The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria.
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 A. 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 Mg(2+) ions. The 3D structure of DMATS belongs to a rare beta/alpha 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).
Metzger
Ute
U
Pharmazeutisches Institut, Universität Tübingen, 72076 Tübingen, Germany.
Schall
Christoph
C
Zocher
Georg
G
Unsöld
Inge
I
Stec
Edyta
E
Li
Shu-Ming
SM
Heide
Lutz
L
Stehle
Thilo
T
D019883:Alkyl and Aryl Transferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001232:Aspergillus fumigatus / Q000201:enzymology* / Q000235:genetics; D001419:Bacteria / Q000201:enzymology; D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004122:Dimethylallyltranstransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005658:Fungi / Q000201:enzymology; D045782:Hemiterpenes / Q000737:chemistry / Q000378:metabolism; D008274:Magnesium / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D013729:Terpenes / Q000737:chemistry / Q000378:metabolism; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism
D005656:Fungal Proteins; D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D013729:Terpenes; C043060:3,3-dimethylallyl pyrophosphate; D014364:Tryptophan; D019883:Alkyl and Aryl Transferases; D004122:Dimethylallyltranstransferase; C032409:tryptophan dimethylallyltransferase; D008274:Magnesium
Eur J Biochem. 2002 Jul;269(14):3339-54
12135472
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2316-21
12618544
J Biol Chem. 2005 May 27;280(21):20762-74
15788389
Chembiochem. 2008 Sep 1;9(13):2055-8
18677738
Bioinformatics. 2008 Dec 1;24(23):2780-1
18818215
Nature. 2005 Jun 16;435(7044):983-7
15959519
J Biol Chem. 2008 Jun 6;283(23):16068-76
18390548
Biochem J. 2009 Jun 26;421(2):231-41
19392660
Biochem Biophys Res Commun. 1971 Sep;44(5):1244-51
5160408
Biochem Biophys Res Commun. 1995 Nov 2;216(1):119-25
7488077
Eur J Obstet Gynecol Reprod Biol. 1995 Jun;60(2):109-16
7641960
Am J Respir Crit Care Med. 2006 Apr 1;173(7):707-17
16387806
FEBS Lett. 2007 Jun 26;581(16):2889-93
17543953
Chem Biol. 2008 Jul 21;15(7):729-38
18635009
Mol Gen Genet. 1999 Feb;261(1):133-41
10071219
Plant Physiol. 2008 May;147(1):296-305
18344419
J Biol Chem. 2009 Jan 2;284(1):100-109
19001367
Microbiology (Reading). 2005 May;151(Pt 5):1499-1505
15870460
Arch Biochem Biophys. 1992 Jul;296(1):308-13
1605639
J Biol Chem. 2009 May 22;284(21):14439-47
19339241
Chembiochem. 2008 Apr 14;9(6):982-92
18338424
J Biol Chem. 1981 Nov 10;256(21):10917-23
7287742
Drugs. 1998 Oct;56(4):523-35
9806101
Chembiochem. 2007 Jul 23;8(11):1298-307
17577899
Alkaloids Chem Biol. 2006;63:45-86
17133714
Cell Mol Life Sci. 2008 May;65(10):1459-63
18322648
Curr Opin Chem Biol. 2009 Apr;13(2):171-9
19299193
Microbiology (Reading). 2007 Oct;153(Pt 10):3409-3416
17906140
Bioorg Med Chem. 2008 Sep 1;16(17):8117-26
18682327
Curr Med Chem. 2009;16(2):218-31
19149573
Arch Biochem Biophys. 1976 Nov;177(1):84-94
999297