Proteins undergo various modifications after their creation, known as post-translational modification (PTM). These modifications add chemical tags to proteins, altering their structure and function. Among PTMs, acetylation is a widespread and fundamental mechanism, playing a role in numerous cellular processes.
The Basics of Acetylation
Acetylation involves the addition of a small chemical tag called an acetyl group (CH₃CO) to a protein. This modification primarily occurs on lysine residues, specific amino acids. The acetyl group is transferred from acetyl coenzyme A (acetyl-CoA).
Adding an acetyl group to a lysine residue neutralizes its positive charge, which can alter the protein’s shape, stability, and interactions with other molecules. These changes can act like a molecular switch, turning protein functions on or off, or influencing a protein’s cellular location. The dynamic and reversible nature of this modification allows cells to rapidly respond to internal and external signals.
Key Players: Enzymes and Substrates
The addition and removal of acetyl groups are controlled by specific enzyme families. Histone acetyltransferases (HATs) catalyze the addition of acetyl groups to proteins and are often called “writers.” Conversely, histone deacetylases (HDACs) remove these acetyl groups and are called “erasers.”
While historically named for their activity on histones, HATs and HDACs modify many non-histone proteins. Histones are proteins that help package DNA into a compact structure called chromatin within the cell nucleus. Acetylation of histones influences how tightly DNA is wound, affecting gene accessibility.
Beyond histones, many other proteins are acetylated, including transcription factors regulating gene activity, metabolic enzymes controlling cellular energy, and structural proteins maintaining cell shape. This broad range of substrates highlights acetylation’s extensive influence across different cellular functions.
Biological Roles and Significance
Acetylation’s impact on cell biology is diverse, influencing many fundamental processes. One well-understood role is regulating gene expression. Histone acetylation can loosen chromatin, making DNA more accessible for gene transcription, essentially turning genes “on.” Conversely, deacetylation by HDACs condenses chromatin, suppressing gene activity.
Acetylation also plays a significant role in metabolic regulation. Many enzymes involved in crucial metabolic pathways, such as glycolysis, gluconeogenesis, fatty acid oxidation, and the tricarboxylic acid (TCA) cycle, are subject to acetylation. This modification can fine-tune the activity and stability of these enzymes, allowing cells to adapt their energy production and utilization based on nutrient availability. In fact, up to 90% of enzymes in central metabolic pathways have been found to undergo acetylation.
Acetylation can influence protein stability and subcellular localization, determining a protein’s functional lifespan and cellular location. This modification also participates in signal transduction, as a component of cellular communication pathways, coordinating responses to stimuli like DNA damage or interferon signals.
Acetylation and Human Health
Dysregulation of acetylation, an imbalance of acetylation, is linked to various human diseases. For instance, altered activity of HATs or HDACs can contribute to the uncontrolled cell growth seen in cancer. In cancer, increased histone acetylation can promote tumor proliferation by affecting gene expression.
Acetylation is also implicated in neurodegenerative conditions like Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In these disorders, altered acetylation can contribute to the accumulation of misfolded proteins, such as tau and alpha-synuclein, and impair neuronal function. Imbalances in acetylation have been connected to metabolic disorders, including diabetes, where abnormal acetylation can lead to glucose abnormalities.
The understanding of acetylation pathways has opened new avenues for therapeutic development. Histone deacetylase inhibitors (HDAC inhibitors) are a class of drugs that block HDAC activity, leading to increased acetylation of proteins. These inhibitors are being investigated and used in the treatment of cancers, such as cutaneous T-cell lymphoma, and explored for potential in neurodegenerative and inflammatory diseases.