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Cyp18a1  -  Cytochrome P450-18a1

Drosophila melanogaster

Synonyms: 181H6T, 18a1, CG6816, CT20826, CYP18, ...
 
 
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Disease relevance of Cyp18a1

 

High impact information on Cyp18a1

  • Using the Somatic Mutation And Recombination Test (SMART) we have demonstrated that transgenic larvae expressing the P450 are hypersensitive to the anticancer drug cyclophosphamide, a procarcinogenic substrate which is activated by the enzyme [2].
  • In this study we have used precise genetic mapping to identify a mechanism of lufenuron resistance: the overexpression of the cytochrome P450 gene Cyp12a4 [3].
  • Shade is the Drosophila P450 enzyme that mediates the hydroxylation of ecdysone to the steroid insect molting hormone 20-hydroxyecdysone [4].
  • The present data show that the wild-type genes of two members of the Halloween family of embryonic lethals, disembodied (dib) and shadow (sad), code for mitochondrial cytochromes P450 that mediate the last two hydroxylation reactions in the ecdysteroidogenic pathway in Drosophila, namely the C22- and C2-hydroxylases [5].
  • Five different enzymatic activities, catalyzed by both microsomal and mitochondrial cytochrome P450 monooxygenases (CYPs), are strongly implicated in the biosynthesis of ecdysone (E) from cholesterol [5].
 

Biological context of Cyp18a1

  • In contrast, we show here that several dipteran genomes encode two novel, highly related, microsomal P450 enzymes, Cyp307A1 and Cyp307A2, that likely participate as stage-specific components of the ecdysone biosynthetic machinery [6].
  • The genetic map of the distribution of D. melanogaster P450 genes shows (a) the absence of P450 genes on the chromosome 4 and Y, (b) more than half of the P450 genes are found on chromosome 2, and (c) the largest cluster contains nine genes [7].
  • Of these 90 P450 sequences, 83 code for apparently functional genes whereas seven are apparent pseudogenes [7].
  • The cytochrome P450 gene superfamily in Drosophila melanogaster: annotation, intron-exon organization and phylogeny [7].
  • Cytochrome P450 gene clusters in Drosophila melanogaster [8].
 

Anatomical context of Cyp18a1

  • High Cyp18 expression was observed in body wall and gut while negligible expression was observed in salivary glands and fat body [9].
  • Furthermore, analysis of c/ebp beta-deficient mice shows that mutant animals are defective in expression of a murine CYP2D5 homolog in hepatic cells, confirming the selective ability of C/EBP beta to activate this liver-specific P-450 gene in vivo [10].
  • In contrast, increases in the rate of BP turnover per molecule of cytochrome P-450, intensity of the hemoprotein band with apparent molecular weight 56,000 and the yield of BP 7,8-dihydrodiol and 9,10-dihydrodiol occurred only in microsomes of BP-pretreated 364yv flies but not of Turku ones [11].
  • Feeding of these compounds in combination with the inhibition of cytochrome P-450 by 1-phenylimidazole (PhI) allowed sufficient quantities of the mutagen to reach the gonads and to produce significant genetic damage [12].
  • These results indicate that the fat body participates in the P450-mediated metabolism of excess furanocoumarins unmetabolized by the midgut [13].
 

Associations of Cyp18a1 with chemical compounds

  • The CYP18 protein is most closely related to steroid and xenobiotic metabolizing P450s of family CYP2 (30-33% identity), and to vertebrate steroidogenic P450s of families CYP17 and CYP21 (25-28% identity) [9].
  • This pattern of expression is consistent with the known induction of Cyp18 transcription by 20-hydroxyecdysone at the time of pupariation and suggests that ecdysteroids are major regulators of Cyp18 expression throughout postembryonic development [9].
  • However, there is some controversy as to how the second step of the reaction, from NHA to NO and L-citrulline, occurs within the P450 domain of NOS [14].
  • A genetic variation between the strains was observed after phenobarbital (PB) treatment in the content of cytochrome P-450 and in the various enzyme activities, varying from non-responsiveness to a 4- to 5-fold increase [15].
  • Dimethylnitrosamine demethylase, a P-450 enzyme, is a component of band b [16].
 

Other interactions of Cyp18a1

  • Cytochrome P450 CYP307A1/Spook: a regulator for ecdysone synthesis in insects [17].
  • Preliminary studies of a partial cDNA clone of the Eig17-1 gene from Drosophila melanogaster have shown that it encodes a probable cytochrome P450 of unknown function [9].
 

Analytical, diagnostic and therapeutic context of Cyp18a1

  • Sequence alignments were used to draw phylogenetic trees and to analyze the intron-exon organization of each functional P450 gene [7].
  • Twelve cytochrome P450 cDNA fragments were cloned from Drosophila melanogaster by reverse transcriptase/PCR (RT/PCR) using degenerate oligonucleotide primers [8].
  • Developmental Northern blot analysis revealed five distinct periods of Cyp18 expression during postembryonic development [9].
  • P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature [18].
  • Although the chromosome 2 locus was not associated with a significant increase in cytochrome P-450 content, SDS polyacrylamide gel electrophoresis of microsomal proteins detected increased silver staining of a polypeptide having a relative molecular mass (Mr) of about 52,000 [19].

