FMAG_ASPFU
ID FMAG_ASPFU Reviewed; 536 AA.
AC Q4WAZ6;
DT 07-SEP-2016, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 99.
DE RecName: Full=Multifunctional cytochrome P450 monooxygenase af510 {ECO:0000303|PubMed:24568283};
DE EC=1.-.-.- {ECO:0000269|PubMed:24568283};
DE AltName: Full=Fumagillin biosynthesis cluster P450 monooxygenase {ECO:0000303|PubMed:24568283};
DE Short=Fma-P450 {ECO:0000303|PubMed:24568283};
GN Name=af510 {ECO:0000303|PubMed:23488861};
GN Synonyms=fmaG {ECO:0000303|PubMed:24082142}; ORFNames=AFUA_8G00510;
OS Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC
OS A1100) (Aspergillus fumigatus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Fumigati.
OX NCBI_TaxID=330879;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100;
RX PubMed=16372009; DOI=10.1038/nature04332;
RA Nierman W.C., Pain A., Anderson M.J., Wortman J.R., Kim H.S., Arroyo J.,
RA Berriman M., Abe K., Archer D.B., Bermejo C., Bennett J.W., Bowyer P.,
RA Chen D., Collins M., Coulsen R., Davies R., Dyer P.S., Farman M.L.,
RA Fedorova N., Fedorova N.D., Feldblyum T.V., Fischer R., Fosker N.,
RA Fraser A., Garcia J.L., Garcia M.J., Goble A., Goldman G.H., Gomi K.,
RA Griffith-Jones S., Gwilliam R., Haas B.J., Haas H., Harris D.E.,
RA Horiuchi H., Huang J., Humphray S., Jimenez J., Keller N., Khouri H.,
RA Kitamoto K., Kobayashi T., Konzack S., Kulkarni R., Kumagai T., Lafton A.,
RA Latge J.-P., Li W., Lord A., Lu C., Majoros W.H., May G.S., Miller B.L.,
RA Mohamoud Y., Molina M., Monod M., Mouyna I., Mulligan S., Murphy L.D.,
RA O'Neil S., Paulsen I., Penalva M.A., Pertea M., Price C., Pritchard B.L.,
RA Quail M.A., Rabbinowitsch E., Rawlins N., Rajandream M.A., Reichard U.,
RA Renauld H., Robson G.D., Rodriguez de Cordoba S., Rodriguez-Pena J.M.,
RA Ronning C.M., Rutter S., Salzberg S.L., Sanchez M., Sanchez-Ferrero J.C.,
RA Saunders D., Seeger K., Squares R., Squares S., Takeuchi M., Tekaia F.,
RA Turner G., Vazquez de Aldana C.R., Weidman J., White O., Woodward J.R.,
RA Yu J.-H., Fraser C.M., Galagan J.E., Asai K., Machida M., Hall N.,
RA Barrell B.G., Denning D.W.;
RT "Genomic sequence of the pathogenic and allergenic filamentous fungus
RT Aspergillus fumigatus.";
RL Nature 438:1151-1156(2005).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=14913169; DOI=10.1126/science.115.2977.71;
RA Killough J.H., Magill G.B., Smith R.C.;
RT "The treatment of amebiasis with fumagillin.";
RL Science 115:71-72(1952).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=9177176; DOI=10.1073/pnas.94.12.6099;
RA Sin N., Meng L., Wang M.Q., Wen J.J., Bornmann W.G., Crews C.M.;
RT "The anti-angiogenic agent fumagillin covalently binds and inhibits the
RT methionine aminopeptidase, MetAP-2.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:6099-6103(1997).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=12075057; DOI=10.1056/nejmoa012924;
RG Agence Nationale de Recherches sur le SIDA 090 Study Group;
RA Molina J.M., Tourneur M., Sarfati C., Chevret S., de Gouvello A.,
RA Gobert J.G., Balkan S., Derouin F.;
RT "Fumagillin treatment of intestinal microsporidiosis.";
RL N. Engl. J. Med. 346:1963-1969(2002).
RN [5]
RP BIOTECHNOLOGY.
