Question

There are two distinct immunodeficiency diseases that lead to the formation of uric acid as the end product. Mutation in genes for adenosine deaminase (ADA) leads to severe combined immunodeficiency (SCID) in which both T-cells and B-cells are affected. Defects in purine nucleoside phosphorylase (PNP) affect only T-cells. These two enzymes are in the pathways for degradation of nucleic acids. Gene therapy has had some success in treating ADA deficiency. The best estimate of the turnover of DNA comes from a measurement in urine of A. uric acid. B. \(\mathrm{NH}_{4}^{+}\) and \(\mathrm{CO}_{2}\) C. \(\beta\) -alanine. D. \(\beta\) -aminoisobutyrate. E. cytidine.

Short answer

Answer: A. Uric acid.

Step-by-step solution

Assess each choice

Let's go through each choice and understand its relation to the turnover of DNA. A. Uric acid: Uric acid is the final product of purine catabolism, which includes the breakdown of DNA. This option might be a good estimate for the turnover of DNA. B. \(\mathrm{NH}_{4}^{+}\) and \(\mathrm{CO}_{2}\): Ammonium (\(\mathrm{NH}_{4}^{+}\)) and carbon dioxide (\(\mathrm{CO}_{2}\)) are common byproducts of various metabolic processes, not specifically related to DNA turnover. Hence, this choice is not the best estimate for the turnover of DNA. C. \(\beta\)-alanine: \(\beta\)-Alanine is a non-essential amino acid and is not directly related to the turnover of DNA. Hence, this choice is not the best estimate for the turnover of DNA. D. \(\beta\) -aminoisobutyrate: \(\beta\) -aminoisobutyrate is a non-proteinogenic amino acid and is not directly related to the turnover of DNA. Hence, this choice is not the best estimate for the turnover of DNA. E. Cytidine: Cytidine is a nucleoside and a component of DNA. However, it would not provide a direct estimate of DNA turnover since it could come from RNA degradation, not just from DNA degradation. Therefore, this choice is not the best estimate for the turnover of DNA.

Choose the best estimate

Based on our analysis, the best estimate for the turnover of DNA comes from a measurement of: A. Uric acid. Uric acid is the final product of purine catabolism, which includes the breakdown of DNA, making it a better estimate for the turnover of DNA than the other options provided.

Key concepts

Adenosine Deaminase Deficiency

Adenosine deaminase (ADA) deficiency is a rare genetic disorder that has a significant impact on the immune system. It results in a form of severe combined immunodeficiency (SCID), where both T-cell and B-cell lymphocytes are compromised. ADA is a crucial enzyme in purine catabolism, responsible for converting adenosine to inosine, which is then further broken down into uric acid.

When ADA is deficient, toxic levels of adenosine and deoxyadenosine accumulate, particularly affecting lymphocytes. This hampers their growth and function, leading to the weakened immune response seen in SCID patients. The buildup of these substances can also disrupt other cellular processes, contributing to the broad spectrum of symptoms associated with ADA deficiency.

Purine Nucleoside Phosphorylase Deficiency

Another immunodeficiency disorder is purine nucleoside phosphorylase (PNP) deficiency. PNP plays an essential role in the breakdown of purines, specifically in the conversion of inosine to hypoxanthine and guanosine to guanine. Without this enzyme's activity, there is an accumulation of purine nucleosides and a decrease in uric acid production.

PNP deficiency primarily affects the T-cell arm of the immune system, which can lead to a selective T-cell immunodeficiency. Patients with PNP deficiency present with susceptibility to infections, autoimmune disorders, and neurological symptoms. While the deficiency impairs T-cell function, B-cell immunity appears to be less affected compared to ADA deficiency.

DNA Turnover Measurement

The best estimate of the turnover of DNA can be obtained by measuring byproducts of DNA catabolism in the urine. DNA turnover refers to the process by which DNA is synthesized and degraded as part of cell maintenance and division.

One of the end products of purine breakdown within DNA turnover is uric acid. By measuring uric acid levels in the urine, scientists can gauge the extent of DNA degradation in the body. This measurement offers an indirect but valuable indication of cell proliferation and DNA repair processes, which can be vital for understanding metabolic conditions and monitoring treatment efficacy in disorders such as cancers or immunodeficiencies.

Gene Therapy for ADA Deficiency

Gene therapy holds promise as a treatment for ADA deficiency. This therapeutic approach involves introducing a correct copy of the ADA gene into the patient's cells to restore the function of the ADA enzyme.

The most common method of gene therapy for ADA deficiency involves using retroviruses or lentiviruses as vectors to deliver the healthy gene into hematopoietic (blood) stem cells. These genetically modified stem cells are then returned to the patient's body, where they can differentiate and repopulate the immune system with cells capable of producing ADA. This groundbreaking treatment has been successful in several patients, offering hope for a long-term cure for this debilitating immunodeficiency.

Purine Catabolism

Purine catabolism is the metabolic process through which purine bases derived from nucleic acids are broken down. It begins with the breakdown of nucleotides into nucleosides and then to the respective purine bases, adenine and guanine.

Key enzymes, such as ADA and PNP, help in converting these purine bases into intermediate compounds like inosine, hypoxanthine, and xanthine, which are ultimately metabolized into uric acid. This final waste product is excreted from the body through urine. Defects in the enzymes involved in purine catabolism lead to the accumulation of intermediates, which can be toxic to cells and cause disorders like ADA and PNP deficiencies.