Ergocryptine
{{Short description|Chemical compound}}
{{Distinguish|Ergocristine}}
{{Drugbox
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| verifiedrevid = 422827080
| IUPAC_name =
| image = Ergocryptine.svg
| width = 250
| drug_name = α-Ergocryptine
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| IUPHAR_ligand = 271
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 511-09-1
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 6WFB60157B
| ATC_prefix =
| ATC_suffix =
| PubChem = 134551
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1403281
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| ChemSpiderID = 118591
| smiles = O=C3N1CCC[C@H]1[C@]2(O)O[C@](C(=O)N2[C@H]3CC(C)C)(NC(=O)[C@@H]7/C=C6/c4cccc5c4c(c[nH]5)C[C@H]6N(C)C7)C(C)C
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C32H41N5O5/c1-17(2)12-25-29(39)36-11-7-10-26(36)32(41)37(25)30(40)31(42-32,18(3)4)34-28(38)20-13-22-21-8-6-9-23-27(21)19(15-33-23)14-24(22)35(5)16-20/h6,8-9,13,15,17-18,20,24-26,33,41H,7,10-12,14,16H2,1-5H3,(H,34,38)/t20-,24-,25+,26+,31-,32+/m1/s1
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = YDOTUXAWKBPQJW-NSLWYYNWSA-N
| C=32 | H=41 | N=5 | O=5
}}
{{Chembox
| Name = β-Ergocryptine
| ImageFile = Beta-Ergocryptine.svg
| ImageSize = 250px
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| IUPACName =
| OtherNames = (5'αS)-sec-Butyl-12'-hydroxy-2'-isopropylergotaman-3',6',18-trione
|Section1={{Chembox Identifiers
| IUPHAR_ligand = 988
| CASNo = 20315-46-2
| CASNo_Ref = {{cascite|correct|CAS}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 6ZAY944SI4
| ChemSpiderID = 141699
| EINECS = 243-728-6
| PubChem = 161309
| InChI=1S/C32H41N5O5/c1-6-18(4)27-29(39)36-12-8-11-25(36)32(41)37(27)30(40)31(42-32,17(2)3)34-28(38)20-13-22-21-9-7-10-23-26(21)19(15-33-23)14-24(22)35(5)16-20/h7,9-10,13,15,17-18,20,24-25,27,33,41H,6,8,11-12,14,16H2,1-5H3,(H,34,38)/t18-,20+,24+,25-,27+,31+,32-/m0/s1
| InChIKey= YYWXOXLDOMRDHW-SGVWFJRMSA-N
| SMILES = CC[C@H](C)[C@@H]1C(=O)N2CCC[C@H]2[C@]3(N1C(=O)[C@](O3)(C(C)C)NC(=O)[C@H]4CN([C@@H]5CC6=CNC7=CC=CC(=C67)C5=C4)C)O}}
|Section2={{Chembox Properties
| C=32 | H=41 | N=5 | O=5
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|Section3={{Chembox Hazards
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Ergocryptine is an ergopeptine and one of the ergoline alkaloids. It is isolated from ergot or fermentation broth and it serves as starting material for the production of bromocriptine.{{cite book | vauthors = Kren V, Cvak L | title = Ergot: the genus Claviceps | url = https://archive.org/details/ergotgenusclavic00kenv | url-access = limited | location = Amsterdam | publisher = Harwood Academic Publishers | date = 1999 | pages = [https://archive.org/details/ergotgenusclavic00kenv/page/n405 399]–401 | isbn = 9789057023750 }} Two isomers of ergocryptine exist, α-ergocryptine and β-ergocryptine.{{cite journal| vauthors = Yates SG, Plattner RD, Garner GB |doi=10.1021/jf00064a038 |title=Detection of ergopeptine alkaloids in endophyte-infected, toxic Ky-31 tall fescue by mass spectrometry/mass spectrometry |journal=Journal of Agricultural and Food Chemistry |volume=33 |issue=4 |pages=719–722 |year=1985 |bibcode=1985JAFC...33..719Y |url=http://ddr.nal.usda.gov/bitstream/10113/23986/1/IND86034816.pdf }}{{dead link|date=December 2016 |bot=InternetArchiveBot |fix-attempted=yes }} The beta differs from the alpha form only in the position of a single methyl group, which is a consequence of the biosynthesis in which the proteinogenic amino acid leucine is replaced by isoleucine. β-Ergocryptine was first identified in 1967 by Albert Hofmann.