The ability to detect and respond to hypoxia within a developing tumor appears to be a common feature amongst most cancers. This hypoxic response has many molecular drivers, but none as widely studied as Hypoxia-Inducible Factor 1 (HIF-1). Recent evidence suggests that HIF-1 biology within lung adenocarcinoma (LUAD) may be associated with expression levels of adenylate kinases (AKs). Using LUAD patient transcriptome data, we sought to characterize AK gene signatures related to lung cancer hallmarks, such as hypoxia and metabolic reprogramming, to identify conserved biological themes across LUAD tumor progression. Transcriptomic analysis revealed perturbation of HIF-1 targets to correlate with altered expression of most AKs, with AK4 having the strongest correlation. Enrichment analysis of LUAD tumor AK4 gene signatures predicts signatures involved in pyrimidine, and by extension, nucleotide metabolism across all LUAD tumor stages. To further discriminate potential drivers of LUAD tumor progression within AK4 gene signatures, partial least squares discriminant analysis was used at LUAD stage-stage interfaces, identifying candidate genes that may promote LUAD tumor growth or regression. Collectively, these results characterize regulatory gene networks associated with the expression of all nine human AKs that may contribute to underlying metabolic perturbations within LUAD and reveal potential mechanistic insight into the complementary role of AK4 in LUAD tumor development.