FMAF_ASPFU
ID FMAF_ASPFU Reviewed; 309 AA.
AC Q4WAZ3;
DT 07-SEP-2016, integrated into UniProtKB/Swiss-Prot.
DT 17-APR-2007, sequence version 2.
DT 03-AUG-2022, entry version 75.
DE RecName: Full=Dioxygenase af480 {ECO:0000303|PubMed:24568283};
DE EC=1.14.11.- {ECO:0000269|PubMed:24568283};
DE AltName: Full=Fumagillin biosynthesis cluster C-6 hydroxylase {ECO:0000303|PubMed:24568283};
DE Short=Fma-C6H {ECO:0000303|PubMed:24568283};
GN Name=af480 {ECO:0000303|PubMed:23488861};
GN Synonyms=fmaF {ECO:0000303|PubMed:24082142}; ORFNames=AFUA_8G00480;
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, DISRUPTION PHENOTYPE, AND CATALYTIC ACTIVITY.
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: Dioxygenase; part of the gene cluster that mediates the
CC biosynthesis of fumagillin, a meroterpenoid that has numerous
CC biological activities including irreversible inhibition of human type 2
CC methionine aminopeptidase (METAP2) (PubMed:23488861, PubMed:24568283).
CC The pathway begins with the conversion of farnesyl pyrophosphate (FPP)
CC to beta-trans-bergamotene by the membrane-bound beta-trans-bergamotene
CC synthase af520 (PubMed:23488861). The initial oxidation of beta-trans-
CC bergamotene by the multifunctional cytochrome P450 monooxygenase af510
CC involves C-H hydroxylation at the bridgehead C5 position to yield 5R-
CC hydroxyl-beta-trans-bergamotene (PubMed:24568283). Subsequently, a four
CC electron oxidation initiated at C-9 coupled to cleavage of the
CC cyclobutane C5-C8 bond of the bicyclo[3.1.1] core yields the
CC epoxyketone intermediate 5-keto-cordycol (PubMed:24568283). An
CC additional epoxidation reaction also catalyzed by af510 then furnishes
CC the characteristic bisepoxide ketone 5-keto-demethoxyfumagillol
CC (PubMed:24568283). 5-keto-demethoxyfumagillol is then subjected to
CC successive C-6 hydroxylation and O-methylation by the dioxygenase af480
CC and O-methyltransferase af390-400, respectively, to yield 5-keto-
CC fumagillol, which is then stereoselectively reduced by the keto-
CC reductase af490 to 5R-hydroxy-seco-sesquiterpene (PubMed:24568283). The
CC next step is the polyketide transferase af380-catalyzed transfer of a
CC dodecapentaenoyl group synthesized by the polyketide synthase af370
CC onto 5R-hydroxy-seco-sesquiterpene which leads to the production of
CC prefumagillin (PubMed:24568283). Finally, oxidative cleavage by the
CC monooxygenase af470 converts prefumagillin to fumagillin
CC (PubMed:24568283). {ECO:0000269|PubMed:23488861,
CC ECO:0000269|PubMed:24568283}.
CC -!- COFACTOR:
CC Name=Fe cation; Xref=ChEBI:CHEBI:24875;
CC Evidence={ECO:0000250|UniProtKB:O14832};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:24568283}.
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 6-demethoxyfumagillin
CC (PubMed:24082142, PubMed:24568283). {ECO:0000269|PubMed:24082142,
CC 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 PhyH family. {ECO:0000305}.
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DR EMBL; AAHF01000014; EAL85119.2; -; Genomic_DNA.
DR RefSeq; XP_747157.2; XM_742064.2.
DR AlphaFoldDB; Q4WAZ3; -.
DR SMR; Q4WAZ3; -.
DR STRING; 746128.CADAFUBP00008387; -.
DR EnsemblFungi; EAL85119; EAL85119; AFUA_8G00480.
DR GeneID; 3504545; -.
DR KEGG; afm:AFUA_8G00480; -.
DR VEuPathDB; FungiDB:Afu8g00480; -.
DR eggNOG; ENOG502SKX1; Eukaryota.
DR HOGENOM; CLU_047725_3_1_1; -.
DR InParanoid; Q4WAZ3; -.
DR OMA; RVWHTSG; -.
DR OrthoDB; 623398at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000002530; Chromosome 8.
DR GO; GO:0051213; F:dioxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:1902086; P:fumagillin biosynthetic process; IGC:AspGD.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR InterPro; IPR008775; Phytyl_CoA_dOase.
DR Pfam; PF05721; PhyH; 1.
PE 1: Evidence at protein level;
KW Dioxygenase; Iron; Metal-binding; Oxidoreductase; Reference proteome.
FT CHAIN 1..309
FT /note="Dioxygenase af480"
FT /id="PRO_0000437046"
FT BINDING 153
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:O14832"
FT BINDING 155
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:O14832"
FT BINDING 228
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:O14832"
SQ SEQUENCE 309 AA; 34231 MW; 2538AF4E22CFBB04 CRC64;
MLGRHECTIS ESVSALDPTA QEPEYTLVPS TSRDLVRDMT LNMEDAQAHL KEHGWVKIPA
VLSKAEAEDA LSRLWEAKAA SEARGECTFQ PILDPNPANV RVFYLPELDA YWRDMLVNPT
ALDLAKSLLG DQLLVSNFSA NIARPGAESM ALHSDQSIVL PAPWLDVWAV NVIWCLTRMT
KENGATLYIP GSNKWTTWED VPDNAPDLLV PFEADAGDIV VIDGRLWHTS GSNVTEDEDR
AILFAYYSAP HMRPLTNWSA KLPKELQETL SPQLKELLAL SHIGYVVKGD LTYMAQKYPS
EKGTTAVSA
