3o2k

From Proteopedia
Jump to navigation Jump to search

Crystal Structure of Brevianamide F Prenyltransferase Complexed with Brevianamide F and Dimethylallyl S-thiolodiphosphateCrystal Structure of Brevianamide F Prenyltransferase Complexed with Brevianamide F and Dimethylallyl S-thiolodiphosphate

Structural highlights

3o2k is a 1 chain structure with sequence from Aspergillus fumigatus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.4Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FTMB_ASPFU Brevianamide F prenyltransferase; part of the gene cluster that mediates the biosynthesis of fumitremorgins, indole alkaloids that carry not only intriguing chemical structures, but also interesting biological and pharmacological activities (PubMed:16000710, PubMed:23649274). The biosynthesis of fumitremorgin-type alkaloids begins by condensation of the two amino acids L-tryptophan and L-proline to brevianamide F, catalyzed by the non-ribosomal peptide synthetase ftmA (PubMed:16755625). Brevianamide F is then prenylated by the prenyltransferase ftmPT1/ftmB in the presence of dimethylallyl diphosphate, resulting in the formation of tryprostatin B (PubMed:16000710, PubMed:19113967, PubMed:21105662, PubMed:23090579). FtmPT1/ftmB shows also tryptophan aminopeptidase activity with preference for linear peptides containing a tryptophanyl moiety at the N-terminus (PubMed:18635009). The three cytochrome P450 monooxygenases, ftmP450-1/ftmC, ftmP450-2/ftmE and ftmP450-3/FtmG, are responsible for the conversion of tryprostatin B to 6-hydroxytryprostatin B, tryprostatin A to fumitremorgin C and fumitremorgin C to 12,13-dihydroxyfumitremorgin C, respectively (PubMed:19226505). The putative methyltransferase ftmMT/ftmD is expected for the conversion of 6-hydroxytryprostatin B to tryprostatin A (Probable). FtmPT2/FtmH catalyzes the prenylation of 12,13-dihydroxyfumitre-morgin C in the presence of dimethylallyl diphosphate, resulting in the formation of fumitremorgin B (PubMed:18683158). Fumitremorgin B is further converted to verruculogen by ftmOx1/ftmF via the insertion of an endoperoxide bond between the two prenyl moieties (PubMed:19763315). In some fungal species, verruculogen is further converted to fumitremorgin A, but the enzymes involved in this step have not been identified yet (Probable).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

Publication Abstract from PubMed

Fungal 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[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Grundmann A, Li SM. Overproduction, purification and characterization of FtmPT1, a brevianamide F prenyltransferase from Aspergillus fumigatus. Microbiology. 2005 Jul;151(Pt 7):2199-207. PMID:16000710 doi:http://dx.doi.org/10.1099/mic.0.27962-0
  2. ↑ Maiya S, Grundmann A, Li SM, Turner G. The fumitremorgin gene cluster of Aspergillus fumigatus: identification of a gene encoding brevianamide F synthetase. Chembiochem. 2006 Jul;7(7):1062-9. PMID:16755625 doi:10.1002/cbic.200600003
  3. ↑ Kremer A, Li SM. Tryptophan aminopeptidase activity of several indole prenyltransferases from Aspergillus fumigatus. Chem Biol. 2008 Jul 21;15(7):729-38. PMID:18635009 doi:10.1016/j.chembiol.2008.05.019
  4. ↑ Grundmann A, Kuznetsova T, Afiyatullov SSh, Li SM. FtmPT2, an N-prenyltransferase from Aspergillus fumigatus, catalyses the last step in the biosynthesis of fumitremorgin B. Chembiochem. 2008 Sep 1;9(13):2059-63. PMID:18683158 doi:10.1002/cbic.200800240
  5. ↑ Zou H, Zheng X, Li SM. Substrate promiscuity of the cyclic dipeptide prenyltransferases from Aspergillus fumigatus ( section sign). J Nat Prod. 2009 Jan;72(1):44-52. PMID:19113967 doi:10.1021/np800501m
  6. ↑ Kato N, Suzuki H, Takagi H, Asami Y, Kakeya H, Uramoto M, Usui T, Takahashi S, Sugimoto Y, Osada H. Identification of cytochrome P450s required for fumitremorgin biosynthesis in Aspergillus fumigatus. Chembiochem. 2009 Mar 23;10(5):920-8. PMID:19226505 doi:10.1002/cbic.200800787
  7. ↑ Steffan N, Grundmann A, Afiyatullov S, Ruan H, Li SM. FtmOx1, a non-heme Fe(II) and alpha-ketoglutarate-dependent dioxygenase, catalyses the endoperoxide formation of verruculogen in Aspergillus fumigatus. Org Biomol Chem. 2009 Oct 7;7(19):4082-7. doi: 10.1039/b908392h. Epub 2009 Aug 6. PMID:19763315 doi:http://dx.doi.org/10.1039/b908392h
  8. ↑ Jost M, Zocher G, Tarcz S, Matuschek M, Xie X, Li SM, Stehle T. Structure-Function Analysis of an Enzymatic Prenyl Transfer Reaction Identifies a Reaction Chamber with Modifiable Specificity. J Am Chem Soc. 2010 Nov 24. PMID:21105662 doi:10.1021/ja106817c
  9. ↑ Wollinsky B, Ludwig L, Xie X, Li SM. Breaking the regioselectivity of indole prenyltransferases: identification of regular C3-prenylated hexahydropyrrolo[2,3-b]indoles as side products of the regular C2-prenyltransferase FtmPT1. Org Biomol Chem. 2012 Dec 14;10(46):9262-70. doi: 10.1039/c2ob26149a. Epub 2012, Oct 23. PMID:23090579 doi:http://dx.doi.org/10.1039/c2ob26149a
  10. ↑ Kato N, Suzuki H, Okumura H, Takahashi S, Osada H. A point mutation in ftmD blocks the fumitremorgin biosynthetic pathway in Aspergillus fumigatus strain Af293. Biosci Biotechnol Biochem. 2013;77(5):1061-7. PMID:23649274 doi:10.1271/bbb.130026
  11. ↑ Grundmann A, Li SM. Overproduction, purification and characterization of FtmPT1, a brevianamide F prenyltransferase from Aspergillus fumigatus. Microbiology. 2005 Jul;151(Pt 7):2199-207. PMID:16000710 doi:http://dx.doi.org/10.1099/mic.0.27962-0
  12. ↑ Jost M, Zocher G, Tarcz S, Matuschek M, Xie X, Li SM, Stehle T. Structure-Function Analysis of an Enzymatic Prenyl Transfer Reaction Identifies a Reaction Chamber with Modifiable Specificity. J Am Chem Soc. 2010 Nov 24. PMID:21105662 doi:10.1021/ja106817c

3o2k, resolution 2.40Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=3o2k&oldid=3868639"