FMAA_ASPFU
ID FMAA_ASPFU Reviewed; 289 AA.
AC M4VQY9; Q4WAZ7;
DT 07-SEP-2016, integrated into UniProtKB/Swiss-Prot.
DT 29-MAY-2013, sequence version 1.
DT 25-MAY-2022, entry version 38.
DE RecName: Full=Fumagillin beta-trans-bergamotene synthase af520 {ECO:0000303|PubMed:23488861};
DE EC=4.2.3.- {ECO:0000269|PubMed:23488861};
DE AltName: Full=Fumagillin biosynthesis terpene cyclase {ECO:0000303|PubMed:23488861};
DE Short=Fma-TC {ECO:0000303|PubMed:23488861};
GN Name=af520 {ECO:0000303|PubMed:23488861};
GN Synonyms=fmaA {ECO:0000303|PubMed:24082142}; ORFNames=AFUA_8G00520;
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 [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RC STRAIN=ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100;
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 [2]
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 [3]
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 [4]
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 [5]
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 [6]
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 [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.
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: Beta-trans-bergamotene synthase; part of the gene cluster
CC that mediates the biosynthesis of fumagillin, a meroterpenoid that has
CC numerous biological activities including irreversible inhibition of
CC human type 2 methionine aminopeptidase (METAP2) (PubMed:23488861,
CC PubMed:24568283). The pathway begins with the conversion of farnesyl
CC pyrophosphate (FPP) to beta-trans-bergamotene by the membrane-bound
CC beta-trans-bergamotene synthase af520 (PubMed:23488861). The initial
CC oxidation of beta-trans-bergamotene by the multifunctional cytochrome
CC P450 monooxygenase af510 involves C-H hydroxylation at the bridgehead
CC C5 position to yield 5R-hydroxyl-beta-trans-bergamotene
CC (PubMed:24568283). Subsequently, a four electron oxidation initiated at
CC C-9 coupled to cleavage of the cyclobutane C5-C8 bond of the
CC bicyclo[3.1.1] core yields the epoxyketone intermediate 5-keto-cordycol
CC (PubMed:24568283). An additional epoxidation reaction also catalyzed by
CC af510 then furnishes the characteristic bisepoxide ketone 5-keto-
CC demethoxyfumagillol (PubMed:24568283). 5-keto-demethoxyfumagillol is
CC then subjected to successive C-6 hydroxylation and O-methylation by the
CC dioxygenase af480 and O-methyltransferase af390-400, respectively, to
CC yield 5-keto-fumagillol, which is then stereoselectively reduced by the
CC keto-reductase af490 to 5R-hydroxy-seco-sesquiterpene
CC (PubMed:24568283). The next step is the polyketide transferase af380-
CC catalyzed transfer of a dodecapentaenoyl group synthesized by the
CC polyketide synthase af370 onto 5R-hydroxy-seco-sesquiterpene which
CC leads to the production of prefumagillin (PubMed:24568283). Finally,
CC oxidative cleavage by the monooxygenase af470 converts prefumagillin to
CC fumagillin (PubMed:24568283). {ECO:0000269|PubMed:23488861,
CC ECO:0000269|PubMed:24568283}.
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:23488861}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-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 (PubMed:24082142). {ECO:0000269|PubMed:24082142}.
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 paxB family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=EAL85115.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; KC407776; AGI05042.1; -; mRNA.
DR EMBL; AAHF01000014; EAL85115.1; ALT_SEQ; Genomic_DNA.
DR RefSeq; XP_747153.1; XM_742060.1.
DR AlphaFoldDB; M4VQY9; -.
DR STRING; 746128.CADAFUBP00008383; -.
DR GeneID; 3504512; -.
DR KEGG; afm:AFUA_8G00520; -.
DR VEuPathDB; FungiDB:Afu8g00520; -.
DR eggNOG; ENOG502RZB9; Eukaryota.
DR OrthoDB; 1231215at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000002530; Chromosome 8.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016829; F:lyase activity; IEA:UniProtKB-KW.
DR GO; GO:0016765; F:transferase activity, transferring alkyl or aryl (other than methyl) groups; IEA:InterPro.
DR GO; GO:1902086; P:fumagillin biosynthetic process; IMP:AspGD.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.357.140; -; 1.
DR InterPro; IPR000537; UbiA_prenyltransferase.
DR InterPro; IPR044878; UbiA_sf.
DR Pfam; PF01040; UbiA; 1.
PE 1: Evidence at protein level;
KW Lyase; Membrane; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..289
FT /note="Fumagillin beta-trans-bergamotene synthase af520"
FT /id="PRO_0000437038"
FT TRANSMEM 35..55
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 95..115
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 142..162
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 165..185
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 222..242
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 262..282
FT /note="Helical"
FT /evidence="ECO:0000255"
SQ SEQUENCE 289 AA; 31676 MW; 3F836CC17360104F CRC64;
MDRVLSLGKL PISFLKTLYL FSKSDIPAAT LPSMAVALVL AAPCSFHLII KGFLWNQLHL
LTFQVKNQID GIDEDSIAKP HRPLPSGRIT PGQATLLYRV LFFLMWVAAV YTNTISCTLV
YSIAIVVYNE GGLAAIPVVK NLIGAIGLGC YCWGTTIIFD GGKELHGLKA VAVLMIVGIF
ATTGHAQDFR DRTADATRGR KTIPLLLSQP VARWSLATIT AAWTIGLIAL WKPPAIVTLA
YVAASLRCLD GFLSSYDEKD DYVSYCWYGF WLLGSNILPI FPRLRGELP
