Flavin-dependent monooxygenases as a detoxification mechanism in insects: new insights from the arctiids (lepidoptera).
Insects experience a wide array of chemical pressures from plant allelochemicals and pesticides and have developed several effective counterstrategies to cope with such toxins. Among these, cytochrome P450 monooxygenases are crucial in plant-insect interactions. Flavin-dependent monooxygenases (FMOs) seem not to play a central role in xenobiotic detoxification in insects, in contrast to mammals. However, the previously identified senecionine N-oxygenase of the arctiid moth Tyria jacobaeae (Lepidoptera) indicates that FMOs have been recruited during the adaptation of this insect to plants that accumulate toxic pyrrolizidine alkaloids. Identification of related FMO-like sequences of various arctiids and other Lepidoptera and their combination with expressed sequence tag (EST) data and sequences emerging from the Bombyx mori genome project show that FMOs in Lepidoptera form a gene family with three members (FMO1 to FMO3). Phylogenetic analyses suggest that FMO3 is only distantly related to lepidopteran FMO1 and FMO2 that originated from a more recent gene duplication event. Within the FMO1 gene cluster, an additional gene duplication early in the arctiid lineage provided the basis for the evolution of the highly specific biochemical, physiological, and behavioral adaptations of these butterflies to pyrrolizidine-alkaloid-producing plants. The genes encoding pyrrolizidine-alkaloid-N-oxygenizing enzymes (PNOs) are transcribed in the fat body and the head of the larvae. An N-terminal signal peptide mediates the transport of the soluble proteins into the hemolymph where PNOs efficiently convert pro-toxic pyrrolizidine alkaloids into their non-toxic N-oxide derivatives. Heterologous expression of a PNO of the generalist arctiid Grammia geneura produced an N-oxygenizing enzyme that shows noticeably expanded substrate specificity compared with the related enzyme of the specialist Tyria jacobaeae. The data about the evolution of FMOs within lepidopteran insects and the functional characterization of a further member of this enzyme family shed light on this almost uncharacterized detoxification system in insects.
Sehlmeyer
Sven
S
Institute for Pharmaceutical Biology, TU Braunschweig, Braunschweig, Germany.
Wang
Linzhu
L
Langel
Dorothee
D
Heckel
David G
DG
Mohagheghi
Hoda
H
Petschenka
Georg
G
Ober
Dietrich
D
D000595:Amino Acid Sequence; D000818:Animals; D001285:Atropine / Q000737:chemistry / Q000378:metabolism; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D005415:Flavins / Q000378:metabolism*; D008658:Inactivation, Metabolic; D019476:Insect Proteins / Q000737:chemistry / Q000378:metabolism; D007915:Lepidoptera / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010802:Phylogeny; D011763:Pyrrolizidine Alkaloids / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013379:Substrate Specificity
D018076:DNA, Complementary; D005415:Flavins; D019476:Insect Proteins; D011763:Pyrrolizidine Alkaloids; D011994:Recombinant Proteins; D001285:Atropine; D006899:Mixed Function Oxygenases
Trends Ecol Evol. 2007 Jun;22(6):298-307
17324485
Phytochemistry. 2006 Jul;67(14):1493-502
16815502
Annu Rev Pharmacol Toxicol. 1993;33:179-99
8494339
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2939-44
14981232
Arch Insect Biochem Physiol. 2004 Sep;57(1):28-39
15352153
Insect Biochem Mol Biol. 1997 May;27(5):377-85
9219364
Insect Biochem Mol Biol. 2001 Apr 27;31(6-7):679-90
11267906
J Mol Biol. 2001 Jan 19;305(3):567-80
11152613
Arch Insect Biochem Physiol. 2001 Dec;48(4):179-89
11746562
Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9029-32
15173598
Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):121-6
10618381
Insect Mol Biol. 2006 Oct;15(5):615-36
17069637
J Mol Biol. 2000 Jul 21;300(4):1005-16
10891285
Drug Metab Dispos. 1987 Mar-Apr;15(2):200-3
2882978
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14777-82
10611289
J Chem Ecol. 1989 Mar;15(3):1077-93
24271908
Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):50-5
7816847
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2687-91
10077572
J Chem Ecol. 1990 Feb;16(2):543-52
24263510
Proc Natl Acad Sci U S A. 2003 Nov 25;100 Suppl 2:14593-8
12968082
Arch Biochem Biophys. 2002 Jul 15;403(2):277-83
12139977
Genetica. 2009 Nov;137(2):173-87
19579011
Drug Metab Rev. 2002 Aug;34(3):503-11
12214662
J Mol Biol. 2004 Jul 16;340(4):783-95
15223320
Drug Metab Rev. 2004 Feb;36(1):1-55
15072438
Proc Natl Acad Sci U S A. 1988 Aug;85(16):5992-6
3413071
Eur J Biochem. 1997 May 1;245(3):626-36
9182998
J Biol Chem. 1999 Nov 5;274(45):32040-7
10542236
Trends Plant Sci. 2007 Sep;12(9):412-8
17765596
FEBS Lett. 1991 Dec 16;295(1-3):10-2
1765138
Mol Biol Evol. 1987 Jul;4(4):406-25
3447015
Dev Genet. 1989;10(3):220-31
2500286
Arch Biochem Biophys. 2000 Sep 15;381(2):317-22
11032421
Biochem Biophys Res Commun. 2005 Dec 9;338(1):599-604
16112078
Proc Int Conf Intell Syst Mol Biol. 1997;5:147-52
9322029
Methods Enzymol. 1990;185:60-89
2199796
Arch Biochem Biophys. 1995 Feb 20;317(1):275-84
7872795
Gene. 2001 Jan 10;262(1-2):189-98
11179683
Proc Natl Acad Sci U S A. 2008 May 6;105(18):6572-7
18443301
Phytochemistry. 2009 Mar;70(4):508-16
19254800
Plant Physiol. 2008 Oct;148(2):751-60
18701671
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6085-90
11972041
J Biol Chem. 2008 Jul 11;283(28):19219-28
18482980
Chem Res Toxicol. 1995 Mar;8(2):166-81
7766799
Cell Mol Biol (Noisy-le-grand). 1994 Jul;40(5):635-44
7981620
Oecologia. 1993 Oct;96(1):9-18
28313747
Arch Biochem Biophys. 1994 Jan;308(1):254-7
8311461
J Med Chem. 2006 Feb 9;49(3):1125-39
16451077
PLoS One. 2009;4(3):e4796
19274098
Nucleic Acids Res. 1997 Dec 15;25(24):4876-82
9396791
Insect Biochem Mol Biol. 2005 Oct;35(10):1083-99
16102415
Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9832-7
16777962