View source for Chemistry:Arachidonate 5-lipoxygenase inhibitor

'''Arachidonate 5-lipoxygenase inhibitors''' are compounds that slow or stop the action of the [[Biology:Arachidonate 5-lipoxygenase|arachidonate 5-lipoxygenase]] (5-lipoxygenase or 5-LOX) enzyme, which is responsible for the production of inflammatory [[Biology:Leukotriene|leukotriene]]s. The overproduction of leukotrienes is a major cause of inflammation in [[Medicine:Asthma|asthma]], allergic [[Medicine:Rhinitis|rhinitis]], and [[Medicine:Osteoarthritis|osteoarthritis]].<ref>David L. Nelson, Michael M. Cox. ''Lehninger's Principles of Biochemistry, Fifth Edition''. W.H. Freeman and Co., 2008, p. 359.</ref><ref>{{cite journal|last1=Laufer|first1=S|title=Role of eicosanoids in structural degradation in osteoarthritis|journal=Curr Opin Rheumatol|volume=15|issue=5|pages=623–627|pmid=12960491|doi=10.1097/00002281-200309000-00017|year=2003|s2cid=1103848}}</ref>
Examples of 5-LOX inhibitors include the pharmaceutical drugs meclofenamate sodium, [[Chemistry:Zileuton|zileuton]]<ref name="MEDRS review" /><ref name="USFDA Zileuton">{{cite web|title=Zyflo (Zileuton tablets) | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020471s017lbl.pdf | website=United States Food and Drug Administration | publisher=Cornerstone Therapeutics Inc. |access-date=12 December 2014 |page=1| date=June 2012| quote=Zileuton is a specific inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation. Both the (''R'')-(+)- and (''S'')-(-)-enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in ''in vitro'' systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients.}}</ref> and the natural products myxochelins/pseudochelin<ref>{{Cite journal|last1=Schieferdecker|first1=Sebastian|last2=König|first2=Stefanie|last3=Koeberle|first3=Andreas|last4=Dahse|first4=Hans-Martin|last5=Werz|first5=Oliver|last6=Nett|first6=Markus|date=2015-02-27|title=Myxochelins Target Human 5-Lipoxygenase|url=https://pubs.acs.org/doi/10.1021/np500909b|journal=Journal of Natural Products|language=en|volume=78|issue=2|pages=335–338|doi=10.1021/np500909b|pmid=25686392 |issn=0163-3864}}</ref><ref>{{Cite journal|last1=Sester|first1=Angela|last2=Winand|first2=Lea|last3=Pace|first3=Simona|last4=Hiller|first4=Wolf|last5=Werz|first5=Oliver|last6=Nett|first6=Markus|date=2019-09-27|title=Myxochelin- and Pseudochelin-Derived Lipoxygenase Inhibitors from a Genetically Engineered Myxococcus xanthus Strain|url=https://pubs.acs.org/doi/10.1021/acs.jnatprod.9b00403|journal=Journal of Natural Products|language=en|volume=82|issue=9|pages=2544–2549|doi=10.1021/acs.jnatprod.9b00403|pmid=31465225 |s2cid=201675694 |issn=0163-3864}}</ref> as well as [[Chemistry:Nordihydroguaiaretic acid|nordihydroguaiaretic acid]] (NDGA).<ref name=":0">{{Cite journal|last1=Gilbert|first1=Nathaniel C.|last2=Gerstmeier|first2=Jana|last3=Schexnaydre|first3=Erin E.|last4=Börner|first4=Friedemann|last5=Garscha|first5=Ulrike|last6=Neau|first6=David B.|last7=Werz|first7=Oliver|last8=Newcomer|first8=Marcia E.|date=July 2020|title=Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products|url= |journal=Nature Chemical Biology|language=en|volume=16|issue=7|pages=783–790|doi=10.1038/s41589-020-0544-7|issn=1552-4450|pmc=7747934|pmid=32393899}}</ref>

