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The cytochromes P450 (CYPs) comprise a vast superfamily of enzymes found in virtually all life forms. In mammals, xenobiotic metabolizing CYPs provide crucial protection from the effects of exposure to a wide variety of chemicals, including environmental toxins and therapeutic drugs. Ideally, the information on the possible metabolism by CYPs required during drug development would be obtained from crystal structures of all the CYPs of interest. For some years only crystal structures of distantly related bacterial CYPs were available and homology modelling techniques were used to bridge the gap and produce structural models of human CYPs, and thereby obtain useful functional information. A significant step forward in the reliability of these models came seven years ago with the first crystal structure of a mammalian CYP, rabbit CYP2C5, followed by the structures of six human enzymes, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6 and CYP3A4, and a second rabbit enzyme, CYP2B4. In this review we describe as a case study the evolution of a CYP2D6 model, leading to the validation of the model as an in silico tool for predicting binding and metabolism. This work has led directly to the successful design of CYP2D6 mutants with novel activity-including creating a testosterone hydroxylase, converting quinidine from inhibitor to substrate, creating a diclofenac hydroxylase and creating a dextromethorphan O-demethylase. Our modelling-derived hypothesis-driven integrated interdisciplinary studies have given key insight into the molecular determinants of CYP2D6 and other important drug metabolizing enzymes.

Additional file 2. Additional results from the population resistance comparisons including Figure S2. The distributions of paired pyrethroid susceptibility test mortality values for An. gambiae s.l. Figure S3. The distributions of paired pyrethroid susceptibility test mortality values for the An. funestus subgroup. Figure S4. The distributions of paired pyrethroid susceptibility test mortality values for four species. Figure S5. The distributions of paired susceptibility test mortality values for four species exposed to deltamethrin and a non-pyrethroid insecticide. Figure S6. Comparisons between resistance to etofenprox and five other pyrethroids in the An. gambiae complex and the An. funestus subgroup. Figure S7. Comparison of resistance to three pyrethroids within the An. gambiae complex and An. funestus subgroup. Figure S8. Comparisons of resistance to three pyrethroids in four malaria vector species. Figure S9. Comparison of resistance to deltamethrin and six insecticides from other classes. Table S4. Correlations between resistance to deltamethrin and non-pyrethroid insecticides in four African malaria vector species.

Additional file 1. Further details of the functional activity data including Table S1. Primers used for amplification of CYP6Z3 and in vitro functional characterisation. Figure S1. Fe2+-CO vs. Fe2+ difference spectrum of E. coli membranes expressing AgCYP6Z3. Table S2. IC50 values (��M) of pyrethroid insecticides. Table S3. Pyrethroid metabolism by mosquito P450s.

Additional file 2. Additional results from the population resistance comparisons including Figure S2. The distributions of paired pyrethroid susceptibility test mortality values for An. gambiae s.l. Figure S3. The distributions of paired pyrethroid susceptibility test mortality values for the An. funestus subgroup. Figure S4. The distributions of paired pyrethroid susceptibility test mortality values for four species. Figure S5. The distributions of paired susceptibility test mortality values for four species exposed to deltamethrin and a non-pyrethroid insecticide. Figure S6. Comparisons between resistance to etofenprox and five other pyrethroids in the An. gambiae complex and the An. funestus subgroup. Figure S7. Comparison of resistance to three pyrethroids within the An. gambiae complex and An. funestus subgroup. Figure S8. Comparisons of resistance to three pyrethroids in four malaria vector species. Figure S9. Comparison of resistance to deltamethrin and six insecticides from other classes. Table S4. Correlations between resistance to deltamethrin and non-pyrethroid insecticides in four African malaria vector species.

Additional file 3. Further details of the analyses of resistance in Aedes populations including Table S5. Diagnostic doses and data volumes for each pyrethroid. Table S6. Correlations in resistance to different pyrethroids in Ae. aegypti samples. Table S7. Comparisons of mean mortality between pairs of pyrethroids.

Additional file 1. Further details of the functional activity data including Table S1. Primers used for amplification of CYP6Z3 and in vitro functional characterisation. Figure S1. Fe2+-CO vs. Fe2+ difference spectrum of E. coli membranes expressing AgCYP6Z3. Table S2. IC50 values (��M) of pyrethroid insecticides. Table S3. Pyrethroid metabolism by mosquito P450s.

Honey bees, Apis mellifera, are markedly less sensitive to neonicotinoid insecticides containing a cyanoimino pharmacophore than to those with a nitroimino group. Although previous work has suggested that this results from enhanced metabolism of the former by detoxification enzymes, the specific enzyme(s) involved remain to be characterized. In this work, a pretreatment of honey bees with a sublethal dose of thiacloprid resulted in induced insensitivity to the same compound immediately following thiacloprid feeding. A longer pretreatment time resulted in no, or increased, sensitivity. Transcriptome profiling, using microarrays, identified a number of genes encoding detoxification enzymes that were over-expressed significantly in insecticide-treated bees compared with untreated controls. These included five P450s, CYP6BE1, CYP305D1, CYP6AS5, CYP315A1, CYP301A1, and a carboxyl/cholinesterase (CCE) CCE8. Four of these P450s were functionally expressed in Escherichia coli and their ability to metabolize thiacloprid examined by liquid chromatography-mass spectrometry (LC-MS) analysis.

Additional file 3. Further details of the analyses of resistance in Aedes populations including Table S5. Diagnostic doses and data volumes for each pyrethroid. Table S6. Correlations in resistance to different pyrethroids in Ae. aegypti samples. Table S7. Comparisons of mean mortality between pairs of pyrethroids.

The glycoprotein, gp30, is the major soluble cuticular antigen of the adult lymphatic fiarial worm Brugia pahangi (Maizels et al., 1983, Devaney, 1988). Cookson et al., 1992 suggested that gp30 may function as an antioxidant enzyme protecting B. pahangi from the vertebrate host defence mechanism. In this communication we report that the gp30 transcript is present in each of the life cycle stages, including mosquito derived L3's, and that there is a 50 fold increase in the transcription of gp30 in young adults (28 days post infection) compared to mature adults. These findings suggest that gp30 performs a general function relevant throughout the B. pahangi life cycle and in particular to young adults.