Chemistry:Ergocryptine

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Short description: Chemical compound
α-Ergocryptine
Ergocryptine.svg
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC32H41N5O5
Molar mass575.710 g·mol−1
3D model (JSmol)
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β-Ergocryptine
Beta-Ergocryptine.svg
Names
Other names
(5'αS)-sec-Butyl-12'-hydroxy-2'-isopropylergotaman-3',6',18-trione
Identifiers
3D model (JSmol)
EC Number
  • 243-728-6
UNII
Properties
C32H41N5O5
Molar mass 575.710 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
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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.[1] Two isomers of ergocryptine exist, α-ergocryptine and β-ergocryptine.[2] 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.[3] Ergot from different sources have different ratios of the two isomers.[4]

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.[5][6] 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).[6] 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.[7]

Ergocryptine-part1 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.[8] 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.[6][9] 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.[10] 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.[11] 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.[12] 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.[6]

Figure 5 - part 5 in the biosynthesis of ergocryptine

See also

References

  1. ↑ Ergot: the genus Claviceps. Amsterdam: Harwood Academic Publishers. 1999. pp. 399–401. ISBN 9789057023750. https://archive.org/details/ergotgenusclavic00kenv. 
  2. ↑ "Detection of ergopeptine alkaloids in endophyte-infected, toxic Ky-31 tall fescue by mass spectrometry/mass spectrometry". Journal of Agricultural and Food Chemistry 33 (4): 719–722. 1985. doi:10.1021/jf00064a038. http://ddr.nal.usda.gov/bitstream/10113/23986/1/IND86034816.pdf. [yes|permanent dead link|dead link}}]
  3. ↑ "Beta-ergokryptine, a new alkaloid of the ergotoxine group". Experientia 23 (12): 991–992. December 1967. doi:10.1007/BF02136400. PMID 4965668. 
  4. ↑ "Ergot alkaloids. LXVII. β-Ergocryptine, a new alkaloid of the ergotoxin series". Pharmaceutica Acta Helvetiae 43 (8): 497–509. 1968. 
  5. ↑ "Purification and properties of dimethylallylpyrophosphate:tryptopharm dimethylallyl transferase, the first enzyme of ergot alkaloid biosynthesis in Claviceps. sp. SD 58". Archives of Biochemistry and Biophysics 177 (1): 84–94. November 1976. doi:10.1016/0003-9861(76)90418-5. PMID 999297. 
  6. ↑ 6.0 6.1 6.2 6.3 "Biosynthetic pathways of ergot alkaloids". Toxins 6 (12): 3281–3295. December 2014. doi:10.3390/toxins6123281. PMID 25513893. 
  7. ↑ "Ergot alkaloid biosynthesis in Aspergillus fumigatus. Overproduction and biochemical characterization of a 4-dimethylallyltryptophan N-methyltransferase". The Journal of Biological Chemistry 283 (40): 26859–26868. October 2008. doi:10.1074/jbc.M804979200. PMID 18678866. 
  8. ↑ "Ergot cluster-encoded catalase is required for synthesis of chanoclavine-I in Aspergillus fumigatus". Current Genetics 57 (3): 201–211. June 2011. doi:10.1007/s00294-011-0336-4. PMID 21409592. 
  9. ↑ "An old yellow enzyme gene controls the branch point between Aspergillus fumigatus and Claviceps purpurea ergot alkaloid pathways". Applied and Environmental Microbiology 76 (12): 3898–3903. June 2010. doi:10.1128/AEM.02914-09. PMID 20435769. Bibcode: 2010ApEnM..76.3898C. 
  10. ↑ "The ergot alkaloid gene cluster in Claviceps purpurea: extension of the cluster sequence and intra species evolution". Phytochemistry 66 (11): 1312–1320. June 2005. doi:10.1016/j.phytochem.2005.04.011. PMID 15904941. Bibcode: 2005PChem..66.1312H. 
  11. ↑ "Mechanism of alkaloid cyclopeptide synthesis in the ergot fungus Claviceps purpurea". Chemistry & Biology 4 (3): 223–230. March 1997. doi:10.1016/s1074-5521(97)90292-1. PMID 9115414. 
  12. ↑ Genetics and Biochemistry of Antibiotic Production. Boston: Butterworth-Heinemann. 1995. 



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