Some chemicals found in trace amounts in food, as well as some dietary supplements, have been shown to inhibit 5-LOX; these include [[Chemistry:Baicalein|baicalein]], [[Chemistry:Caffeic acid|caffeic acid]], [[Chemistry:Curcumin|curcumin]],<ref name="MEDRS review">{{cite journal |vauthors=Bishayee K, Khuda-Bukhsh AR | title = 5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy | journal = Acta Biochim. Biophys. Sin. (Shanghai) | volume = 45 | issue = 9 | pages = 709–719 | date = September 2013 | pmid = 23752617 | doi = 10.1093/abbs/gmt064 | doi-access = free }}</ref> [[Chemistry:Hyperforin|hyperforin]] and St John's wort.<ref name="Hyperforin HMDB 5-LOX COX1">{{cite encyclopedia |version=3.6 |section=Enzymes |title=Hyperforin |section-url=http://www.hmdb.ca/metabolites/HMDB30463#enzymes |publisher=University of Alberta |access-date=12 December 2014 |date=30 June 2013 |quote=Hyperforin is found in alcoholic beverages. Hyperforin is a constituent of Hypericum perforatum (St John's Wort) Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum (St John's wort). The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975. Hyperforin is a prenylated phloroglucinol derivative. Total synthesis of hyperforin has not yet been accomplished, despite attempts by several research groups. Hyperforin has been shown to exhibit anti-inflammatory, anti-tumor, antibiotic and anti-depressant functions}} <br /> {{pb}}{{cite journal | pmid = 17696442 | doi=10.1021/jf0710074 | volume=55 | title=Inhibition of prostaglandin E(2) production by anti-inflammatory hypericum perforatum extracts and constituents in RAW264.7 Mouse Macrophage Cells | pmc=2365463 | year=2007 | vauthors=Hammer KD, Hillwig ML, Solco AK, Dixon PM, Delate K, Murphy PA, Wurtele ES, Birt DF | journal=J Agric Food Chem | issue=18 | pages=7323–31}} {{pb}}{{cite journal | pmid = 21751836 | doi=10.1080/10286020.2011.584532 | volume=13 | title=In-vitro antitumor activity evaluation of hyperforin derivatives | year=2011 |vauthors=Sun F, Liu JY, He F, Liu Z, Wang R, Wang DM, Wang YF, Yang DP | journal=J Asian Nat Prod Res | issue=8 | pages=688–99| s2cid=43743086 }} {{pb}}{{cite journal | pmid = 12725578 | doi=10.1078/094471103321659951 | volume=10 | title=Treatment with Hypericum perforatum L. does not trigger decreased resistance in Staphylococcus aureus against antibiotics and hyperforin | year=2003 | author=Hübner AT | journal=Phytomedicine | issue=2–3 | pages=206–8}} {{pb}}{{cite journal | pmid = 12018529 | volume=39 | title=Antidepressant activity of hyperforin conjugates of the St. John's wort, Hypericum perforatum Linn.: an experimental study | year=2001 |vauthors=Muruganandam AV, Bhattacharya SK, Ghosal S | journal=Indian J Exp Biol | issue=12 | pages=1302–4}} <br />1. Arachidonate 5-lipoxygenase&nbsp;...Specific function: Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes&nbsp;...<br />2. Prostaglandin G/H synthase 1&nbsp;... General function: Involved in peroxidase activity</ref><ref name="Systematic review hypericum">{{cite journal |vauthors=de Melo MS, Quintans Jde S, Araújo AA, Duarte MC, Bonjardim LR, Nogueira PC, Moraes VR, de Araújo-Júnior JX, Ribeiro EA, Quintans-Júnior LJ | title = A systematic review for anti-inflammatory property of clusiaceae family: a preclinical approach | journal = Evid Based Complement Alternat Med | volume = 2014 | pages = 960258 | year = 2014 | pmid = 24976853 | pmc = 4058220 | doi = 10.1155/2014/960258 | quote = These researches are according to an investigation of the effect of H. perforatum on the NF-κB inflammation factor, conducted by Bork et al. (1999), in which hyperforin provided a potent inhibition of TNFα-induced activation of NF-κB [58]. Another important activity for hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase [59]. Moreover, this species attenuated the expression of iNOS in periodontal tissue, which may contribute to the attenuation of the formation of nitrotyrosine, an indication of nitrosative stress [26]. In this context, a combination of several active constituents of Hypericum species is the carrier of their anti-inflammatory activity.| doi-access = free }}</ref><ref name="5-Lox review number 2">{{cite journal |vauthors=Wölfle U, Seelinger G, Schempp CM | title = Topical application of St. John's wort (Hypericum perforatum) | journal = Planta Med. | volume = 80 | issue = 2–3 | pages = 109–20 |date=February 2014  | pmid = 24214835 | doi = 10.1055/s-0033-1351019 | quote = Anti-inflammatory mechanisms of hyperforin have been described as inhibition of cyclooxygenase-1 (but not COX-2) and 5-lipoxygenase at low concentrations of 0.3 μmol/L and 1.2 μmol/L, respectively [52], and of PGE2 production in vitro [53] and in vivo with superior efficiency (ED50 = 1 mg/kg) compared to indomethacin (5 mg/kg) [54]. Hyperforin turned out to be a novel type of 5-lipoxygenase inhibitor with high effectivity in vivo [55] and suppressed oxidative bursts in polymorphonuclear cells at 1.8 μmol/L in vitro [56]. Inhibition of IFN-γ production, strong downregulation of CXCR3 expression on activated T cells, and downregulation of matrix metalloproteinase 9 expression caused Cabrelle et al. [57] to test the effectivity of hyperforin in a rat model of experimental allergic encephalomyelitis (EAE). Hyperforin attenuated the symptoms significantly, and the authors discussed hyperforin as a putative therapeutic molecule for the treatment of autoimmune inflammatory diseases sustained by Th1 cells.| doi-access = free }}</ref>

