Purines, the fundamental building blocks of nucleic acids, are indispensable for various cellular processes, including DNA replication, RNA synthesis, and energy metabolism. Additionally, purines and their derivatives play critical roles in cellular signaling as neurotransmitters, neuromodulators, and immune modulators. The intricate regulation of purine metabolism and purinergic signaling pathways is essential for maintaining cellular homeostasis and orchestrating physiological responses. However, dysregulation of these pathways can lead to a wide range of diseases, from hyperuricemia and gout to neurological disorders, chronic pain, inflammatory diseases, and cancer.
Fig. 1 The causative role of purinergic signalling in human diseases (Huang Z., et al. 2021).
Related Products
Purinosome as the Fundamental Unit to Regulate Purine Metabolism
The purinosome, a dynamic multi-enzyme complex, serves as the fundamental unit for regulating purine metabolism. Purine metabolism is vital for numerous cellular processes, including energy production and nucleic acid synthesis. ATP is metabolized to ADP and further to AMP, fulfilling energy demands and aiding in nucleotide assembly. Additionally, cyclic AMP (cAMP) acts as a ubiquitous second messenger, controlling various cellular responses. Adenosine, a product of AMP dephosphorylation, is transported across cell membranes via nucleoside transporters, contributing to purine homeostasis. Two major pathways, salvage and de novo synthesis, maintain cellular purine pools. The salvage pathway recycles degraded bases to generate purine nucleotides, while de novo synthesis consumes phosphoribosyl pyrophosphate (PRPP) to produce inosine monophosphate (IMP). The purinosome, a metabolon comprising six enzymes involved in de novo synthesis, facilitates efficient substrate utilization and metabolic flux. Purinosome assembly is dynamically regulated in response to cellular purine levels, involving phosphorylation cascades mediated by kinases like mTOR and CK2. Microtubule-mediated transport and GPCR signaling also play roles in purinosome regulation, highlighting the intricate molecular mechanisms governing purine metabolism.
Aberrant Purine Metabolism Causes Hyperuricemia and Gout
Gout, a classic purine-related ailment, is increasingly prevalent due to lifestyle changes. Hyperuricemia, a major risk factor for gout, results from disrupted purine metabolism, leading to the deposition of urate crystals in joints. Contributing factors include purine-rich diets, alcohol consumption, and impaired uric acid excretion. Genetic variations in urate transporters further influence susceptibility to gout. Mechanistically, urate crystals trigger inflammation and intense pain, with immune cell recruitment and cytokine release exacerbating symptoms. Long-term urate-lowering therapy, primarily through xanthine oxidase inhibitors like allopurinol and febuxostat, is essential for gout management. However, careful consideration of individual factors and potential side effects is crucial for effective treatment.
Purinergic Neurotransmission in Neurodevelopment and the Pathogenesis of Brain Diseases
Purinergic neurotransmission plays a crucial role in neurodevelopment and contributes to the pathogenesis of various brain diseases. ATP, a recognized neurotransmitter, is stored in synaptic vesicles by the vesicular nucleotide transporter VNUT/SLC17A9, with its release regulated by calcium influx. ATP can also be released through non-vesicular mechanisms involving channels like P2X7 receptors and connexins. Upon release, ATP activates P2 receptors autocrinally/paracrinally, influencing both pre- and postsynaptic functions. Additionally, ATP breakdown yields adenosine, which further modulates neurotransmission through P1 receptors. Purinergic signaling influences neural proliferation, differentiation, and migration during embryonic neurodevelopment and neuroregeneration in adults. Dysregulated purinergic transmission is implicated in neurodegenerative disorders such as Alzheimer's disease, where A1 and A2A receptors exhibit context-dependent roles, and P2X7 receptor inhibition shows neuroprotective effects. In neuropsychiatric diseases like depression, purinergic receptors play a role in modulating behaviors, with A2A receptor activation associated with depressive symptoms and P2X7 receptor involvement in stress-induced depression. Genetic variations in purinergic receptor genes are linked to neuropsychiatric pathology, while enzymes and metabolites involved in purine metabolism serve as potential biomarkers for depression. Understanding purinergic neurotransmission offers insights into both normal brain function and the development of therapeutic interventions for brain diseases.
Purinergic Transmission in Mechanosensory Transduction and Pain
Purinergic signaling plays a critical role in mechanosensory transduction, the process by which mechanical stimuli are converted into electrical signals by sensory neurons. ATP released from mechanosensitive cells acts on purinergic receptors, initiating neuronal signaling cascades that culminate in the perception of touch, pain, and proprioception. Dysregulated purinergic transmission has been implicated in chronic pain conditions, such as neuropathic pain, fibromyalgia, and migraine. Elucidating the role of purinergic signaling in pain processing offers new avenues for the development of analgesic therapies with enhanced efficacy and fewer side effects.
Purinergic Transmission Integrates Immune System and Modulates Inflammatory Responses
Purinergic transmission, involving purines like ATP and adenosine, plays a crucial role in immune system regulation and inflammation control. Immune cells express purinergic receptors and ectoenzymes like CD39 and CD73, which modulate immune responses by regulating ATP to adenosine conversion. Extracellular ATP, released from cells under various conditions, activates P2 receptors to initiate immune responses, while adenosine attenuates inflammation through P1 receptors. The P2X7 receptor, a key player in purinergic signaling, influences cytokine release and immune cell activation, thus shaping immune and inflammatory responses. Additionally, other purines like oxidized NAD+ can synergistically activate P2X7 receptors with ATP, further modulating immune and inflammatory processes. Understanding purinergic signaling mechanisms provides insights into therapeutic strategies for immune-related diseases.
Purinergic Signaling Regulates Tumor Development and Progression
Purinergic signaling profoundly influences tumor development and progression by shaping the inflammatory and immunosuppressive microenvironment characteristic of cancer. ATP and adenosine, key purines with opposing roles in inflammation, are abundant in tumor sites. While ATP activates antitumor immunity, adenosine promotes tumor growth by suppressing immune responses. Various P2 and P1 receptors expressed in both immune and cancer cells mediate these effects. ATP's impact on tumor growth depends on its concentration; high levels activate antitumor immunity, while lower levels promote cancer cell proliferation. Adenosine, derived from ATP breakdown by ectoenzymes like CD39 and CD73, modulates cancer cell behavior and immune responses. Purinergic receptors influence downstream signaling pathways like adenylate cyclase and PLC, affecting cell proliferation, migration, and immune evasion. Alterations in cAMP and other secondary messengers are implicated in various cancers. Genetic variations in purinergic receptor loci can affect tumor prognosis and response to chemotherapy. Understanding purinergic signaling offers potential avenues for cancer immunotherapy and targeted therapy.
Conclusion
Purine metabolism and purinergic signaling pathways are intricately linked to various physiological processes and pathological conditions, ranging from hyperuricemia and gout to neurodegenerative diseases, chronic pain, inflammation, and cancer. Elucidating the molecular mechanisms underlying purine metabolism and purinergic signaling provides valuable insights into disease pathogenesis and identifies novel therapeutic targets for intervention. By targeting purine-related pathways, researchers and clinicians aim to develop more effective treatments for a wide range of human diseases, ultimately improving patient outcomes and quality of life.
Reference
- Huang Z., et al. From purines to purinergic signalling: molecular functions and human diseases. Signal Transduction and Targeted Therapy. 2021, 6(1): 162.
.