References

  1. Relation between the somatic toxicity of dimethylnitrosamine and a genetically determined variation in the level and induction of cytochrome P450 in Drosophila melanogaster. Hällström, I., Magnusson, J., Ramel, C. Mutat. Res. (1982) [Pubmed]
  2. Mammalian genes expressed in Drosophila: a transgenic model for the study of mechanisms of chemical mutagenesis and metabolism. Jowett, T., Wajidi, M.F., Oxtoby, E., Wolf, C.R. EMBO J. (1991) [Pubmed]
  3. Cyp12a4 confers lufenuron resistance in a natural population of Drosophila melanogaster. Bogwitz, M.R., Chung, H., Magoc, L., Rigby, S., Wong, W., O'Keefe, M., McKenzie, J.A., Batterham, P., Daborn, P.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. Shade is the Drosophila P450 enzyme that mediates the hydroxylation of ecdysone to the steroid insect molting hormone 20-hydroxyecdysone. Petryk, A., Warren, J.T., Marqués, G., Jarcho, M.P., Gilbert, L.I., Kahler, J., Parvy, J.P., Li, Y., Dauphin-Villemant, C., O'Connor, M.B. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  5. Molecular and biochemical characterization of two P450 enzymes in the ecdysteroidogenic pathway of Drosophila melanogaster. Warren, J.T., Petryk, A., Marques, G., Jarcho, M., Parvy, J.P., Dauphin-Villemant, C., O'Connor, M.B., Gilbert, L.I. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  6. Spook and Spookier code for stage-specific components of the ecdysone biosynthetic pathway in Diptera. Ono, H., Rewitz, K.F., Shinoda, T., Itoyama, K., Petryk, A., Rybczynski, R., Jarcho, M., Warren, J.T., Marqu??s, G., Shimell, M.J., Gilbert, L.I., O'connor, M.B. Dev. Biol. (2006) [Pubmed]
  7. The cytochrome P450 gene superfamily in Drosophila melanogaster: annotation, intron-exon organization and phylogeny. Tijet, N., Helvig, C., Feyereisen, R. Gene (2001) [Pubmed]
  8. Cytochrome P450 gene clusters in Drosophila melanogaster. Dunkov, B.C., Rodriguez-Arnaiz, R., Pittendrigh, B., ffrench-Constant, R.H., Feyereisen, R. Mol. Gen. Genet. (1996) [Pubmed]
  9. Sequence and developmental expression of Cyp18, a member of a new cytochrome P450 family from Drosophila. Bassett, M.H., McCarthy, J.L., Waterman, M.R., Sliter, T.J. Mol. Cell. Endocrinol. (1997) [Pubmed]
  10. The ability of C/EBP beta but not C/EBP alpha to synergize with an Sp1 protein is specified by the leucine zipper and activation domain. Lee, Y.H., Williams, S.C., Baer, M., Sterneck, E., Gonzalez, F.J., Johnson, P.F. Mol. Cell. Biol. (1997) [Pubmed]
  11. Xenobiotic-metabolizing enzymes and benzo[a]pyrene metabolism in the benzo[a]pyrene-sensitive mutant strain of Drosophila simulans. Fuchs SYu, n.u.l.l., Spiegelman, V.S., Safaev, R.D., Belitsky, G.A. Mutat. Res. (1992) [Pubmed]
  12. Metabolic inactivation of mutagens in Drosophila melanogaster. Zijlstra, J.A., Vogel, E.W. Mutat. Res. (1988) [Pubmed]
  13. Expression of CYP6B1 and CYP6B3 cytochrome P450 monooxygenases and furanocoumarin metabolism in different tissues of Papilio polyxenes (Lepidoptera: Papilionidae). Petersen, R.A., Zangerl, A.R., Berenbaum, M.R., Schuler, M.A. Insect Biochem. Mol. Biol. (2001) [Pubmed]
  14. The crucial roles of Asp-314 and Thr-315 in the catalytic activation of molecular oxygen by neuronal nitric-oxide synthase. A site-directed mutagenesis study. Sagami, I., Shimizu, T. J. Biol. Chem. (1998) [Pubmed]
  15. Genetic variation in cytochrome P-450 and xenobiotic metabolism in Drosophila melanogaster. Hällström, I., Blanck, A., Atuma, S. Biochem. Pharmacol. (1984) [Pubmed]
  16. Natural variation in the expression of cytochrome P-450 and dimethylnitrosamine demethylase in Drosophila. Waters, L.C., Simms, S.I., Nix, C.E. Biochem. Biophys. Res. Commun. (1984) [Pubmed]
  17. Cytochrome P450 CYP307A1/Spook: a regulator for ecdysone synthesis in insects. Namiki, T., Niwa, R., Sakudoh, T., Shirai, K., Takeuchi, H., Kataoka, H. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  18. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Nelson, D.R., Koymans, L., Kamataki, T., Stegeman, J.J., Feyereisen, R., Waxman, D.J., Waterman, M.R., Gotoh, O., Coon, M.J., Estabrook, R.W., Gunsalus, I.C., Nebert, D.W. Pharmacogenetics (1996) [Pubmed]
  19. Genes controlling malathion resistance in a laboratory-selected population of Drosophila melanogaster. Houpt, D.R., Pursey, J.C., Morton, R.A. Genome (1988) [Pubmed]
 
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