Editing Inosine

{{Short description|Chemical compound}}
{{drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 461935819
| IUPAC_name = 9-[(2''R'',3''R'',4''S'',5''R'')-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6,9-dihydro-3''H''-purin-6-one
| image = Inosin.svg
| image_class = skin-invert-image
| image2 = Inosine ball-and-stick.png
| image_class2 = bg-transparent
<!--Clinical data-->
| Drugs.com = {{drugs.com|international|inosine}}
| pregnancy_category =
| legal_status = OTC
| routes_of_administration =
<!--Pharmacokinetic data-->
| bioavailability =
| protein_bound =
| metabolism = [[Liver|Hepatic]]
| elimination_half-life =
<!--Identifiers-->
| IUPHAR_ligand = 4554
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 58-63-9
| ATC_prefix = D06
| ATC_suffix = BB05
| ATC_supplemental = {{ATC|G01|AX02}} {{ATC|S01|XA10}}
| PubChem = 6021
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB04335
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5799
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 5A614L51CT
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C00294
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 17596
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1556
<!--Chemical data-->
| C=10 | H=12 | N=4 | O=5
| smiles = c1[nH]c2c(c(=O)n1)ncn2[C@H]3[C@@H]([C@@H]([C@H](O3)CO)O)O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C10H12N4O5/c15-1-4-6(16)7(17)10(19-4)14-3-13-5-8(14)11-2-12-9(5)18/h2-4,6-7,10,15-17H,1H2,(H,11,12,18)/t4-,6-,7-,10-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = UGQMRVRMYYASKQ-KQYNXXCUSA-N
}}
'''Inosine''' is a [[nucleoside]] that is formed when [[hypoxanthine]] is attached to a [[ribose]] ring (also known as a [[ribofuranose]]) via a β-N<sub>9</sub>-[[glycosidic bond]]. It was discovered in 1965 in analysis of RNA transferase.<ref name="pmid33921764">{{cite journal | vauthors = Srinivasan S, Torres AG, Ribas de Pouplana L | title = Inosine in Biology and Disease | journal = Genes | volume = 12 | issue = 4 | date = April 2021 | page = 600 | pmid = 33921764 | pmc = 8072771 | doi = 10.3390/genes12040600 | doi-access = free }}</ref>
Inosine is commonly found in [[tRNA]]s and is essential for proper translation of the genetic code in [[wobble base pair]]s.
[[Image:Wobble.svg|thumb|right|225px|Wobble base pairs for '''inosine''' and [[guanine]]]]

Knowledge of inosine metabolism has led to advances in [[immunotherapy]] in recent decades. Inosine monophosphate is oxidised by the enzyme [[inosine monophosphate dehydrogenase]], yielding [[xanthosine monophosphate]], a key precursor in [[purine]] metabolism.  [[Mycophenolate mofetil]] is an anti-metabolite, anti-proliferative drug that acts as an inhibitor of inosine monophosphate dehydrogenase. It is used in the treatment of a variety of [[autoimmune]] diseases including [[granulomatosis with polyangiitis]] because the uptake of purine by actively dividing [[B cell]]s can exceed 8 times that of normal body cells, and, therefore, this set of white cells (which cannot operate purine salvage pathways) is selectively targeted by the purine deficiency resulting from inosine monophosphate dehydrogenase (IMD) inhibition.

==Reactions==
[[Adenine]] is converted to [[adenosine]] or [[inosine monophosphate]] (IMP), either of which, in turn, is converted into inosine (I), which pairs with adenine (A), [[cytosine]] (C), and [[uracil]] (U).<ref name="pmid33921764"></ref>

[[Purine nucleoside phosphorylase]] intraconverts inosine and [[hypoxanthine]].

Inosine is also an intermediate in a chain of purine nucleotide reactions required for muscle movements.