'''Acetyl-keto-beta-boswellic acid ([[Chemistry:Boswellic acid|AKBA]])''', one of the bioactive boswellic acids found in Boswellia serrata (Indian Frankincense) has been found to inhibit 5-lipoxygenase strongly as an allosteric inhibitor.<ref name=":0" /> Boswellia administration has been shown to reduce brain edema in patients irradiated for brain tumor and it's believed to be due to 5-lipoxygenase inhibition.<ref name="Simon Kirste 2009">{{cite thesis |degree=MD | author=Simon Kirste  | title=Antiödematöse Wirkung von Boswellia serrata auf dasStrahlentherapie - assoziierte Hirnödem | year= 2009 | url=https://d-nb.info/101045384X/34 |publisher=Albert-Ludwigs-Universität Freiburg im Breisgau |via=Deutsche National Bibliothek}}</ref><ref name="pmid21287538">{{cite journal |vauthors=Kirste S, Treier M, Wehrle SJ, Becker G, Abdel-Tawab M, Gerbeth K | display-authors=0| title=Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: a prospective, randomized, placebo-controlled, double-blind pilot trial. | journal=Cancer | year= 2011 | volume= 117 | issue= 16 | pages= 3788–95 | pmid=21287538 | doi=10.1002/cncr.25945 |doi-access=free}}</ref>

==See also==
*Antileukotriene agents
*[[Biology:Arachidonate 5-lipoxygenase#ALOX5-inhibiting drugs|Arachidonate 5-lipoxygenase ALOX5-inhibiting drugs]]

==References==
{{Reflist}}

==External links==
* {{MeshName|Lipoxygenase+inhibitors}}
* {{MeshPharmaList|82016859}}
* [https://hmdb.ca/unearth/q?utf8=%E2%9C%93&query=Arachidonic+5-lipoxygenase&searcher=metabolites Human Metabolome Database – Metabolites of 5-LOX]

{{Enzyme inhibition}}
{{Drugs for obstructive airway diseases}}
{{Leukotrienergics}}

[[Category:Oxidoreductase inhibitors]]



{{Sourceattribution|Arachidonate 5-lipoxygenase inhibitor}}