{{Chembox | ImageFile = Protopine structure.svg | ImageClass = skin-invert-image | ImageSize = | ImageFile1 = Protopine-from-xtal-Mercury-3D-balls.png | ImageClass1 = bg-transparent | IUPACName = 7-Methyl-2′''H'',2′′''H''-7,13a-secobis([1,3]dioxolo)[4′,5′:2,3;4′′,5′′:9,10]berbin-13a-one | SystematicName = 5-Methyl-4,6,7,14-tetrahydro-2''H'',10''H''-bis([1,3]benzodioxolo)[4,5-''c'':5′,6′-''g'']azecin-13(5''H'')-one | Reference = <ref>{{cite book|title=The Merck Index|publisher=Merck & Co|location=New Jersey|year=1976|edition=9|page=1023}}</ref> |Section1={{Chembox Identifiers | CASNo_Ref = {{cascite|correct|??}} | CASNo = 130-86-9 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = UIW569HT35 | PubChem = 4970 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 453019<!--486179 different isomer, inchi does not match--> | SMILES = c15cc3OCOc3cc5CCN(C)Cc2c(CC1=O)ccc4c2OCO4 | EINECS = 204-999-6 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 4799 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C20H19NO5/c1-21-5-4-13-7-18-19(25-10-24-18)8-14(13)16(22)6-12-2-3-17-20(15(12)9-21)26-11-23-17/h2-3,7-8H,4-6,9-11H2,1H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = GPTFURBXHJWNHR-UHFFFAOYSA-N | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 16415 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = C05189 }} |Section2={{Chembox Properties | Formula = C<sub>20</sub>H<sub>19</sub>NO<sub>5</sub> | MolarMass = 353.369 g/mol | Appearance = white crystals | Density = 1.399 g/cm<sup>3</sup> | MeltingPtC = 208 | BoilingPt = | Solubility = practically insoluble | SolubleOther = 1:15 | Solvent = chloroform }} }}

'''Protopine''' is an alkaloid occurring in opium poppy,<ref>[http://www.thefreedictionary.com/Protopine The Free Dictionary: Protopine]</ref> ''Corydalis'' tubers<ref>{{cite journal |doi=10.1016/j.ejphar.2004.11.004|pmid=15588728 |year=2004 |last1=Jiang |first1=B |last2=Cao |first2=K |last3=Wang |first3=R |title=Inhibitory effect of protopine on K(ATP) channel subunits expressed in HEK-293 cells.|volume=506|issue=2|pages=93–100|journal=European Journal of Pharmacology}}</ref> and other plants of the family papaveraceae, like ''Fumaria officinalis''.<ref>{{cite journal |last1= Vrba |first1= Jiri |last2= Vrublova |first2= Eva |last3= Modriansky |first3= Martin |last4= Ulrichova |first4= Jitka |title= Protopine and allocryptopine increase mRNA levels of cytochromes P450 1A in human hepatocytes and HepG2 cells independently of AhR |journal= Toxicology Letters |date= 2011 |volume= 203 |issue= 2 |pages= 135–141 |doi= 10.1016/j.toxlet.2011.03.015 |pmid= 21419197 }}</ref>

It has been found to inhibit histamine H1 receptors and platelet aggregation, and acts as an analgesic.<ref>{{cite journal|pmid=9368908|year=1997|last1=Saeed|first1=SA|last2=Gilani|last3=Majoo|last4=Shah|title=Anti-thrombotic and anti-inflammatory activities of protopine.|volume=36|issue=1|pages=1–7|doi=10.1006/phrs.1997.0195|journal=Pharmacological Research|first2=AH|first3=RU|first4=BH}}</ref><ref>{{MeshName|Protopine}}</ref>

==Biosynthesis== Protopine is derived in the plants such as the opium poppy, ''Papaver somniferum'', from the benzylisoquinoline alkaloid (''S'')-reticuline through a progressive series of five enzymatic transformations: 1) berberine bridge enzyme to (''S'')-scoulerine; 2) (''S'')-cheilanthifoline synthase/CYP719A25 to (''S'')-cheilanthifoline; 3)&nbsp; (''S'')-stylopine synthase/CYP719A20 to (''S'')-stylopine; 4) (''S'')-tetrahydroprotoberberine ''N''-methyltransferase to (''S'')-''cis''-''N''-methylstylopine.<ref>{{Cite journal|last=Hagel|first=Jillian M|last2=Morris|first2=Jeremy S|last3=Lee|first3=Eun-Jeong|last4=Desgagne-Penix|first4=Isabel|last5=Bross|first5=Crystal D|last6=Chang|first6=Limei|last7=Chen|first7=Xue|last8=Farrow|first8=Scott C|last9=Zhang|first9=Ye|date=2015|title=Transcriptome analysis of 20 taxonomically related benzylisoquinoline alkaloid-producing plants|url=http://openlib.tugraz.at/download.php?id=564f2fa60a35b&location=browse|journal=BMC Plant Biology|volume=15|pages=227|doi=10.1186/s12870-015-0596-0| pmc=4575454 |pmid=26384972|doi-access=free}}</ref>

