lupinine

Lupinine is a hepatotoxin prevalent in the seeds of leguminous herbs of the genus Lupinus. Lupinine and other quinolizidine alkaloids give a bitter taste to naturally growing lupin flowers. Due to the toxicity of quinolizidine alkaloids, lupin beans are soaked overnight and rinsed to remove some of their alkaloid content. However, when the cooking and rinsing procedure is insufficient, 10 grams of seeds are able to liberate as much as 100 milligrams of lupinine.{{Cite web |url=http://natoxaq.ku.dk/toxin-of-the-week/lupanine/ |title=Lupinine - the chemical stopping you from eating Lupin |last=Kirkensgaard |first=Kristine |date=2017-12-11 |website=natoxaq.ku.dk |language=en |access-date=2018-04-27 |archive-date=2020-11-26 |archive-url=https://web.archive.org/web/20201126123113/https://natoxaq.ku.dk/toxin-of-the-week/lupanine/ |url-status=dead }}

The neurotoxicity of lupinine has been known within veterinary medical circles for some time due to the use of lupins as a forage feed for grazing livestock since it has high protein content. It{{clarification needed|date=August 2022}}{{citation needed|date=August 2022}} is found to produce [https://www.merckvetmanual.com/toxicology/mycotoxicoses/mycotoxic-lupinosis lupinosis], which is a morbid, and often fatal condition that results in acute atrophy of liver function and which affects domestic animals such as cattle and sheep. When ingested by humans, quinolizidine alkaloid poisoning causes trembling, shaking, excitation, as well as convulsions.{{Cite journal |last1=Resta |first1=Donatella |last2=Boschin |first2=Giovanna |last3=D'Agostina |first3=Alessandra |last4=Arnoldi |first4=Anna |date=2008 |title=Evaluation of total quinolizidine alkaloids content in lupin flours, lupin-based ingredients, and foods |journal=Molecular Nutrition & Food Research |language=en |volume=52 |issue=4 |pages=490–495 |doi=10.1002/mnfr.200700206 |pmid=18324702 |issn=1613-4125}} Lupinine, in addition to being orally toxic to mammals, is also an insect antifeedant as well as a growth inhibitor for the grasshopper.{{Cite book |title=Dictionary of plant toxins |date=1996 |publisher=Wiley |others=Harborne, J. B. (Jeffrey B.), Baxter, Herbert, 1928-, Moss, Gerard P. |isbn=978-0471951070 |location=Chichester |oclc=34281328}}

File:Lupinine Graphic 1.png

Lupinine, in comparison to other quinolizidine alkaloids commonly found in lupins, such as lupanine and sparteine, shows a lower toxicity. Lupinine, with a minimal lethal dose of 28–30 mg/kg and a toxic dose of 25–28 mg/kg, is about 85 percent as toxic as d-lupanine and about 90% as toxic as sparteine. The relative toxicity of lupinine with other quinolizidine alkaloids commonly found in lupins is shown in the table below.{{Cite journal |last=Couch |first=James |date=1926 |title=Relative Toxicity of the Lupine Alkaloids |url=https://naldc-legacy.nal.usda.gov/naldc/download.xhtml?id=IND43967196&content=PDF |journal=Journal of Agricultural Research |volume=XXXII |pages=51–67 |access-date=2018-12-29 |archive-date=2021-12-25 |archive-url=https://web.archive.org/web/20211225112030/https://naldc.nal.usda.gov/ |url-status=dead }}

File:Lupinine_Graphic_5.png

Studies on the hydrochloride of lupinine have shown it to be a reversible inhibitor of acetylcholinesterases. Lupinine, a nitrogen-containing heterocycle, has a structure similar to the ammonium "head" of the acetylcholinesterase endogenous agonist, acetylcholine.{{Cite journal |last1=Tilyabaev |first1=Z. |last2=Abduvakhabov |first2=A. A. |date=1998-05-01 |title=Alkaloids of Anabasis aphylla and their cholinergic activities |journal=Chemistry of Natural Compounds |language=en |volume=34 |issue=3 |pages=295–297 |doi=10.1007/BF02282405 |bibcode=1998CNatC..34..295T |s2cid=30640524 |issn=0009-3130}} At physiological pH, the amine of lupinine is protonated which leads to ion-ion interaction with the acetylcholinesterase anionic site in the same manner as the ammonium on acetylcholine interacts. Previous studies of reversible ammonium inhibitors similar to lupinine have shown that the ammonium groups (corresponding to the protonated amine of lupinine) enter the gorge of the active center of the acetylcholinesterase in the region of the Trp⁸⁴ residue. This leads to the formation of an enzyme-sorption complex with the anionic portion of the acetylcholinesterase located on the active site of lupinine, namely the amine. This complex blocks the access of acetylcholine to the active center which decreases the catalytic hydrolysis and subsequent breakdown of acetylcholine by acetylcholinesterase. Enzyme inactivation leads to an accumulation of acetylcholine in the body, hyperstimulation of both the muscarinic and nicotinic acetylcholine receptors, as well as subsequent disruption of neurotransmission.{{Cite journal |last1=Colovic |first1=Mirjana B. |last2=Krstic |first2=Danijela Z. |last3=Lazarevic-Pasti |first3=Tamara D. |last4=Bondzic |first4=Aleksandra M. |last5=Vasic |first5=Vesna M. |date=2013-04-01 |title=Acetylcholinesterase Inhibitors: Pharmacology and Toxicology |journal=Current Neuropharmacology |language=en |volume=11 |issue=3 |pages=315–335 |doi=10.2174/1570159x11311030006 |pmc=3648782 |pmid=24179466}} However, it was found that the time of incubation did not affect the inhibition, leading to the conclusion that lupinine is a reversible inhibitor.

