humulone
{{distinguish|humulene}}
{{Chembox
| ImageFile = (S)-Humulone.svg
| ImageSize = 200px
| ImageFile2 = Humulone-3D-xray.gif
| ImageSize2 = 200px
| PIN = (6S)-3,5,6-Trihydroxy-2-(3-methylbutanoyl)-4,6-bis(3-methylbut-2-en-1-yl)cyclohexa-2,4-dien-1-one{{cite journal | year = 2013 | last1 = Urban | first1 = Jan | last2 = Dahlberg | first2 = Clinton | last3 = Carroll | first3 = Brian | last4 = Kaminsky | first4 = Werner | title = Absolute Configuration of Beer's Bitter Compounds | volume = 52 | issue = 5 | pages = 1553–1555 | doi = 10.1002/anie.201208450 | pmid = 23239507 | journal = Angew. Chem. Int. Ed.| pmc = 3563212 }}
| OtherNames = α-Lupulic acid; α-Bitter acid
|Section1={{Chembox Identifiers
| CASNo = 26472-41-3
| CASNo_Ref = {{cascite|correct|CAS}}
| PubChem = 442911
| ChemSpiderID = 391214
| UNII = KHB4767H3K
| SMILES = O=C(\C1=C(/O)\C(=C(\O)[C@](O)(C1=O)C\C=C(/C)C)C\C=C(/C)C)CC(C)C
| InChI = InChI=1S/C21H30O5/c1-12(2)7-8-15-18(23)17(16(22)11-14(5)6)20(25)21(26,19(15)24)10-9-13(3)4/h7,9,14,23-24,26H,8,10-11H2,1-6H3/t21-/m1/s1
}}
|Section2={{Chembox Properties
| C=21 | H=30 | O=5
| Appearance =
| Density =
| MeltingPt =
| BoilingPt =
| Solubility =
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|Section3={{Chembox Hazards
| MainHazards =
| FlashPt =
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Humulone (α-lupulic acid), a vinylogous type of organic acid, is a bitter-tasting chemical compound found in the resin of mature hops (Humulus lupulus).{{cite journal | pmid = 12848522 | year = 2003 | last1 = De Keukeleire | first1 = J | last2 = Ooms | first2 = G | last3 = Heyerick | first3 = A | last4 = Roldan-Ruiz | first4 = I | last5 = Van Bockstaele | first5 = E | last6 = De Keukeleire | first6 = D | title = Formation and accumulation of alpha-acids, beta-acids, desmethylxanthohumol, and xanthohumol during flowering of hops (Humulus lupulus L.) | volume = 51 | issue = 15 | pages = 4436–41 | doi = 10.1021/jf034263z | journal = Journal of Agricultural and Food Chemistry}} Humulone is a prevalent member of the class of compounds known as alpha acids, which collectively give hopped beer its characteristic bitter flavor.
