Biosynthese Des Peptidteils Der Mutterkornalkaloide Vom Cyclol–typ

Abstract

A review is given on the biosynthesis o f the peptide moiety in ergot alkaloids.Feeding experiments with labeled amino acids have revealed that phenylalanine, proline, valine and leucine are specifically incorporated into the appropriate constituents of the peptides of ergotamine, ergocornine and ergokryptine, respectively. The a-hydroxy-&-amino acid residue of the ergotoxine alkaloids is derived from valine. In the case of ergotamine alanine or a close relative is the immediate precursor of the hydroxyamino acid fragment.The exact mechanism of cyclol formation in ergot alkaloid biosynthesis is not yet clarified. Abe's group in Japan has found the intact incorporation of lysergylalanine and lysergylvaline in peptide alkaloids of various ergot strains. Furthermore they demonstrated the incorporation of L-lezrcyl-L-proline lactam and Lphenylalanyl-l-proline-lactam in ergokryptine and ergotamine, respectively. Other authors (Floss, Groger) did not confirm these results. They have tested the possible involvement o f free simple lysergic acid derivatives, various di-and tripeptides as well as the corresponding diketopiperazines. In these experiments the added precursors were split by the fulzgus into the correspo~zding compounds (lysergic acid and amino acids) prior to incorporation into the peptide moitety o f ergot alkaloids. Based on these results and on inhibitor experiments one may speculate that the synthesis o f the peptide portion is a nonribosomal process. Apparently like in the biosynthesis of peptide antibiotics the peptide chain formation takes place on a multienzyme complex. EinfiihrungBislang sind etwa 50 Mutterkornalkaloide bekannt. Die iiberwiegende Zahl dieser Indolalkaloide wurde aus verschiedenen Claviceps-Arten isoliert. Lange Zeit war man der Ansicht, dat3 nur Vertreter dieser Ascomyceten-Gattung in der Heruntergeladen von: University of Illinois. Urheberrechtlich geschützt.

Multifunctional Peptide Synthetases

“…Numerous studies of in vitro and in vivo biosynthesis of alkaloid peptides have been performed by academic and industrial groups aiming to widen the pharmacological spectrum of these compounds. [147][148][149][150] These studies have helped to clarify the biosynthetic origins of the ergoline ring system of D-lysergic acid and of the amino acids of the peptide portion of these compounds, the latter being derived from the cellular amino acid pool. 151 In vivo experiments provided indirect evidence that D-lysergic acid peptides are synthesized by a mechanism resembling the formation of antibiotic peptides of bacterial and fungal origin.…”

“…151 In vivo experiments provided indirect evidence that D-lysergic acid peptides are synthesized by a mechanism resembling the formation of antibiotic peptides of bacterial and fungal origin. 150 However, enzymatic investigations of Dlysergyl peptide assembly were hampered by the apparent instability of the enzyme system responsible for ergopeptine formation in Claviceps purpurea. In addition, the question as to which chemical form of the precursor of peptide-bound D-lysergic acidsi.e., either free D-lysergic acid, D-lysergyl Coenzyme A, or a simple clavinesmay serve as substrate in the assembly process remained a central controversial issue in these investigations.…”

“…The structures of acylpeptide lactones with aromatic side chains have been reviewed elsewhere. 150,164 Many of these compounds have therapeutic value as antibiotics or antitumor reagents. The enzymatic steps in the biosyntheses of the different aromatic acyl peptide lactones appear to be similar.…”

“…Numerous studies of in vitro and in vivo biosynthesis of alkaloid peptides have been performed by academic and industrial groups aiming to widen the pharmacological spectrum of these compounds. − These studies have helped to clarify the biosynthetic origins of the ergoline ring system of d -lysergic acid and of the amino acids of the peptide portion of these compounds, the latter being derived from the cellular amino acid pool . However, enzymatic investigations of d -lysergyl peptide assembly were hampered by the apparent instability of the enzyme system responsible for ergopeptine formation in Claviceps purpurea .…”

“…They are almost exclusively produced by streptomycetes. , These compounds combine nearly all features of peptide structural elements containing l - and d -, as well as N -methylated, amino acids. The structures of acylpeptide lactones with aromatic side chains have been reviewed elsewhere. , Many of these compounds have therapeutic value as antibiotics or antitumor reagents. The enzymatic steps in the biosyntheses of the different aromatic acyl peptide lactones appear to be similar. , Much of the knowledge of these pathways has been obtained from studies of the biosynthesis of actinomycin.…”