RX PubMed=18209961; DOI=10.1007/s00011-007-7075-5;
RA Lazarus D.D., Doyle E.G., Bernier S.G., Rogers A.B., Labenski M.T.,
RA Wakefield J.D., Karp R.M., Clark E.J., Lorusso J., Hoyt J.G.,
RA Thompson C.D., Hannig G., Westlin W.F.;
RT "An inhibitor of methionine aminopeptidase type-2, PPI-2458, ameliorates
RT the pathophysiological disease processes of rheumatoid arthritis.";
RL Inflamm. Res. 57:18-27(2008).
RN [6]
RP FUNCTION.
RX PubMed=23488861; DOI=10.1021/ja312503y;
RA Lin H.C., Chooi Y.H., Dhingra S., Xu W., Calvo A.M., Tang Y.;
RT "The fumagillin biosynthetic gene cluster in Aspergillus fumigatus encodes
RT a cryptic terpene cyclase involved in the formation of beta-trans-
RT bergamotene.";
RL J. Am. Chem. Soc. 135:4616-4619(2013).
RN [7]
RP INDUCTION.
RX PubMed=24116213; DOI=10.1371/journal.pone.0077147;
RA Dhingra S., Lind A.L., Lin H.C., Tang Y., Rokas A., Calvo A.M.;
RT "The fumagillin gene cluster, an example of hundreds of genes under veA
RT control in Aspergillus fumigatus.";
RL PLoS ONE 8:E77147-E77147(2013).
RN [8]
RP IDENTIFICATION, INDUCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24082142; DOI=10.1073/pnas.1313258110;
RA Wiemann P., Guo C.J., Palmer J.M., Sekonyela R., Wang C.C., Keller N.P.;
RT "Prototype of an intertwined secondary-metabolite supercluster.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:17065-17070(2013).
RN [9]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24568283; DOI=10.1021/ja500881e;
RA Lin H.C., Tsunematsu Y., Dhingra S., Xu W., Fukutomi M., Chooi Y.H.,
RA Cane D.E., Calvo A.M., Watanabe K., Tang Y.;
RT "Generation of complexity in fungal terpene biosynthesis: discovery of a
RT multifunctional cytochrome P450 in the fumagillin pathway.";
RL J. Am. Chem. Soc. 136:4426-4436(2014).
CC -!- FUNCTION: Multifunctional cytochrome P450 monooxygenase; part of the
CC gene cluster that mediates the biosynthesis of fumagillin, a
CC meroterpenoid that has numerous biological activities including
CC irreversible inhibition of human type 2 methionine aminopeptidase
CC (METAP2) (PubMed:23488861, PubMed:24568283). The pathway begins with
CC the conversion of farnesyl pyrophosphate (FPP) to beta-trans-
CC bergamotene by the membrane-bound beta-trans-bergamotene synthase af520
CC (PubMed:23488861). The initial oxidation of beta-trans-bergamotene by
CC the multifunctional cytochrome P450 monooxygenase af510 involves C-H
CC hydroxylation at the bridgehead C5 position to yield 5R-hydroxyl-beta-
CC trans-bergamotene (PubMed:24568283). Subsequently, a four electron
CC oxidation initiated at C-9 coupled to cleavage of the cyclobutane C5-C8
CC bond of the bicyclo[3.1.1] core yields the epoxyketone intermediate 5-
CC keto-cordycol (PubMed:24568283). An additional epoxidation reaction
CC also catalyzed by af510 then furnishes the characteristic bisepoxide
CC ketone 5-keto-demethoxyfumagillol (PubMed:24568283). 5-keto-
CC demethoxyfumagillol is then subjected to successive C-6 hydroxylation
CC and O-methylation by the dioxygenase af480 and O-methyltransferase
CC af390-400, respectively, to yield 5-keto-fumagillol, which is then
CC stereoselectively reduced by the keto-reductase af490 to 5R-hydroxy-
CC seco-sesquiterpene (PubMed:24568283). The next step is the polyketide
CC transferase af380-catalyzed transfer of a dodecapentaenoyl group
CC synthesized by the polyketide synthase af370 onto 5R-hydroxy-seco-
CC sesquiterpene which leads to the production of prefumagillin
CC (PubMed:24568283). Finally, oxidative cleavage by the monooxygenase
CC af470 converts prefumagillin to fumagillin (PubMed:24568283).