{{cite journal | vauthors = Schlientz W, Brunner R, Rüegger A, Berde B, Stürmer E, Hofman A | title = Beta-ergokryptine, a new alkaloid of the ergotoxine group | journal = Experientia | volume = 23 | issue = 12 | pages = 991–992 | date = December 1967 | pmid = 4965668 | doi = 10.1007/BF02136400 | s2cid = 2328419 }} Ergot from different sources have different ratios of the two isomers.{{cite journal | title = Ergot alkaloids. LXVII. β-Ergocryptine, a new alkaloid of the ergotoxin series | vauthors = Schlientz W, Brunner R, Ruegger A, Berde B, Stuermer E, Hofmann A | journal = Pharmaceutica Acta Helvetiae | date = 1968 | volume = 43 | issue = 8 | pages = 497–509 }}
Biosynthesis
The biosynthetic pathways to ergocryptine starts with the prenylation of L-tryptophan in an SN1 fashion with dimethylallyl pyrophosphate (DMAPP). DMAPP is derived from mevalonic acid. This reaction is catalyzed by a prenyltransferase enzyme (Prenyltransferase 4-dimethylallyltryptophan synthase) named FgaPT2 in Aspergillus fumigatus.{{cite journal | vauthors = Lee SL, Floss HG, Heinstein P | title = Purification and properties of dimethylallylpyrophosphate:tryptopharm dimethylallyl transferase, the first enzyme of ergot alkaloid biosynthesis in Claviceps. sp. SD 58 | journal = Archives of Biochemistry and Biophysics | volume = 177 | issue = 1 | pages = 84–94 | date = November 1976 | pmid = 999297 | doi = 10.1016/0003-9861(76)90418-5 }}{{cite journal | vauthors = Gerhards N, Neubauer L, Tudzynski P, Li SM | title = Biosynthetic pathways of ergot alkaloids | journal = Toxins | volume = 6 | issue = 12 | pages = 3281–3295 | date = December 2014 | pmid = 25513893 | pmc = 4280535 | doi = 10.3390/toxins6123281 | doi-access = free }} An X-ray structure of the prenyltransferase FgaPT2 and tryptophan has been reported, and used to propose a three step mechanism: (1) formation of allylic carbocation; (2) nucleophile attack of tryptophan on the carbocation; (3) deprotonation to restore aromaticity and generate the product, 4-dimethylallyltryptophan (DMAT). DMAT is then N-methylated at the amino of the tryptophan backbone with the EasF enzyme, named FgaMT in A. fumigatus. S-adenosylmethionine (SAM) being the methyl source.{{cite journal | vauthors = Rigbers O, Li SM | title = Ergot alkaloid biosynthesis in Aspergillus fumigatus. Overproduction and biochemical characterization of a 4-dimethylallyltryptophan N-methyltransferase | journal = The Journal of Biological Chemistry | volume = 283 | issue = 40 | pages = 26859–26868 | date = October 2008 | pmid = 18678866 | doi = 10.1074/jbc.M804979200 | doi-access = free }}
The next step in the biosynthesis of ergocryptine is the transformation of 4-dimethylallyl abrine to Chanoclavine-I. It has been shown that the [enzyme EasE and EasC (FgaOx1 and FgaCat in A. fumigatus, respectively) are both required to generate Chanoclavine-I from 4-DMA abrine.{{cite journal | vauthors = Goetz KE, Coyle CM, Cheng JZ, O'Connor SE, Panaccione DG | title = Ergot cluster-encoded catalase is required for synthesis of chanoclavine-I in Aspergillus fumigatus | journal = Current Genetics | volume = 57 | issue = 3 | pages = 201–211 | date = June 2011 | pmid = 21409592 | doi = 10.1007/s00294-011-0336-4 | s2cid = 3031547 }} Mutation experiments altering these enzymes independently stopped the pathway at abrine. This indicates that cooperation between EasE and EasC is necessary.
