Micronutrient Supplementation and Ergogenesis — Metabolic Intermediates
Luke Bucci in Nutrients as Ergogenic Aids for Sports and Exercise, 2020
Inosine is both a precursor and a breakdown product of adenosine.571 Increases of inosine in cells are thought to force additional synthesis of adenosine (and ultimately ATP) by providing precursors and inhibiting catabolism of adenine nucleotides. Inosine may also contribute to nucleotide pools for DNA, RNA, and protein synthesis. Also, inosine is thought to improve oxygen utilization because of its effects on erythrocyte metabolism.572 Inosine is used in vitro to maintain viability of stored erythrocytes.573 In French clinical trials, parenteral inosine has shown benefit in therapy for cardiac insufficiency, angina, digitalis toxicity, extrasystoles, and senility in older patients.574,575 These results were attributed to inotropic hormone-like effects rather than enhancement of cellular ATP levels.576
Synergistic Combinations of Hyperthermia and Inhibitors of Nucleic Acids and Protein Synthesis
Leopold J. Anghileri, Jacques Robert in Hyperthermia In Cancer Treatment, 2019
Inosine and its analogues undergo phosphorolysis by the enzyme purine nucleoside Phosphorylase. The liberated bases may then be converted to the corresponding nucleotide by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Similarly, 2′-deoxyinosine and related analogues may react with purine nucleoside Phosphorylase, the product of which (a purine base or analogue) is then converted to the corresponding ribonucleoside 5′-monophosphate. 6-Mercaptopurine (6-MP, see Figure 4) is an excellent substrate for HGPRT, resulting in the formation of 6-thioinosine-5-phosphate (T-IMP) which accumulates within the cell. This may then lead to the inhibition of several vital metabolic processes, e.g., the conversion of inosinate (IMP) to adenylosuccinate (AMPS) and then to adenosine-5′-phosphate (AMP) as well as the oxidation of IMP to xanthylate (XMP) by inosinate dehydrogenase. In addition, T-IMP may result in “pseudo-feedback inhibition” of the first committed step in the de novo pathway of purine biosynthesis. In view of these various effects, it can be appreciated that the accumulation of T-IMP (and analogues of various purine nucleotides) can cause severe metabolic disruptions and may lead to cell death.
Inosine
Linda M. Castell, Samantha J. Stear (Nottingham), Louise M. Burke in Nutritional Supplements in Sport, Exercise and Health, 2015
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring (also known as a ribofuranose) via a β-N9-glycosidic bond. Inosine plays a role in a number of metabolic functions including increasing red blood cell concentrations of 2-3-diphosphoglycerate (2,3-DPG) which is involved in oxygen transport (Valeri, 1976). It may also potentiate the action of endogenously formed adenosine and inhibit its uptake and clearance. It has been proposed that inosine enhances exercise performance via the effects on 2,3-DPG, or by increasing ATP concentrations (Harmsen et al., 1984). An accumulation of inosine monophosphate, together with other factors, has been observed during prolonged exercise, suggesting a link with fatigue (Bowtell et al., 2007).
Inosine induces acute hyperuricaemia in rhesus monkey (Macaca mulatta) as a potential disease animal model
Published in Pharmaceutical Biology, 2021
Dong-hong Tang, Chen-yun Wang, Xi Huang, Hong-kun Yi, Zhe-li Li, Kai-li Ma, You-song Ye, Jian-wen Zhang
We demonstrated that inosine-treated rhesus monkeys exhibit symptoms of HUA. PNP and XO are key enzymes involved in the purine metabolism pathway. Our results showed that the PNP mRNA level was increased by inosine compared with saline. The protein level of PNP was not significantly increased in monkeys after treatment. Furthermore, we observed that the XO mRNA and protein levels in the liver were decreased by inosine compared with saline in monkeys after treatment. It is known that XO is the target of allopurinol and febuxostat in lowering the SUA level. In this study, inosine significantly downregulated the expression of XO mRNA and protein. The mechanism underlying these effects of inosine requires further analysis. A possible underlying mechanism is the initially increased SUA inhibits the expression of XO, the key enzyme involved in UA formation to avoid excessive accumulation of SUA, the final product of purine metabolism. Uric acid production and metabolism are complex processes involving various factors that regulate uric acid production in the liver and reabsorption or excretion from the kidneys and gut.
Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?
Published in Expert Opinion on Orphan Drugs, 2021
Ruofan Connie Han, Lewis E. Fry, Ariel Kantor, Michelle E. McClements, Kanmin Xue, Robert E. MacLaren
Finally, CRISPR-directed RNA editing represents another novel approach to targeted correction of single nucleotide variants, in RNA rather than DNA [54]. A wide variety of approaches have been developed to edit RNA in vitro. Each approach currently uses a variant of the Adenosine Deaminase Acting on RNA (ADAR), naturally expressed enzymes in human cells that undertake physiological RNA editing functions. These deaminases convert adenosine bases to inosine in RNA, which is read as a guanosine in cellular processes such as translation and splicing [63]. This effectively creates an A > G edit in RNA and can be harnessed for the correction of G > A mutations. ADAR variants have also been engineered to create C > U edits: together, they can theoretically address up to 10% of known CHM mutations [64,65]. Harnessed for site-directed RNA editing, ADAR can be recruited to editing sites of interest by systems that link ADAR to an effector molecule and direct the ADAR-effector system with a gRNA to the base to be edited [54]. Many effectors have been developed including those based on CRISPR-Cas13 [65,66] or Cas9 systems [67], bacteriophage-derived λN peptide [71] and BoxB system, aptamer-like systems such as the MS2 bacteriophage coat protein (MCP) or GluR2 system [69]. Additionally, systems that deliver only a gRNA and use only endogenously expressed ADAR have been developed [69–71], in contrast [68] to other systems that require ADAR overexpression.
Inosine supplements only reach the CNS in molybdenum deficient humans and may cause astrocyte degeneration and bulbar–respiratory disease
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
I have read the article entitled “ALSUntangled No. 37: Inosine” by Paganoni S, Bedlack R et al published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration (2017;18: 309–312). This was a well-intentioned review that explored the potential utility of oral inosine supplements in patients with ALS, Parkinson’s disease and Alzheimer’s disease. The thinking behind the review was that high urate levels are associated with less risk of developing these diseases and urate is the end product of inosine metabolism, so oral inosine could increase blood and CSF urate levels and thereby improve patient survival. The review supported this notion without considering an alternative viewpoint. Namely that lower urate levels in ALS are likely to be the result of lower molybdenum enzyme activity hence reduced conversion of purines to urate, making Mo status the disease driver and urate levels a consequence.
Related Knowledge Centers
- Glycosidic Bond
- Hypoxanthine
- Immunotherapy
- Mycophenolic Acid
- Nucleoside
- Purine
- Transfer Rna
- Wobble Base Pair
- Inosine-5′-Monophosphate Dehydrogenase
- Xanthosine Monophosphate