Deacetylases are enzymes that remove acetyl groups from various molecules, particularly proteins, within cells. This process alters the function or behavior of these molecules, regulating cellular processes by controlling the presence or absence of acetyl groups.
The Genetic “On-Off Switch”
Cells manage their vast genetic information, DNA, by packaging it tightly around spool-like proteins called histones, forming a complex known as chromatin. The way DNA is wrapped around these histones can be loose or tight, influencing whether genes are accessible and active. This dynamic regulation of gene activity without changing the underlying DNA sequence is known as epigenetics.
Deacetylases play a direct role in this epigenetic control by working on the histone proteins. They remove acetyl groups from specific points on these histones, which increases the positive charge on the histone tails. This change strengthens the attraction between the histones and the negatively charged DNA, causing the chromatin to condense and become more tightly packed. This tightened structure makes it physically harder for the cellular machinery responsible for gene transcription to access the DNA, effectively turning the genes in that region “off” or silencing them.
To maintain a balance, other enzymes called histone acetyltransferases (HATs) perform the opposite function. HATs add acetyl groups to histones, which neutralizes the positive charge and weakens the DNA-histone interaction. This leads to a more relaxed, open chromatin structure, making genes accessible and effectively turning them “on.” The interplay between deacetylases and HATs acts like a dimmer switch, finely tuning gene expression by controlling the accessibility of DNA, rather than permanently altering the genetic code itself.
Major Deacetylase Families
Deacetylases are a diverse group of enzymes, with the most prominent families being Histone Deacetylases (HDACs) and Sirtuins (SIRTs). Human HDACs are categorized into four classes: Class I (HDACs 1, 2, 3, and 8), Class II (subdivided into IIa with HDACs 4, 5, 7, and 9, and IIb with HDACs 6 and 10), and Class IV (HDAC11). These HDACs are involved in regulating gene expression by removing acetyl groups from histones and various other non-histone proteins.
Sirtuins, also known as Class III HDACs, form a distinct family of seven enzymes (SIRT1-7). Unlike other HDACs, sirtuins require the coenzyme nicotinamide adenine dinucleotide (NAD+) for their deacetylase activity. This reliance on NAD+ links sirtuin activity directly to the cell’s metabolic state. Sirtuins play roles in metabolic processes, responses to cellular stress, and aspects of aging, deacetylating both histone and non-histone proteins to influence these pathways.
The Role in Human Disease
When the balanced activity of deacetylases is disrupted, it can contribute to the development and progression of various human diseases. In cancer, an imbalance in deacetylase activity can lead to uncontrolled cell growth. Overactive deacetylases, particularly certain HDACs, can mistakenly remove acetyl groups from histones in regions containing tumor suppressor genes. This deacetylation causes the chromatin around these genes to tighten, effectively silencing their expression. Since tumor suppressor genes are responsible for halting abnormal cell division and promoting cell death in cancerous cells, their inactivation allows malignant cells to proliferate unchecked.
Deacetylase imbalance also plays a role in neurodegenerative disorders, such as Alzheimer’s and Huntington’s diseases. In these conditions, abnormal deacetylase activity can disrupt the proper production and function of proteins essential for neuronal health. For instance, certain HDACs can contribute to the accumulation of misfolded proteins or impair the transport of necessary components within neurons, leading to cellular dysfunction and eventual neuronal death. The precise mechanisms vary by disease, but the common thread is the disruption of gene expression and protein function, which are both influenced by deacetylase activity.
Deacetylase Inhibitors in Medicine
Deacetylase inhibitors, particularly histone deacetylase (HDAC) inhibitors, have been developed as therapeutic drugs. These small molecules block the enzymatic activity of deacetylases, preventing the removal of acetyl groups from histones and other proteins. This action promotes histone hyperacetylation, leading to a more open chromatin structure.
The loosened chromatin allows access for transcription machinery, effectively turning “on” genes that were previously silenced, including tumor suppressor genes. This re-expression of tumor suppressor genes can help to induce cell cycle arrest, promote programmed cell death (apoptosis), and inhibit the growth of cancer cells. HDAC inhibitors are primarily used in oncology, with several approved for the treatment of specific blood cancers, such as certain types of lymphomas and multiple myeloma. Vorinostat and romidepsin are examples of HDAC inhibitors approved for treating cutaneous T-cell lymphoma.