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Showing Protein Multifunctional cytochrome P450 monooxygenase af510 (HMDBP12160)

IdentificationBiological propertiesGene propertiesProtein propertiesExternal linksReferencesXMLShow 2 metabolites
Identification
HMDB Protein ID HMDBP12160
Secondary Accession Numbers None
Name Multifunctional cytochrome P450 monooxygenase af510
Synonyms
  1. Fumagillin biosynthesis cluster P450 monooxygenase
  2. Fma-P450
Gene Name AF510
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function Multifunctional cytochrome P450 monooxygenase; part of the gene cluster that mediates the biosynthesis of fumagillin, a meroterpenoid that has numerous biological activities including irreversible inhibition of human type 2 methionine aminopeptidase (METAP2) (PubMed:23488861, PubMed:24568283). The pathway begins with the conversion of farnesyl pyrophosphate (FPP) to beta-trans-bergamotene by the membrane-bound beta-trans-bergamotene synthase af520 (PubMed:23488861). The initial oxidation of beta-trans-bergamotene by the multifunctional cytochrome P450 monooxygenase af510 involves C-H hydroxylation at the bridgehead C5 position to yield 5R-hydroxyl-beta-trans-bergamotene (PubMed:24568283). Subsequently, a four electron oxidation initiated at C-9 coupled to cleavage of the cyclobutane C5-C8 bond of the bicyclo[3.1.1] core yields the epoxyketone intermediate 5-keto-cordycol (PubMed:24568283). An additional epoxidation reaction also catalyzed by af510 then furnishes the characteristic bisepoxide ketone 5-keto-demethoxyfumagillol (PubMed:24568283). 5-keto-demethoxyfumagillol is then subjected to successive C-6 hydroxylation and O-methylation by the dioxygenase af480 and O-methyltransferase af390-400, respectively, to yield 5-keto-fumagillol, which is then stereoselectively reduced by the keto-reductase af490 to 5R-hydroxy-seco-sesquiterpene (PubMed:24568283). The next step is the polyketide transferase af380-catalyzed transfer of a dodecapentaenoyl group synthesized by the polyketide synthase af370 onto 5R-hydroxy-seco-sesquiterpene which leads to the production of prefumagillin (PubMed:24568283). Finally, oxidative cleavage by the monooxygenase af470 converts prefumagillin to fumagillin (PubMed:24568283).
Pathways
  • terpenoid biosynthesis
Reactions Not Available
GO Classification
Biological Process
terpenoid biosynthetic process
fumagillin biosynthetic process
Cellular Component
integral to membrane
Molecular Function
monooxygenase activity
iron ion binding
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
heme binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 536
Molecular Weight 60964.615
Theoretical pI 8.248
Pfam Domain Function
Signals Not Available
Transmembrane Regions
  • 4-24;
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID Q4WAZ6
UniProtKB/Swiss-Prot Entry Name FMAG_ASPFU
PDB IDs Not Available
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
  1. Molina JM, Tourneur M, Sarfati C, Chevret S, de Gouvello A, Gobert JG, Balkan S, Derouin F: Fumagillin treatment of intestinal microsporidiosis. N Engl J Med. 2002 Jun 20;346(25):1963-9. [PubMed:12075057 ]
  2. Lin HC, Tsunematsu Y, Dhingra S, Xu W, Fukutomi M, Chooi YH, Cane DE, Calvo AM, Watanabe K, Tang Y: Generation of complexity in fungal terpene biosynthesis: discovery of a multifunctional cytochrome P450 in the fumagillin pathway. J Am Chem Soc. 2014 Mar 19;136(11):4426-36. doi: 10.1021/ja500881e. Epub 2014 Mar 11. [PubMed:24568283 ]
  3. Nierman WC, Pain A, Anderson MJ, Wortman JR, Kim HS, Arroyo J, Berriman M, Abe K, Archer DB, Bermejo C, Bennett J, Bowyer P, Chen D, Collins M, Coulsen R, Davies R, Dyer PS, Farman M, Fedorova N, Fedorova N, Feldblyum TV, Fischer R, Fosker N, Fraser A, Garcia JL, Garcia MJ, Goble A, Goldman GH, Gomi K, Griffith-Jones S, Gwilliam R, Haas B, Haas H, Harris D, Horiuchi H, Huang J, Humphray S, Jimenez J, Keller N, Khouri H, Kitamoto K, Kobayashi T, Konzack S, Kulkarni R, Kumagai T, Lafon A, Latge JP, Li W, Lord A, Lu C, Majoros WH, May GS, Miller BL, Mohamoud Y, Molina M, Monod M, Mouyna I, Mulligan S, Murphy L, O'Neil S, Paulsen I, Penalva MA, Pertea M, Price C, Pritchard BL, Quail MA, Rabbinowitsch E, Rawlins N, Rajandream MA, Reichard U, Renauld H, Robson GD, Rodriguez de Cordoba S, Rodriguez-Pena JM, Ronning CM, Rutter S, Salzberg SL, Sanchez M, Sanchez-Ferrero JC, Saunders D, Seeger K, Squares R, Squares S, Takeuchi M, Tekaia F, Turner G, Vazquez de Aldana CR, Weidman J, White O, Woodward J, Yu JH, Fraser C, Galagan JE, Asai K, Machida M, Hall N, Barrell B, Denning DW: Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature. 2005 Dec 22;438(7071):1151-6. doi: 10.1038/nature04332. [PubMed:16372009 ]
  4. KILLOUGH JH, MAGILL GB, SMITH RC: The treatment of amebiasis with fumagillin. Science. 1952 Jan 18;115(2977):71-2. doi: 10.1126/science.115.2977.71. [PubMed:14913169 ]
  5. Sin N, Meng L, Wang MQ, Wen JJ, Bornmann WG, Crews CM: The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6099-103. doi: 10.1073/pnas.94.12.6099. [PubMed:9177176 ]
  6. Lazarus DD, Doyle EG, Bernier SG, Rogers AB, Labenski MT, Wakefield JD, Karp RM, Clark EJ, Lorusso J, Hoyt JG, Thompson CD, Hannig G, Westlin WF: An inhibitor of methionine aminopeptidase type-2, PPI-2458, ameliorates the pathophysiological disease processes of rheumatoid arthritis. Inflamm Res. 2008 Jan;57(1):18-27. doi: 10.1007/s00011-007-7075-5. [PubMed:18209961 ]
  7. Lin HC, Chooi YH, Dhingra S, Xu W, Calvo AM, Tang Y: The fumagillin biosynthetic gene cluster in Aspergillus fumigatus encodes a cryptic terpene cyclase involved in the formation of beta-trans-bergamotene. J Am Chem Soc. 2013 Mar 27;135(12):4616-9. doi: 10.1021/ja312503y. Epub 2013 Mar 19. [PubMed:23488861 ]
  8. Dhingra S, Lind AL, Lin HC, Tang Y, Rokas A, Calvo AM: The fumagillin gene cluster, an example of hundreds of genes under veA control in Aspergillus fumigatus. PLoS One. 2013 Oct 7;8(10):e77147. doi: 10.1371/journal.pone.0077147. eCollection 2013. [PubMed:24116213 ]
  9. Wiemann P, Guo CJ, Palmer JM, Sekonyela R, Wang CC, Keller NP: Prototype of an intertwined secondary-metabolite supercluster. Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17065-70. doi: 10.1073/pnas.1313258110. Epub 2013 Sep 30. [PubMed:24082142 ]