A child with recurrent bacterial and viral infections is found to have absent lymphocytes and absent adenosine deaminase (ADA) activity. Deoxyadenosine accumulates intracellularly in lymphocytes, and dATP pools become massively elevated. The primary mechanism by which elevated dATP causes lymphocyte death is:
- A dATP allosterically inhibits ribonucleotide reductase, blocking DNA synthesis ✓
- B dATP directly activates caspase-9 via Apaf-1 in the apoptosome
- C dATP inhibits adenylate kinase disrupting ATP generation
- D Deoxyadenosine methylates DNA causing epigenetic silencing of immune genes
Explanation
In ADA-SCID (severe combined immunodeficiency), deoxyadenosine accumulates and is phosphorylated to dATP in lymphocytes (which have high deoxynucleoside kinase activity). Markedly elevated dATP allosterically inhibits ribonucleotide reductase (RNR) at the activity site and overall substrate specificity site, blocking the reduction of all NDPs to dNDPs. This halts DNA synthesis, causing lymphocyte apoptosis and lymphopenia. Additionally, S-adenosylhomocysteine (SAH) hydrolase is also inhibited by deoxyadenosine, interfering with methylation reactions. ADA gene therapy was among the first successful human gene therapy.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.