CC {ECO:0000269|PubMed:23488861, ECO:0000269|PubMed:24568283}.
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:24568283}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- INDUCTION: Expression is controlled by the fumagillin biosynthesis
CC cluster regulator fumR (PubMed:24082142). Expression is also under the
CC control of the developmental and secondary metabolism regulator veA
CC (PubMed:24116213). {ECO:0000269|PubMed:24082142,
CC ECO:0000269|PubMed:24116213}.
CC -!- DISRUPTION PHENOTYPE: Completely abolishes the production of fumagillin
CC but leads to the accumulation of the intermediate beta-trans-
CC bergamotene (PubMed:24082142, PubMed:24568283).
CC {ECO:0000269|PubMed:24082142, ECO:0000269|PubMed:24568283}.
CC -!- BIOTECHNOLOGY: Fumagillin and its derivatives have been intensely
CC studied for their potential use in the treatment of amebiasis,
CC microsporidiosis and rheumatoid arthritis (PubMed:14913169,
CC PubMed:12075057, PubMed:18209961). They have also interesting
CC antiangiogenic properties by the irreversible inhibition of human type
CC 2 methionine aminopeptidase (METAP2) (PubMed:9177176).
CC {ECO:0000269|PubMed:12075057, ECO:0000269|PubMed:14913169,
CC ECO:0000269|PubMed:18209961, ECO:0000269|PubMed:9177176}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; AAHF01000014; EAL85116.1; -; Genomic_DNA.
DR RefSeq; XP_747154.1; XM_742061.1.
DR AlphaFoldDB; Q4WAZ6; -.
DR SMR; Q4WAZ6; -.
DR STRING; 746128.CADAFUBP00008384; -.
DR EnsemblFungi; EAL85116; EAL85116; AFUA_8G00510.
DR GeneID; 3504542; -.
DR KEGG; afm:AFUA_8G00510; -.
DR VEuPathDB; FungiDB:Afu8g00510; -.
DR eggNOG; KOG0156; Eukaryota.
DR HOGENOM; CLU_001570_2_3_1; -.
DR InParanoid; Q4WAZ6; -.
DR OMA; FDGKNHE; -.
DR OrthoDB; 702827at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000002530; Chromosome 8.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR GO; GO:1902086; P:fumagillin biosynthetic process; IGC:AspGD.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..536
FT /note="Multifunctional cytochrome P450 monooxygenase af510"
FT /id="PRO_0000437044"
FT TRANSMEM 4..24
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 448
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P04798"
FT CARBOHYD 210
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 293
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 536 AA; 60965 MW; 8BB699E2A41E3E7E CRC64;
MAYELSTLQL SCVAFVAFMA VLVFRTRTRN LKQNVPPGPR PLPIIGNFFD LPPKGQPEYL
HWFKHKDAYG PVSSINVMGT TLVIFHDKDA AHAVMGKKAQ KTSARPQLNF AQLCGFENFL
ITHQYNDKYR LHRKMVHQEI GTKGLSAGFR PIQEQESIRF ILQTFNRPDD ILQHLKTLAA
AIVLKITYGY SIERKGQDPL VELIEHAMEN LSQAFVPLAW AVDSVPAIKY LPDWFPGMSY
RKTARKWRAI NEAAAELPYD FVKRQMAHKA HQPSYVSNLL EKHMIKSEDN KINVSAADEE
AIKWTAVSLY AAGSDSTVAI IHSVICGLVM FPEVVTRAQE EIDRVVGSDR LPNFDDRTNL
PYVDGIIKEA WRWNPVGPMG LTHKSEEDLV CGEYLIPKGS YLLPSLWWFL NDPKEYPEPR
VFKPERYMEP FNHPDPSEIA FGYGRRSCAG RYFADASVYI TVVQLLAVFN VRKARDDQGN
EIPVTLQAIP GMVNRPAPFQ FKVEPRSQHH IDLLRRIESE QIPEVSHASL LKPSTV