==Clinical significance==
Subsequent studies in humans suggest that inosine supplementation has no effect on athletic performance.<ref name="ISSN">{{cite journal | vauthors = Kerksick CM, Wilborn CD, Roberts MD, Smith-Ryan A, Kleiner SM, Jäger R, Collins R, Cooke M, Davis JN, Galvan E, Greenwood M, Lowery LM, Wildman R, Antonio J, Kreider RB | display-authors = 6 | title = ISSN exercise & sports nutrition review update: research & recommendations | journal = Journal of the International Society of Sports Nutrition | volume = 15 | issue = 1 | pages = 38 | date = August 2018 | pmid = 30068354 | pmc = 6090881 | doi = 10.1186/s12970-018-0242-y | doi-access = free }}</ref> Animal studies have suggested that inosine has neuroprotective properties. It has been proposed for spinal cord injury<ref>{{cite journal | vauthors = Liu F, You SW, Yao LP, Liu HL, Jiao XY, Shi M, Zhao QB, Ju G | display-authors = 6 | title = Secondary degeneration reduced by inosine after spinal cord injury in rats | journal = Spinal Cord | volume = 44 | issue = 7 | pages = 421–426 | date = July 2006 | pmid = 16317421 | doi = 10.1038/sj.sc.3101878 | doi-access = free }}</ref> and for administration after [[stroke]], because observation suggests that inosine induces axonal rewiring.<ref>{{cite journal | vauthors = Chen P, Goldberg DE, Kolb B, Lanser M, Benowitz LI | title = Inosine induces axonal rewiring and improves behavioral outcome after stroke | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 13 | pages = 9031–9036 | date = June 2002 | pmid = 12084941 | pmc = 124418 | doi = 10.1073/pnas.132076299 | doi-access = free | bibcode = 2002PNAS...99.9031C }}</ref>

After ingestion, inosine is metabolized into uric acid, which has been suggested to be a natural antioxidant and [[peroxynitrite]] scavenger with potential benefits to patients with [[multiple sclerosis]] (MS).<ref>{{cite web | url=http://www.geocities.com/hotsprings/3468/uric_acid-peroxynitrite2-98.html | archive-url=https://web.archive.org/web/20091027182321/http://www.geocities.com/HotSprings/3468/uric_acid-peroxynitrite2-98.html | url-status=dead | archive-date=2009-10-27 | title=Uric Acid In Multiple Sclerosis | date=2018 | publisher=WebCite}}</ref> Peroxynitrite has been correlated with axon degeneration <ref>{{cite web | vauthors = Neuhaus O, Hartung HO |title= Immune mediated injury, oxidative toxicity and excitotoxicity in multiple sclerosis. Possibilities for immune modulation and neuroprotection | url = http://www.fedem.org/revista/n17/neuhausing.htm |url-status=dead |access-date=2006-04-23 |archive-url= https://web.archive.org/web/20070311064406/http://www.fedem.org/revista/n17/neuhausing.htm |archive-date=2007-03-11}}</ref> In 2003, a study was initiated at the University of Pennsylvania MS Center to determine whether raising the levels of uric acid by the administration of inosine would slow the progression of MS.<ref>{{ClinicalTrialsGov|NCT00067327|Treatment of Multiple Sclerosis Using Over the Counter Inosine}}</ref> The study was completed in 2006 but the results were not reported to NIH. A subsequent publication hinted at potential benefits but the sample size (16 patients) was too small for a definitive conclusion. In addition, the side effect of the treatment was the development of kidney stones in four of 16 patients.<ref>{{cite journal | vauthors = Markowitz CE, Spitsin S, Zimmerman V, Jacobs D, Udupa JK, Hooper DC, Koprowski H | title = The treatment of multiple sclerosis with inosine | journal = Journal of Alternative and Complementary Medicine | volume = 15 | issue = 6 | pages = 619–625 | date = June 2009 | pmid = 19425822 | pmc = 3189001 | doi = 10.1089/acm.2008.0513 }}</ref>

With phase II trials for Parkinson's disease completed, inosine will continue to phase III trials. Earlier trials suggested that patients with the highest serum urate levels had slower progression of Parkinson's symptoms. The trial uses inosine to raise urate levels in those with levels lower than the population mean (6&nbsp;mg/dL).<ref>{{cite web|title=Safety of Urate Elevation in Parkinson's Disease|url=https://foxtrialfinder.michaeljfox.org/trial/468/|publisher= Fox Trial Finder | date=2018}}</ref><ref>{{ClinicalTrialsGov|NCT00833690|Safety of Urate Elevation in Parkinson's Disease}}</ref><ref>{{cite web | vauthors = Kuhl MM |title=Inosine Trial Secures Phase III Funding to Study Effect on Slowing Parkinson's|url=https://www.michaeljfox.org/foundation/news-detail.php?inosine-trial-secures-phase-iii-funding-to-study-effect-on-slowing-parkinson | date = September 1, 2015 | publisher = Michael J. Fox Foundation }}</ref>

Alseres Pharmaceuticals (named Boston Life Sciences when patent was granted) patented the use of inosine to treat stroke<ref>{{cite web |title=Boston Life Sciences Announces Issuance of Inosine Patent for Treatment of Spinal Cord Injury | date = November 17, 2003 |url= http://www.bostonlifesciences.com/news111.htm |url-status=dead |archive-url= https://web.archive.org/web/20050903104420/http://www.bostonlifesciences.com/news111.htm |archive-date=2005-09-03}}</ref> and was investigating the drug in the MS setting.<ref>{{cite journal | vauthors = Lou KJ | title = The inosine conundrum. | journal = Science-Business EXchange | volume = 2 | page = 1132 | date = 2009 | issue = 29 | doi = 10.1038/scibx.2009.1132 | doi-access = free }}</ref>