Studies have also shown that lupinine has a binding affinity for both muscarinic and nicotinic acetylcholine receptors. Lupinine was found to have an IC₅₀ value of >500 μM for nicotinic receptors and an IC₅₀ value of 190 μM for muscarinic receptors. However, it has yet to be determined whether this affinity is agonistic or antagonistic in nature.{{Cite journal |last1=Schmeller |first1=Thorsten |last2=Sauerwein |first2=Martina |last3=Sporer |first3=Frank |last4=Wink |first4=Michael |last5=Müller |first5=Walter E. |date=September 1994 |title=Binding of Quinolizidine Alkaloids to Nicotinic and Muscarinic Acetylcholine Receptors |journal=Journal of Natural Products |language=EN |volume=57 |issue=9 |pages=1316–1319 |doi=10.1021/np50111a026 |pmid=7798968 |bibcode=1994JNAtP..57.1316S |issn=0163-3864}}

File:Lupinine_Graphic_2.png

Lupinine is naturally biosynthesized from l-lysine in the Lupinus genes of plants along with various other quinolizidine alkaloids. In the biosynthetic process, lysine is first decarboxylated into cadaverine, which is then oxidatively deaminated to the corresponding aldehyde. The aldehyde is then spontaneously cyclized into two tautmers which couple through an aldol type mechanism in which the allylic amine attacks the iminium, forming a dissymmetric dimeric intermediate which is then hydrated. The primary amine is then oxidized and an intramolecular condensation occurs, giving the quinolizidinealdehyde. The aldehyde is then reduced to an alcohol, giving, enantioselectively, (-)- lupinine.{{Cite journal |last1=Golebiewski |first1=W. Marek |last2=Spenser |first2=Ian D. |date=1985-10-01 |title=Biosynthesis of the lupine alkaloids. I. Lupinine |journal=Canadian Journal of Chemistry |volume=63 |issue=10 |pages=2707–2718 |doi=10.1139/v85-450 |issn=0008-4042 |doi-access=free|bibcode=1985CaJCh..63.2707G }}{{Cite journal |last=Spenser |first=I. D. |date=1985-01-01 |title=Stereochemical aspects of the biosynthetic routes leading to the pyrrolizidine and the quinolizidine alkaloids |journal=Pure and Applied Chemistry |language=en |volume=57 |issue=3 |pages=453–470 |doi=10.1351/pac198557030453 |s2cid=46220343 |issn=1365-3075|doi-access=free }}

Lupinine has a chiral carbon atom; therefore, total syntheses of lupinine need to be enantioselective for (-)-lupinine in order to provide the biologically active product. The first racemic total synthesis of lupinine occurred in 1937 by Clemo, Morgan, and Raper.{{Cite journal |last1=Clemo |first1=G. R. |last2=Morgan |first2=W. McG. |last3=Raper |first3=R. |date=1937 |title=199. The lupin alkaloids. Part XII. The synthesis of dl-lupinine and dl-isolupinine |journal=Journal of the Chemical Society (Resumed) |language=en |pages=965 |doi=10.1039/jr9370000965 |issn=0368-1769}} Six more total syntheses of lupinine followed between 1940 and 1956, with the first enantioselective synthesis of lupinine occurring in 1966 by Goldberg and Ragade.{{Cite journal |last1=Goldberg |first1=Stanley I. |last2=Ragade |first2=Indukanth |date=April 1967 |title=A total synthesis of optically active lupinine without benefit of resolution |journal=The Journal of Organic Chemistry |language=EN |volume=32 |issue=4 |pages=1046–1050 |doi=10.1021/jo01279a039 |pmid=6042140 |issn=0022-3263}} Since that initial enantioselective synthesis, there have been numerous total syntheses of both enantio-pure and racemic lupinine. One synthesis, notable because it describes the preparation of all four stereoisomers of lupinine, and containing many references to earlier work in this field, was published by Ma and Ni.{{Cite journal |last1=Ma |first1=Shengming |last2=Ni |first2=Bukuo |date=2004-07-05 |title=Double Ring-Closing Metathesis Reaction of Nitrogen-Containing Tetraenes: Efficient Construction of Bicyclic Alkaloid Skeletons and Synthetic Application to Four Stereoisomers of Lupinine and Their Derivatives |journal=Chemistry - A European Journal |language=en |volume=10 |issue=13 |pages=3286–3300 |doi=10.1002/chem.200305581 |pmid=15224338 |issn=0947-6539}} Another total synthesis of specific note due to the enantioselectivity and limited number of steps is by Santos et al. In 2010, Santos et al. synthesized enantioselective (-)- lupinine in 36% yield over eight steps using a double Mitsunobu Reaction.{{Cite journal |last1=Santos |first1=Leonardo |last2=Mirabal-Gallardo |first2=Yaneris |last3=Shankaraiah |first3=Nagula |last4=Simirgiotis |first4=Mario |date=2010-12-08 |title=Short Total Synthesis of (-)-Lupinine and (-)-Epiquinamide by Double Mitsunobu Reaction |journal=Synthesis |language=en |volume=2011 |issue=1 |pages=51–56 |doi=10.1055/s-0030-1258356 |issn=0039-7881 |hdl=10533/132744|hdl-access=free}} First, they employed asymmetric addition of the starting materials using a Lewis acid, followed by treatment with a reducing agent and a base. This gave the (R,R)-alcohol. This configuration was inverted using a Mitsunobu reaction followed by hydrolysis, affording the (R,S) configuration of the alcohol. The alcohol was then reduced with alane, underwent another Mitsunobu reaction, was hydrolyzed to the acid and finally reduced to (-)-lupinine via alane reduction.

