ADSS2 (adenylosuccinate synthase 2) catalyzes the first committed step in AMP biosynthesis from IMP, playing a central role in de novo purine nucleotide metabolism 1. The enzyme functions in both cytoplasmic and mitochondrial compartments, binding GTP and metal ions to facilitate its ligase activity [GO annotations]. ADSS2 is transcriptionally regulated by epigenetic mechanisms; in SETD2-mutant renal cell carcinoma, LEDGF binds H3R17me2a to upregulate ADSS2 expression, promoting tumor cell proliferation through enhanced purine synthesis 1. Clinical relevance extends to childhood asthma, where parent-of-origin effects at SNP rs3003214 near ADSS2 show significant association with maternal inheritance (ratio 1.68, p=1.13E-08), potentially explaining higher asthma prevalence in children of affected mothers 2. In tamoxifen-resistant invasive lobular carcinoma, ADSS2 upregulation accompanies increased nucleotide biosynthesis, supporting endocrine therapy resistance 34. Additionally, ADSS2 expression increases in female rats exposed to mineral oil saturates, reflecting gender-dependent immunometabolic responses 5. SNP-SNP interactions involving ADSS2 contribute to bladder cancer risk stratification in polygenic models 6. These findings establish ADSS2 as a metabolic node linking nucleotide biosynthesis to cancer progression and immune regulation.