In the [[Anatomical Therapeutic Chemical Classification System]], it is classified as an [[Antiviral drug|antiviral]].<ref name="urlATC/DDD Index">{{cite web |url=http://www.whocc.no/atc_ddd_index/?code=D06BB05 |title=ATC/DDD Index | publisher = World Health Organization Collaborating Centre |access-date=Dec 20, 2017}}</ref>

== Binding ==
Inosine is a natural ligand for the [[benzodiazepine]] binding site on the GABA A receptor.<ref>{{cite journal | vauthors = Yarom M, Tang XW, Wu E, Carlson RG, Vander Velde D, Lee X, Wu J | title = Identification of inosine as an endogenous modulator for the benzodiazepine binding site of the GABAA receptors | journal = Journal of Biomedical Science | volume = 5 | issue = 4 | pages = 274–280 | date = July 1998 | pmid = 9691220 | doi = 10.1007/bf02255859 }}</ref>

==Biotechnology==
When designing [[primer (molecular biology)|primer]]s for [[polymerase chain reaction]], inosine is useful in that it can pair with any natural base.<ref>{{cite journal | vauthors = Ben-Dov E, Shapiro OH, Siboni N, Kushmaro A | title = Advantage of using inosine at the 3' termini of 16S rRNA gene universal primers for the study of microbial diversity | journal = Applied and Environmental Microbiology | volume = 72 | issue = 11 | pages = 6902–6906 | date = November 2006 | pmid = 16950904 | pmc = 1636166 | doi = 10.1128/AEM.00849-06 }}</ref>  This allows for design of primers that span a [[single-nucleotide polymorphism]], without the polymorphism disrupting the primer's annealing efficiency.

However, inosine pairs preferentially with cytosine (C) and its introduction to RNA, e.g. by the action of [[ADAR]]s, thereby destabilizes double-stranded RNA by changing AU base-pairs to IU mismatches.<ref name="pmid3203381">{{cite journal | vauthors = Bass BL, Weintraub H | title = An unwinding activity that covalently modifies its double-stranded RNA substrate | journal = Cell | volume = 55 | issue = 6 | pages = 1089–1098 | date = December 1988 | pmid = 3203381 | doi = 10.1016/0092-8674(88)90253-x | s2cid = 11698374 }}</ref>

==Fitness==
Despite  lack of clinical evidence that it improves muscle development, inosine remains an ingredient in some fitness supplements.

==Feeding stimulant==
Inosine has also been found to be an important feed stimulant by itself or in combination with certain [[amino acids]] in some species of farmed [[fish]]. For example, inosine and [[inosine monophosphate|inosine 5-monophosphate]] have been reported as specific feeding stimulants for [[turbot]] fry, (''Scophthalmus maximus'') <ref>{{cite book | vauthors = Mackie AM | date = 1987 | chapter = Identification of the gustatory feeding stimulants. | title = Chemoreception in Fishes | veditors = Hara TJ | publisher = Elsevier Scientific Publishing Co. | location = Amsterdam | pages = 275–291 }}</ref> and [[Japanese amberjack]], (''Seriola quinqueradiata'').<ref>{{cite journal | vauthors = Takeda M, Takii K, Matsui K | title = Identification of feeding stimulants for juvenile eel. | journal = Bulletin of the Japanese Society of Scientific Fisheries | date = 1984 | volume = 50 | issue = 4 | pages =  645–651 | doi = 10.2331/suisan.50.645 | doi-access = free }}</ref> The main problem of using inosine and/or inosine-5-monophosphate as feeding attractants is their high cost. However, their use may be economically justified within larval feeds for marine fish larvae during the early weaning period, since the total quantity of feed consumed is relatively small.

== See also ==
* [[Inosine monophosphate dehydrogenase]]
* [[Inosine pranobex]]
* [[Nucleobase]]

== References ==
{{reflist|2}}

== External links ==
* [https://web.archive.org/web/20081120024756/http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/ino_0144.shtml PDR health study]

{{Nucleobases, nucleosides, and nucleotides}}
{{Antibiotics and chemotherapeutics for dermatological use}}
{{Gynecological anti-infectives and antiseptics}}
{{Antivirals}}
{{Purinergics}}

[[Category:Nucleosides]]
[[Category:Purines]]
[[Category:Antiviral drugs]]
[[Category:Hydroxymethyl compounds]]
[[Category:Ophthalmology drugs]]