3o2k
From Proteopedia
Crystal Structure of Brevianamide F Prenyltransferase Complexed with Brevianamide F and Dimethylallyl S-thiolodiphosphate
Structural highlights
Function[Q4G2I1_ASPFM] Catalyzes the prenylation of brevianamide F. Can also prenylate other tryptophan-containing cyclic dipeptides. Prenylation occurs mainly at C-2, but also at C-3.[1] [2] Publication Abstract from PubMedFungal indole prenyltransferases participate in a multitude of biosynthetic pathways. Their ability to prenylate diverse substrates has attracted interest for potential use in chemoenzymatic synthesis. The fungal indole prenyltransferase FtmPT1 catalyzes the prenylation of brevianamide F in the biosynthesis of fumitremorgin-type alkaloids, which show diverse pharmacological activities and are promising candidates for the development of antitumor agents. Here, we report crystal structures of unliganded Aspergillus fumigatus FtmPT1 as well as of a ternary complex of FtmPT1 bound to brevianamide F and an analogue of its isoprenoid substrate dimethylallyl diphosphate. FtmPT1 assumes a rare alpha/beta-barrel fold, consisting of 10 circularly arranged beta-strands surrounded by alpha-helices. Catalysis is performed in a hydrophobic reaction chamber at the center of the barrel. In combination with mutagenesis experiments, our analysis of the liganded and unliganded structures provides insight into the mechanism of catalysis and the determinants of regiospecificity. Sequence conservation of key features indicates that all fungal indole prenyltransferases possess similar active site architectures. However, while the dimethylallyl diphosphate binding site is strictly conserved in these enzymes, subtle changes in the reaction chamber likely allow for the accommodation of diverse aromatic substrates for prenylation. In support of this concept, we were able to redirect the regioselectivity of FtmPT1 by a single mutation of glycine 115 to threonine. This finding provides support for a potential use of fungal indole prenyltransferases as modifiable bioreactors that can be engineered to catalyze highly specific prenyl transfer reactions. Structure-Function Analysis of an Enzymatic Prenyl Transfer Reaction Identifies a Reaction Chamber with Modifiable Specificity.,Jost M, Zocher G, Tarcz S, Matuschek M, Xie X, Li SM, Stehle T J Am Chem Soc. 2010 Nov 24. PMID:21105662[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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