Fig2- ergot alkaloid biosynthesis
Fig3 - part 3 in biosynthesis of ergocryptine
Chanocalvine-I is then oxidized to chanoclavine-I aldehyde with NAD+ dependent enzyme EasD (FgaDH in A. fumigatus). Chanoclavine-I aldehyde is a branch point, leading to different ergot alkaloids, depending on the specific fungus. In C. purpurea, chanoclavine-I aldehyde is converted to argoclavine with EasA, referred to as the old yellow enzyme or FgaOx3. This process occurs via keto-enol tautomerization to facilitate rotation about a carbon-carbon bond, followed by tautomerization back to the aldehyde, and condensation with the proximal secondary amine.{{cite journal | vauthors = Coyle CM, Cheng JZ, O'Connor SE, Panaccione DG | title = An old yellow enzyme gene controls the branch point between Aspergillus fumigatus and Claviceps purpurea ergot alkaloid pathways | journal = Applied and Environmental Microbiology | volume = 76 | issue = 12 | pages = 3898–3903 | date = June 2010 | pmid = 20435769 | pmc = 2893504 | doi = 10.1128/AEM.02914-09 | bibcode = 2010ApEnM..76.3898C }} The iminium species created by cyclization is then reduced to the tertiary amine, yielding agroclavine.
Fig3-detail look at mechanism in biosynthesis of ergocryptine
A cytochrome P-450 monooxygenase enzyme catalyzes a two electron oxidation of agroclavne to the corresponding primary alcohol, elymoclavine.{{cite journal | vauthors = Haarmann T, Machado C, Lübbe Y, Correia T, Schardl CL, Panaccione DG, Tudzynski P | title = The ergot alkaloid gene cluster in Claviceps purpurea: extension of the cluster sequence and intra species evolution | journal = Phytochemistry | volume = 66 | issue = 11 | pages = 1312–1320 | date = June 2005 | pmid = 15904941 | doi = 10.1016/j.phytochem.2005.04.011 | bibcode = 2005PChem..66.1312H }} Elymoclavine is then oxidized by four electrons by a P450 monooxygenase to give paspalic acid. Paspalic acid then undergoes isomerization of the carbon-carbon double bond that is in conjugation with the acid, to give D-lysergic acid.
Fig4 - part 4 in biosynthesis of ergot alkaloid ergocryptine
Lysergic Acid is a branch point in the biosynthesis of ergoamides and ergopeptines. On the path to ergocryptine, an ergopeptine, the tripeptide is installed by a Non-Ribosomal Peptide Synthase (NRPS). It has been shown that there are two enzymes, D-lysergyl peptide synthases (LPS) 1 and 2, which are responsible for the tripeptide connection to lysergic acid.{{cite journal | vauthors = Walzel B, Riederer B, Keller U | title = Mechanism of alkaloid cyclopeptide synthesis in the ergot fungus Claviceps purpurea | journal = Chemistry & Biology | volume = 4 | issue = 3 | pages = 223–230 | date = March 1997 | pmid = 9115414 | doi = 10.1016/s1074-5521(97)90292-1 | doi-access = free }} The timing of the oxidation of valine to an alcohol is not exactly known. However, it is speculated that the oxidation occurs while bound to the NRPS LPS2.{{cite book | vauthors = Keller U | title = Genetics and Biochemistry of Antibiotic Production | publisher = Butterworth-Heinemann | location = Boston | date = 1995 }} Ergocryptine is found in two forms, differing in the amino acid used by the NRPS. The alpha form contains the amino acid leucine, while the beta-form uses the amino acid isoleucine.
