Purine metabolism

Enzyme

Oxidative stress

Hypoxanthine

Reactive oxygen species

Biology

Xanthine dehydrogenase

Purine

Xanthine oxidase

Oxidative phosphorylation

Cell biology

Biochemistry

动物学研究

Many mammals risk damage from oxidative stress stemming from frequent dives (i.e., cycles of ischemia/reperfusion and hypoxia/reoxygenation), high altitude and subterranean environments, or powered flight. Purine metabolism is an essential response to oxidative stress, and an imbalance between purine salvage and de novo biosynthesis pathways can generate damaging reactive oxygen species (ROS). Here, we examined the evolution of 117 purine metabolism-related genes to explore the accompanying molecular mechanisms of enhanced purine metabolism in mammals under high oxidative stress. We found that positively selected genes, convergent changes, and nonparallel amino acid substitutions are possibly associated with adaptation to oxidative stress in mammals. In particular, the evolution of convergent genes with cAMP and cGMP regulation roles may protect mammals from oxidative damage. Additionally, 32 genes were identified as under positive selection in cetaceans, including key purine salvage enzymes (i.e., HPRT1), suggesting improved re-utilization of non-recyclable purines avoid hypoxanthine accumulation and reduce oxidative stress. Most intriguingly, we found that six unique substitutions in cetacean xanthine dehydrogenase (XDH), an enzyme that regulates the generation of the ROS precursor xanthine oxidase (XO) during ischemic/hypoxic conditions, show enhanced enzyme activity and thermal stability and diminished XO conversion activity. These functional adaptations are likely beneficial for cetaceans by reducing radical oxygen species production during diving. In summary, our findings offer insights into the molecular and functional evolution of purine metabolism genes in mammalian oxidative stress adaptations.许多哺乳动物生存在极端生境下，如低氧的高原和穴居动物、经历潜水缺血/再灌注的海兽、飞行和冬眠的蝙蝠等，它们普遍面临氧化应激的胁迫。嘌呤代谢在氧化应激的发生发展中具有重要作用，嘌呤从头合成和嘌呤补给途径的失衡会导致活性氧（ROS）的产生，从而引发氧化损伤。然而，嘌呤代谢在哺乳动物氧化应激适应中的作用机制尚不清楚。该研究通过对117个嘌呤代谢相关基因的比较基因组学分析发现，氧化应激耐受物种具有共享的正选择基因、趋同氨基酸改变及非平行氨基酸替换等，提示哺乳动物对高氧化应激的环境适应发生了趋同进化。特别地，参与环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）调控的基因在氧化应激耐受物种中检测到趋同进化信号，可能与提高机体cAMP 和cGMP水平从而降低氧化损伤有关。此外，鲸类检测到32个正选择基因，其中包括嘌呤补给通路关键酶 HPRT1，提示鲸类通过提高非循环嘌呤代谢物的再利用，避免次黄嘌呤累积并减少氧化应激。值得注意的是，研究发现嘌呤降解途径关键限速酶—黄嘌呤脱氢酶（XDH）具有鲸类特异位点，且功能实验进一步发现，携带鲸类特异位点的XDH具有较强的酶活性、更高的热稳定性以及较低的黄嘌呤氧化酶（XO）转化率。XO是ROS的主要来源，这些功能改变进一步支持鲸类可能通过减少潜水过程中的ROS的产生从而避免氧化损伤。该研究结果为哺乳动物氧化应激适应中嘌呤代谢基因的分子进化和功能适应提供了新的见解。.

Evolutionary impacts of purine metabolism genes on mammalian oxidative stress adaptation