Question

Many cases of severe combined immunodeficiency disease (SCID) are caused by the lack of the enzyme adenosine deaminase (ADA).

a. What pathway normally contains the enzyme ADA?

b. How does the absence of ADA contribute to the non-functional immune system observed in SCID patients?

Answer 1

a) Enzyme ADA (adenosine deaminase) is normally found in the purine salvage pathway (purinergic signaling pathway), which catalyzes the irreversible deamination of adenosine and 2'-deoxy adenosine into inosine and 2'-deoxy inosine repectively.

1) Deamination of adenosine- Most adenosine derives from endogenous breakdown of ATP and degradation of RNA. This adenosine is deaminated into inosine by the enzyme ADA, which is further converted into hypoxanthine. This xypoxanthine either enters uric acid pathway or salvaged back into other mononucleosides.

ATP <----------> ADP <----------> AMP <----------> adenosine --------(ADA)--------> inosine ----------> hypoxanthine

2) Deamination of 2'-deoxy adenosine- The 2'-deoxy adenosine derived from DNA degradation is deaminated into 2'-deoxy inosine by the enzyme ADA. This 2'-deoxy inosine is converted to hypoxanthine as in the above reaction and it either enters uric acid pathway or salvaged back into other mononucleosides.

dATP -----> dADP -----> dAMP -----> 2'-deoxy adenosine -----(ADA)-----> 2'-deoxyinosine -------> hypoxanthine

b) Deficient or impaired ADA activity results in the increased accumulation of ADA substrates such as adenosine and 2'-deoxy adenosine in the extra-cellular body fluids and may spill over to other pathways. Adenosine deaminase (ADA) deficiency, is caused by the mutations in the ADA gene, mainly affects the immune system by causing lymphopenia and damaged cellular and humoral immunity.

1) Impaired thymocyte development and function- Under normal condition, there is a large amount of ADA is present in the thymus. So an ADA deficiency leads to a reduction in the size of the thymus, decreased level of dendritic cells, increased apoptosis etc

2) Abnormal T-cell function- T cell depletion and defective TCR activation

3) Abnormal B cell development and function- Impaired B-cell development in bone marrow as well as peripheral lymphoid organs. B lymphocytes in ADA deficient conditions shows reduced proliferative activity with accumulation IgM antibodies and low levels of IgG.

4) Causes autoimmunity- Autoimmunity is a condition where the immune system attacks its own cells.