Chemistry
In terms of structure, humulone is a phloroglucinol derivative with three isoprenoid side-chains. Two side-chains are prenyl groups and one is an isovaleryl group. The acidity of the ring enol moieties that give rise to its designation as an acid lie in their vinylogous relationship with the ring and side chain carbonyl functional groups.{{citation needed|date=July 2014}}
Isohumulone
{{main|Isohumulone}}
During the brewing process, humulone degrades to cis- and trans-isohumulone. These “alpha acids” survive the boiling process, although numerous oxidized derivatives are produced.Blanco, C. A.; Rojas, A; Caballero, P. A.; Ronda, F; Gomez, M; Caballero, I., “A better control of beer properties by predicting acidity of hop iso-α-acids”, Trends in Food Science & Technology, Volume 17, Issue 7, July 2006, Pages 373-377, ISSN 0924-2244, {{doi|10.1016/j.tifs.2005.11.012}}. The iso-alpha acids are significantly more soluble than humulone at the pH levels typically present in the brewing process.Esslinger, H. M. and Narziss, L. 2003. “Beer.” in- Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH Verlag GmbH & Co. KGaA, 2009 {{doi|10.1002/14356007.a03_421}}
:File:S-Humulone Isomerization.svg{{clear left}}
Laboratory synthesis
Humulone can be synthesized by the acylation of benzene-1,2,3,5-tetrol with isovaleryl chloride to give 2,3,4,6-tetrahydroxyisovalerophenone. This step is followed by prenylation with 1-bromo-3-methyl-2-butene to give humulone.{{cite journal | author = Obara | title = A Synthetic Route to (±)-humulone | journal = Bull. Chem. Soc. Jpn. | volume = 62 | issue = 9 | pages = 3034–3035 | year = 1989 | display-authors = 1 | doi = 10.1246/bcsj.62.3034 | last2 = Onodera | first2 = Jun-Ichi | last3 = Machida | first3 = Yoshihisa | last4 = Yada | first4 = Shuji| doi-access = free }}
:File:Humulone synthesis.png{{clear-left}}
Biosynthesis
As determined by INADEQUATE 2D NMR, the biosynthesis of humulone in Humulus lupulus starts with an isovaleryl-CoA unit and 3 malonyl-CoA units catalyzed by phlorovalerophenone synthase. This conversion yields the benzenoid 3-methyl-1-(2,4,6-trihydroxyphenyl)butan-1-one. Dimethylallyl pyrophosphate is then obtained from the deoxyxylulose pathway, where prenylation of the benzenoid occurs, yielding humulone.{{cite journal |author1=M. Goese |author2=K. Kammhuber |author3=A. Bacher |author4=M. H. Zenk |author5=W. Eisenreich | title = Biosynthesis of bitter acids in hops. A (13)C-NMR and (2)H-NMR study on the building blocks of humulone | journal = FEBS Journal | volume = 263 |issue = 2| pages = 447–454 | year = 1999|doi=10.1046/j.1432-1327.1999.00518.x |pmid=10406953 |doi-access=free }}
:isovaleryl-CoA + 3 malonyl-CoA → 4 CoASH + 3 CO2 + 3-methyl-1-(2,4,6-trihydroxyphenyl)butan-1-one
:3-methyl-1-(2,4,6-trihydroxyphenyl)butan-1-one + 2 DMAPP →C21H30O5
Research
Humulone is under basic research with in vitro studies to determine if it has biological properties, such as possible GABAA receptor activity{{Cite journal|last1=Benkherouf|first1=Ali Y.|last2=Eerola|first2=Kim|last3=Soini|first3=Sanna L.|last4=Uusi-Oukari|first4=Mikko|date=2020|title=Humulone Modulation of GABAA Receptors and Its Role in Hops Sleep-Promoting Activity|journal=Frontiers in Neuroscience|language=English|volume=14|page=594708|doi=10.3389/fnins.2020.594708|pmid=33177986|pmc=7591795|issn=1662-453X|doi-access=free}}{{Cite journal|last1=Benkherouf|first1=Ali Y.|last2=Logrén|first2=Nora|last3=Somborac|first3=Tamara|last4=Kortesniemi|first4=Maaria|last5=Soini|first5=Sanna L.|last6=Yang|first6=Baoru|last7=Salo-Ahen|first7=Outi M.H.|last8=Laaksonen|first8=Oskar|last9=Uusi-Oukari|first9=Mikko|date=2020-04-01|title=Hops compounds modulatory effects and 6-prenylnaringenin dual mode of action on GABAA receptors|journal=European Journal of Pharmacology|language=en|volume=873|pages=172962|doi=10.1016/j.ejphar.2020.172962|pmid=32001220|doi-access=free}} or antibacterial effects.{{cite journal | pmid = 19201179 | year = 2009 | last1 = Yamaguchi | first1 = N | last2 = Satoh-Yamaguchi | first2 = K | last3 = Ono | first3 = M | title = In vitro evaluation of antibacterial, anticollagenase, and antioxidant activities of hop components (Humulus lupulus) addressing acne vulgaris | volume = 16 | issue = 4 | pages = 369–76 | doi = 10.1016/j.phymed.2008.12.021 | journal = Phytomedicine}}