory Roles of Acylation in Cellular Metabolism?
- Isocitrate dehydrogenase (IDH2)
- Succinate dehydrogenase (SDH)
- Long-chain acyl-CoA dehydrogenase (LCAD)
From a traditional standpoint in metabolic research, investigators have typically focused on metabolic pathways per se, such as glycolysis, the tricarboxylic acid (TCA) cycle, and fatty acid oxidation. Increasing evidence, however, indicates that key enzymes within these pathways do not operate in a fixed manner; rather, their activities are finely tuned by post-translational modifications (PTMs). Among these, protein acylation, particularly reversible acylation on lysine residues, is emerging as a critical molecular link between cellular metabolic states and the regulation of protein function.
What Is Acylation? From Acetylation to Diverse Acyl Species
1. Acetylation: the Earliest Recognized Form of Acylation
Acetylation is one of the earliest and most extensively studied forms of protein acylation. It predominantly occurs on lysine residues, with acetyl-CoA serving as the acetyl-group donor. Acetylation plays important roles in regulating chromatin organization, gene expression, and the activities of metabolic enzymes.
2. Succinylation, Propionylation, and Butyrylation: Signatures of Metabolic Intermediates
With the development of high-resolution mass spectrometry, it has become clear that lysine residues can also undergo succinylation, propionylation, and butyrylation, among other acyl modifications. These modifications are frequently linked to mitochondrial metabolism and can mirror cellular fluctuations in intermediate metabolite availability.
How Does Acylation Influence Metabolic Enzyme Activity?
1. Altering Enzyme Conformation and Substrate Affinity
Acylation can neutralize the positive charge of lysine side chains and thereby affect protein conformation. For example, acetylation may reduce the substrate affinity of certain enzymes, consequently modulating catalytic efficiency.
2. Functioning as a Readout of Metabolic State
Acylation levels are directly shaped by intracellular changes in acyl-CoA abundances, thereby providing a biochemical readout of metabolic status. For instance, under high-glucose or high-fat conditions, increases in intermediates such as acetyl-CoA and succinyl-CoA can markedly elevate the corresponding acylation levels.
The Role of Deacylases: A Precisely Controlled “Erasure” Mechanism
Acylation is reversible and is regulated by deacylating enzymes (deacylases). The best-characterized group is the sirtuin family, which uses NAD+ as a cofactor and thereby couples deacylation to nutrient and energy status.
SIRT3: a core regulator of mitochondrial metabolism
SIRT3 is primarily localized to mitochondria and can deacetylate multiple key metabolic enzymes, such as:
Deacetylation of these enzymes can increase their activities, thereby supporting the TCA cycle and fatty acid oxidation.
How Can Acylation Be Investigated: Integrating Proteomics with Mass Spectrometry
1. Enrichment Strategies: Antibody-Based Pull-Down vs. Chemical Probes
Because acylation modifications are often present at low stoichiometry, targeted enrichment is commonly required, for example via anti-acylation antibody-based enrichment or capture using specific chemical probes.
2. High-Resolution Mass Spectrometry: Integrating Qualitative and Quantitative Analyses
(1) Orbitrap- or Q Exactive–class mass spectrometers enable precise identification of modification sites
(2) TMT/iTRAQ labeling can be incorporated for quantitative analyses
(3) Tandem mass spectrometry (MS/MS) combined with database searching is used to determine both acylation types and their corresponding sites
Links Between Acylation and Metabolic Reprogramming in Disease
1. Cancer and Acylation: PTM Regulation Underlying the Warburg Effect
Tumor cells frequently exhibit dysregulated acylation. For example, elevated acetylation can suppress mitochondrial metabolism while promoting glycolysis, in line with the Warburg effect.
2. Potential Roles in Metabolic Disorders
(1) Type 2 diabetes: increased acetylation of enzymes involved in fatty acid oxidation may contribute to mitochondrial dysfunction;
(2) Non-alcoholic fatty liver disease (NAFLD): elevated succinylation may disrupt hepatic lipid metabolism.
Acylation is not only a chemical signature of metabolite availability, but also a key regulatory node linking protein function to metabolic pathway control. By integrating high-resolution mass spectrometry with multi-omics platforms, researchers are progressively uncovering the diverse roles of acylation in metabolic homeostasis, disease pathogenesis, and therapeutic intervention. If you are studying protein acylation, regulation of metabolic pathways, or disease-associated mechanisms, collaboration with MtoZ Biolabs is welcome. We provide end-to-end services covering modified-protein enrichment, mass spectrometry analysis, and integrative data analysis to support further scientific discovery.
MtoZ Biolabs, an integrated chromatography and mass spectrometry (MS) services provider.
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