File:Lupinine_Graphic_4.png

One of the earliest isolations of lupinine, from Lupinus palmeri collected in Utah, USA, is that reported by Couch, who was able to obtain crystalline lupinine without the use of chromatographic techniques.{{cite journal |author=J. F. Couch |year=1934 |title=Lupine Studies. VIII. The Alkaloids of Lupinus Palmeri, S. Wats |journal=J. Am. Chem. Soc. |volume=56 |issue=11 |pages=2434–2436 |doi=10.1021/ja01326a067|bibcode=1934JAChS..56.2434C }}

File:The_larva_of_a_Culicine_Mosquito_hanging_down_from_the_surfa_Wellcome_V0022597.jpg

Lupinine is an insect antifeedant. Studies of its insecticide activity have shown it to be effective against culicine mosquito larvae which are vectors for viruses, filarial worms, and avian malaria.{{Cite journal |last1=Campbell |first1=F. L. |last2=Sullivan |first2=W. N. |last3=Smith |first3=C. R. |date=1933-04-01 |title=The Relative Toxicity of Nicotine, Anabasine, Methyl Anabasine, and Lupinine for Culicine Mosquito Larvae |journal=Journal of Economic Entomology |language=en |volume=26 |issue=2 |pages=500–509 |doi=10.1093/jee/26.2.500 |issn=1938-291X}}{{Cite journal |last1=Molina-Cruz |first1=Alvaro |last2=Lehmann |first2=Tovi |last3=Knöckel |first3=Julia |date=2013 |title=Could culicine mosquitoes transmit human malaria? |journal=Trends in Parasitology |volume=29 |issue=11 |pages=530–537 |doi=10.1016/j.pt.2013.09.003 |pmid=24140295 |issn=1471-4922|pmc=10987011 }}

Lupins are often found growing with Castilleja (Indian paintbrush) which uses lupins as a host and confers lupinine and other alkaloids to itself. This works in tandem with the increase in nitrogen fixation to increase parasitic reproduction rates and potentially reduce herbivory activity; however, studies have shown mixed results in the efficacy of alkaloid transfer in prevention of herbivory activity.{{Cite journal |last=Adler |first=Lynn S. |date=2003 |journal=Ecology |language=en |volume=84 |issue=8 |pages=2083–2091 |doi=10.1890/02-0542 |issn=0012-9658 |hdl=10919/46839 |url=http://works.bepress.com/cgi/viewcontent.cgi?article=1011&context=lynn_adler |title=Host Species Affects Herbivory, Pollination, and Reproduction in Experiments with Parasitic Castilleja|bibcode=2003Ecol...84.2083A |hdl-access=free}}

The European Chemicals Agency (ECA) labels lupinine under the hazard statement codes H302, H312, and H332, which indicate that lupinine is harmful if swallowed, harmful in contact with skin, and harmful if inhaled, respectively. It is given a GHS07 labeling which indicates its acute oral toxicity is category 4.{{Cite web |url=https://www.echa.europa.eu/web/guest/information-on-chemicals/cl-inventory-database/-/discli/details/100172 |title=Classifications - CL Inventory |website=www.echa.europa.eu |language=en-GB |access-date=2018-04-25}}

• Lupin poisoning
• Sparteine

• {{Commons category-inline}}

Category:Quinolizidine alkaloids

Category:Primary alcohols

Category:Alkaloids found in Fabaceae

Category:Plant toxins