STEREOCHEMISTRY OF THE ISOPRENYLATION OF TRYPTOPHAN CATALYZED BY 4-(GAMMA,GAMMA-DIMETHYLALLYL)TRYPTOPHAN SYNTHASE FROM CLAVICEPS, THE 1ST PATHWAY-SPECIFIC ENZYME IN ERGOT ALKALOID BIOSYNTHESIS

The first pathway-specific reaction in ergot alkaloid biosynthesis, the isoprenylation of tryptophan catalyzed by 4-(γ, γ-dimethylallyl)tryptophan (DMAT) synthase, involves displacement of the allylic pyrophosphate moiety by C-4 of the indole ring with inversion of configuration at C-1 of dimethylallyl pyrophosphate (DMAPP). The geometry of the allylic double bond is retained, and no scrambling of labeled hydrogens between the two methyl groups is observed in the reaction. Occurrence of 8-10% scrambling of a13C label from C-2 of mevalonate between C-7 and C-17 of elymoclavine was confirmed, and it was shown (i) that this scrambling must take place in the formation of DMAPP from mevalonate and (ii) that it is unrelated to another partial scrambling of label, between the two hydrogens derived from C-5 of mevalonate, also observed in ergot alkaloid formation. The results are fully consistent with a mechanism for DMAT synthase involving direct attack of DMAPP on C-4 of the indole, possibly through a stabilized allylic carbocation or ion pair as intermediate. © 1990, American Chemical Society. All rights reserved.