Plasma Hypoxanthine-Guanine Phosphoribosyl Transferase Activity in Bottlenose Dolphins Contributes to Avoiding Accumulation of Non-recyclable Purines

López-Cruz, Roberto I.; Crocker, Daniel E.; Gaxiola-Robles, Ramón; Bernal, Jaime A.; Real-Valle, Roberto A.; Lugo-Lugo, Orlando; Zenteno‐Savín, Tania

doi:10.3389/fphys.2016.00213

Cited by 13 publications

(11 citation statements)

References 38 publications

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“…Intriguingly, we observed that the levels of some nucleotides and organic acids were significantly increased (e.g., hypoxanthine), whereas the levels of some nucleotides and organic acids were significantly reduced [e.g., guanosine monophosphate (GMP)]. Hypoxanthine-guanine phosphoribosyl transferase (HPRT) is an important enzyme involved in nucleotide recycle pathway and can covert hypoxanthine and guanine to inosine 5’-monophosphate (IMP) and GMP, respectively (12, 13). The observed abnormal levels of hypoxanthine and GMP suggested that the function of HPRT had become defective in these COVID-19 fatal patients, which could result in the disorders of purine and pyrimidine metabolism.…”

Section: Resultsmentioning

confidence: 99%

Plasma Metabolomic and Lipidomic Alterations Associated with COVID-19

Shu

Yang

et al. 2020

Preprint

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The pandemic of the coronavirus disease 2019 has become a global public health crisis. The symptoms of COVID-19 range from mild to severe conditions. However, the physiological changes associated with COVID-19 are barely understood.In this study, we performed targeted metabolomic and lipidomic analyses of plasma from a cohort of COVID-19 patients who had experienced different symptoms. We found the metabolite and lipid alterations exhibit apparent correlation with the course of disease in these COVID-19 patients, indicating that the development of COVID-19 affected whole-body metabolism of the patients. In particular, malic acid of the TCA cycle and carbamoyl phosphate of urea cycle reveal the altered energy metabolism and hepatic dysfunction, respectively. It should be noted that carbamoyl phosphate is profoundly down-regulated in fatal patients compared with mild patients. And more importantly, guanosine monophosphate (GMP), which is mediated by not only GMP synthase but also CD39 and CD73, is significant changed between healthy subjects and

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Section: Resultsmentioning

confidence: 99%

Plasma Metabolomic and Lipidomic Alterations Associated with COVID-19

Shu

Yang

et al. 2020

Preprint

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“…This ATP is quickly catabolized to adenosine then to hypoxanthine creating a milieu similar to that described above for moderate hypoxia [30]. Elevated levels of hypoxanthine may consequently trigger upregulation of XOR activity in addition to activating purine salvage via hypoxanthine-guanine phosphoribosyltransferase (HPGRT) [33]. Interestingly, we have previously described upregulation of XOR via adenosine activation of adenosine A 2B receptors on endothelial cells [24].…”

Section: Xor Regulationmentioning

confidence: 87%

The impact of xanthine oxidase (XO) on hemolytic diseases

2019

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Hemolytic diseases are associated with elevated levels of circulating free heme that can mediate endothelial dysfunction directly via redox reactions with biomolecules or indirectly by upregulating enzymatic sources of reactive species. A key enzymatic source of these reactive species is the purine catabolizing enzyme, xanthine oxidase (XO) as the oxidation of hypoxanthine to xanthine and subsequent oxidation of xanthine to uric acid generates superoxide (O2•-) and hydrogen peroxide (H2O2). While XO has been studied for over 120 years, much remains unknown regarding specific mechanistic roles for this enzyme in pathologic processes. This gap in knowledge stems from several interrelated issues including: 1) lethality of global XO deletion and the absence of tissue-specific XO knockout models have coalesced to relegate proof-of-principle experimentation to pharmacology; 2) XO is mobile and thus when upregulated locally can be secreted into the circulation and impact distal vascular beds by high-affinity association to the glycocalyx on the endothelium; and 3) endothelial-bound XO is significantly resistant (> 50%) to inhibition by allopurinol, the principle compound used for XO inhibition in the clinic as well as the laboratory. While it is known that circulating XO is elevated in hemolytic diseases including sickle cell, malaria and sepsis, little is understood regarding its role in these pathologies. As such, the aim of this review is to define our current understanding regarding the effect of hemolysis (free heme) on circulating XO levels as well as the subsequent impact of XO-derived oxidants in hemolytic disease processes.

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“… 76 The apparent disconnect between the present findings and the literature is reconciled by the observation that hypoxanthine levels in mitochondria-free RBC are not necessarily related to plasma levels of this metabolite (especially in the platelet and white blood cell-filtered environment of a packed RBC unit); for example, this is observed in underwater mammals, such as dolphins, which are constantly exposed to prolonged periods of hypoxia. 77 Thus, hypoxanthine levels in isolated RBC (as in stored RBC units), or in circulating RBC after exposure to high altitude, may not directly correlate with plasma hypoxanthine levels.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage

Sun²,

et al. 2017

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Hypoxanthine catabolism in vivo is potentially dangerous as it fuels production of urate and, most importantly, hydrogen peroxide. However, it is unclear whether accumulation of intracellular and supernatant hypoxanthine in stored red blood cell units is clinically relevant for transfused recipients. Leukoreduced red blood cells from glucose-6-phosphate dehydrogenase-normal or -deficient human volunteers were stored in AS-3 under normoxic, hyperoxic, or hypoxic conditions (with oxygen saturation ranging from <3% to >95%). Red blood cells from healthy human volunteers were also collected at sea level or after 1–7 days at high altitude (>5000 m). Finally, C57BL/6J mouse red blood cells were incubated in vitro with 13C1-aspartate or 13C5-adenosine under normoxic or hypoxic conditions, with or without deoxycoformycin, a purine deaminase inhibitor. Metabolomics analyses were performed on human and mouse red blood cells stored for up to 42 or 14 days, respectively, and correlated with 24 h post-transfusion red blood cell recovery. Hypoxanthine increased in stored red blood cell units as a function of oxygen levels. Stored red blood cells from human glucose-6-phosphate dehydrogenase-deficient donors had higher levels of deaminated purines. Hypoxia in vitro and in vivo decreased purine oxidation and enhanced purine salvage reactions in human and mouse red blood cells, which was partly explained by decreased adenosine monophosphate deaminase activity. In addition, hypoxanthine levels negatively correlated with post-transfusion red blood cell recovery in mice and – preliminarily albeit significantly - in humans. In conclusion, hypoxanthine is an in vitro metabolic marker of the red blood cell storage lesion that negatively correlates with post-transfusion recovery in vivo. Storage-dependent hypoxanthine accumulation is ameliorated by hypoxia-induced decreases in purine deamination reaction rates.

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Plasma Hypoxanthine-Guanine Phosphoribosyl Transferase Activity in Bottlenose Dolphins Contributes to Avoiding Accumulation of Non-recyclable Purines

Cited by 13 publications

References 38 publications

Plasma Metabolomic and Lipidomic Alterations Associated with COVID-19

Plasma Metabolomic and Lipidomic Alterations Associated with COVID-19

The impact of xanthine oxidase (XO) on hemolytic diseases

Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage

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