The final step is oxidation by the enzyme methyltetrahydroprotoberberine 14-monooxygenase:<ref name=NPR>{{cite journal |last1=Tian |first1=Ya |last2=Kong |first2=Lingzhe |last3=Li |first3=Qi |last4=Wang |first4=Yifan |last5=Wang |first5=Yongmiao |last6=An |first6=Zhoujie |last7=Ma |first7=Yuwei |last8=Tian |first8=Lixia |last9=Duan |first9=Baozhong |last10=Sun |first10=Wei |last11=Gao |first11=Ranran |last12=Chen |first12=Shilin |last13=Xu |first13=Zhichao |title=Structural diversity, evolutionary origin, and metabolic engineering of plant specialized benzylisoquinoline alkaloids |journal=Natural Product Reports |date=2024 |volume=41 |issue=11 |pages=1787–1810 |doi=10.1039/d4np00029c |pmid=39360417 }}</ref><ref>{{cite journal |vauthors=Rueffer M, Zenk MH | date = 1987 |title=Enzymatic formation of protopines by a microsomal cytochrome-P-450 system of Corydalis vaginans |journal=Tetrahedron Lett. |volume=28 |pages=5307–5310 |doi=10.1016/S0040-4039(00)96715-7 |issue=44 |url=http://nbn-resolving.de/urn:nbn:de:bvb:19-epub-3622-0 }}</ref>

{{chemrxn|width=60%| {{chemrxn/cpd|qid=Q27105298|caption=(''S'')-''cis''-N-methylstylopine }} {{chemrxn/txt|+ NADPH }} {{chemrxn/arw|fwd_in={{chem2|O2}}|fwd_out={{chem2|H2O}} }} {{chemrxn/cpd|protopine }} {{chemrxn/txt|+ NADP+ }} }}

==Metabolism== The enzyme protopine 6-monooxygenase converts protopine into dihydrosanguinarine.<ref name=NPR/><ref>{{cite journal |last1=Tanahashi |first1=Takao |last2=Zenk |first2=Meinhart H. |title=Elicitor induction and characterization of microsomal protopine-6-hydroxylase, the central enzyme in benzophenanthridine alkaloid biosynthesis |journal=Phytochemistry |date=1990 |volume=29 |issue=4 |pages=1113–1122 |doi=10.1016/0031-9422(90)85414-B }}</ref> NADP<sup>+</sup> and water are the by-products.

{{chemrxn|width=60%| {{chemrxn/cpd|protopine }} {{chemrxn/txt|+ NADPH }} {{chemrxn/arw|fwd_in={{chem2|O2}}|fwd_out={{chem2|H2O}} }} {{chemrxn/cpd|dihydrosanguinarine }} {{chemrxn/txt|+ NADP<sup>+</sup> }} }}

The enzyme uses reduced nicotinamide adenine dinucleotide phosphate (NADPH), and oxygen, with the initial product being 6-hydroxyprotopine, which spontaneously forms dihydrosanguinarine, found in plants such as ''Sanguinaria canadensis''.<ref>{{cite journal |last1=Ignatov |first1=Atanas |last2=Clark |first2=W.Gregg |last3=Cline |first3=Steven D. |last4=Psenak |first4=Mikulas |last5=Krueger |first5=Robert J. |last6=Coscia |first6=Carmine J. |title=Elicitation of dihydrobenzophenanthridine oxidase in Sanguinaria canadensis cell cultures |journal=Phytochemistry |date=1996 |volume=43 |issue=6 |pages=1141–1144 |doi=10.1016/S0031-9422(96)00540-7 |pmid=8987906 }}</ref>

== See also == * Cryptopine * Bürgi-Dunitz angle

== References == {{reflist}} {{Components of Opium}}

Category:Alkaloids found in Papaveraceae Category:Natural opium alkaloids Category:Methylenedioxyphenethylamines Category:Heterocyclic compounds with 5 rings Category:Benzodioxoles Category:Azecines