Ergocryptine is an ergopeptine and one of the ergolinealkaloids. 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 acidleucine 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]
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.
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.
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.
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]
^Schlientz W, Brunner R, Rüegger A, Berde B, Stürmer E, Hofman A (December 1967). "Beta-ergokryptine, a new alkaloid of the ergotoxine group". Experientia. 23 (12): 991–992. doi:10.1007/BF02136400. PMID4965668. S2CID2328419.
^Schlientz W, Brunner R, Ruegger A, Berde B, Stuermer E, Hofmann A (1968). "Ergot alkaloids. LXVII. β-Ergocryptine, a new alkaloid of the ergotoxin series". Pharmaceutica Acta Helvetiae. 43 (8): 497–509.
^Lee SL, Floss HG, Heinstein P (November 1976). "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. doi:10.1016/0003-9861(76)90418-5. PMID999297.
^Goetz KE, Coyle CM, Cheng JZ, O'Connor SE, Panaccione DG (June 2011). "Ergot cluster-encoded catalase is required for synthesis of chanoclavine-I in Aspergillus fumigatus". Current Genetics. 57 (3): 201–211. doi:10.1007/s00294-011-0336-4. PMID21409592. S2CID3031547.
^Haarmann T, Machado C, Lübbe Y, Correia T, Schardl CL, Panaccione DG, Tudzynski P (June 2005). "The ergot alkaloid gene cluster in Claviceps purpurea: extension of the cluster sequence and intra species evolution". Phytochemistry. 66 (11): 1312–1320. Bibcode:2005PChem..66.1312H. doi:10.1016/j.phytochem.2005.04.011. PMID15904941.
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