The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria

Ute Metzger; Christoph Schall; Georg Zocher; Inge Unsöld; Edyta Stec; Shu-Ming Li; Lutz Heide; Thilo Stehle

doi:10.1073/pnas.0904897106

Edited by Arnold L. Demain, Drew University, Madison, NJ, and approved July 9, 2009
↵¹U.M. and C.S. contributed equally to this work. (received for review May 5, 2009)

Abstract

Ergot alkaloids are toxins and important pharmaceuticals that are produced biotechnologically on an industrial scale. The first committed step of ergot alkaloid biosynthesis is catalyzed by dimethylallyl tryptophan synthase (DMATS; EC 2.5.1.34). Orthologs of DMATS are found in many fungal genomes. We report here the x-ray structure of DMATS, determined at a resolution of 1.76 Å. A complex of DMATS from Aspergillus fumigatus with its aromatic substrate L-tryptophan and with an analogue of its isoprenoid substrate dimethylallyl diphosphate reveals the structural basis of this enzyme-catalyzed Friedel-Crafts reaction, which shows strict regiospecificity for position 4 of the indole nucleus of tryptophan as well as unusual independence of the presence of Mg²⁺ ions. The 3D structure of DMATS belongs to a rare β/α barrel fold, called prenyltransferase barrel, that was recently discovered in a small group of bacterial enzymes with no sequence similarity to DMATS. These bacterial enzymes catalyze the prenylation of aromatic substrates in the biosynthesis of secondary metabolites (i.e., a reaction similar to that of DMATS).

Footnotes

²To whom correspondence should be addressed at:
Pharmazeutische Biologie, Pharmazeutisches Institut, Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
E-mail: heide{at}uni-tuebingen.de
Author contributions: S.-M.L., L.H., and T.S. designed research; U.M., C.S., G.Z., I.U., and E.S. performed research; U.M., C.S., G.Z., L.H., and T.S. analyzed data; and U.M., C.S., G.Z., L.H., and T.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID codes 3I4X and 3I4Z).
This article contains supporting information online at www.pnas.org/cgi/content/full/0904897106/DCSupplemental.