Cytidine deaminase (CDA) is an enzyme found throughout the human body that modifies genetic material. It functions by changing cytidine, a building block of DNA and RNA, into uridine. This conversion is a fundamental process in cellular metabolism, highlighting CDA’s importance in various biological functions within cells.
Fundamental Biological Role
Cytidine deaminase catalyzes the irreversible hydrolytic deamination of cytidine and deoxycytidine. This process involves removing an amine group from these molecules, converting them into uridine and deoxyuridine, respectively, with the release of ammonia. This enzymatic activity is a key part of pyrimidine metabolism, the process by which cells synthesize and break down pyrimidine nucleotides (components of DNA and RNA).
The enzyme’s role in pyrimidine metabolism includes both the recycling of existing nucleosides and their degradation. By interconverting cytidine and uridine, CDA helps maintain the balance of nucleotide pools within cells, which is necessary for the proper synthesis and repair of DNA and RNA. Different forms of cytidine deaminases exist, but they all share this core function of deaminating cytidine or deoxycytidine.
Role in the Immune System
Activation-Induced Cytidine Deaminase (AID) is a specialized cytidine deaminase important in the adaptive immune system. AID is primarily expressed in activated B lymphocytes, where it diversifies antibodies. It achieves this by deaminating cytosine bases in single-stranded DNA, converting them into uracil.
This change from cytosine to uracil creates a mismatch in the DNA, which the cell’s repair machinery then processes, leading to specific genetic modifications. One such process is somatic hypermutation (SHM), where AID introduces point mutations into the immunoglobulin gene’s variable regions, enhancing antibody diversity and affinity for antigens. Another process is class switch recombination (CSR), where AID induces DNA breaks in the immunoglobulin heavy chain constant regions, allowing B cells to produce different types of antibodies like IgG, IgA, or IgE, while retaining their antigen specificity. These processes are important for generating a robust and specific antibody response against various pathogens.
Connection to Human Diseases
Abnormal cytidine deaminase activity, including AID, can impact human health. A deficiency in Activation-Induced Cytidine Deaminase (AID) can lead to specific immune disorders, such as Hyper-IgM syndrome type 2 (HIGM2). Individuals with HIGM2 experience a complete lack of immunoglobulin class switch recombination and somatic hypermutation, resulting in impaired antibody diversification and recurrent infections.
Dysregulation of AID has also been linked to certain cancers. AID’s ability to induce mutations in DNA can extend beyond its normal targets in the immune system, leading to “off-target” mutations in other genes. This can contribute to genomic instability, promoting the development and progression of various malignancies, particularly B-cell lymphomas and leukemias. Overexpression of AID can drive chromosomal translocations and mutations in tumor-associated genes, which are often observed in approximately 50% of cancer patients.
Cytidine Deaminase in Medicine
Understanding cytidine deaminase’s function has informed medical applications, especially in drug development and therapy. CDA can metabolize certain nucleoside analog drugs, synthetic versions of DNA building blocks used in chemotherapy. For example, CDA rapidly inactivates gemcitabine and decitabine, common anticancer drugs, by converting them into inactive forms.
This inactivation can reduce the effectiveness of these therapies, particularly in cancers like pancreatic ductal adenocarcinoma, where CDA expression is often high. To counteract this, researchers are exploring CDA inhibitors, such as tetrahydrouridine (THU), in combination with these chemotherapy drugs. Inhibiting CDA can prevent the rapid breakdown of chemotherapy agents, allowing them to remain active longer and potentially improve their efficacy against tumors.