ADA

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Biochemistry

ADA is a widely expressed metabolic enzyme with the highest levels observed in lymphatic tissues, especially the thymus and gastrointestinal tract. Together with purine nucleoside phosphorylase, it forms an important part of the purine salvage pathway and is responsible for deaminating adenosine and 2'deoxyadenosine to produce inosine and 2'deoxyinosine. The lack or destruction of this enzyme will cause these substrates to accumulate inside and outside the cell. Adenosine mainly comes from the decomposition of RNA and adenosine triphosphate (ATP), and 2'deoxyadenosine comes from the breakdown of DNA. Increased uptake of 2'deoxyadenosine in the cell, and then phosphorylation by deoxycytidine kinase, will lead to the accumulation of deoxyadenosine triphosphate (dATP), thereby inhibiting ribonucleotide reductase, thereby preventing normal DNA synthesis and repair. Adenosine is an important extracellular signaling molecule, and the destruction of these signaling pathways will interfere with the normal immune response. Adenosine receptors belong to the family of G protein-coupled receptors, including four subtypes (A₁, A_2A, A_2B, and A₃). They play an important role in regulating cell physiology in various tissues such as the brain and cardiovascular system.

Figure 1. The adenosine deaminase (ADA) metabolism (Sauer, A.V.; et al. 2012)

Toxic Effect Caused by Adenosine

Under normal physiological conditions, adenosine plays a role in fine-tuning the immune response. However, when the concentration of adenosine increases (as in ADA deficiency), this balance will be disrupted. For example, the activation of A_2A adenosine receptor by adenosine mediates immunosuppressive effects: cAMP produced downstream of receptor activation acts through a negative feedback loop to inhibit and trigger the "closed" signaling pathway in activated immune cells. Studies have shown that the increase in cAMP generated by the activation of A_2A receptors interferes with the signal transduction events that occur after TCR activation, and therefore may also inhibit downstream effector functions. In CD4+ and CD8+ T cells, both in vivo and in vitro have shown the ability of exogenous adenosine to reduce TCR-triggered activation

Figure 2. ADA deficiency leads to an accumulation of adenosine (A) and deoxyadenosine (B) - different mechanisms are proposed for the increased concentration of each metabolic substrate (Whitmore, K.V.; Gaspar, H.B. 2016)

Diagnosis

The diagnosis of ADA deficiency is established through biochemical and molecular genetic tests. Biochemical tests have shown that ADA activity is missing or greatly reduced, and the metabolite dATP or total dAdo nucleotides (the sum of dAMP, dADP and dATP) are significantly increased in erythrocytes, which is also manifested in the reduction of SAH hydrolase activity in erythrocytes. If a patient suspected of having an ADA deficiency has recently undergone a blood transfusion, an analysis of ADA activity can be measured in the parents, or the analysis can be performed on non-erythroid cells (such as leukocytes). Fibroblasts can also be used for analysis, but fibroblast cultures are usually not readily available, so diagnosis may be delayed. The ADA gene is located on chromosome 20q12-q13.11, and more than 70 pathogenic mutations have been identified on it.

Conclusion

The widespread expression of ADA means that the weakening or loss of its function can lead to complex metabolic disorders involving multiple organs. However, the mechanism by which this occurs is still unknown. After elucidating the mechanism within the immune system, deoxyadenosine may act in a similar toxic manner in other organ systems and may cause serious disease for non-immunological manifestations. In addition, the influence of downstream signaling pathways after activation of adenosine and its receptors should also be considered. The use of matched sibling donors or matched family donors for early definitive treatment of hematopoietic stem cell transplantation can produce good overall efficacy. For patients who do not have a suitable donor, gene therapy is now a recognized treatment option. Regardless of the treatment given, the patient's long-term status is relatively unknown and requires further monitoring.