FMAB_ASPFU
ID FMAB_ASPFU Reviewed; 2435 AA.
AC Q4WAY3; M4VUP2;
DT 07-SEP-2016, integrated into UniProtKB/Swiss-Prot.
DT 07-SEP-2016, sequence version 2.
DT 25-MAY-2022, entry version 116.
DE RecName: Full=Fumagillin dodecapentaenoate synthase {ECO:0000305};
DE EC=2.3.1.- {ECO:0000269|PubMed:23488861};
DE AltName: Full=Fumagillin biosynthesis polyketide synthase {ECO:0000303|PubMed:23488861};
DE Short=Fma-PKS {ECO:0000303|PubMed:23488861};
GN Name=af370 {ECO:0000303|PubMed:23488861};
GN Synonyms=fmaB {ECO:0000303|PubMed:24082142}; ORFNames=AFUA_8G00370;
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.
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: Dodecapentaenoate synthase; part of the gene cluster that
CC 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 -!- 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 -!- DOMAIN: Multidomain protein; including a starter unit:ACP transacylase
CC (SAT) that selects the starter unit; a ketosynthase (KS) that catalyzes
CC repeated decarboxylative condensation to elongate the polyketide
CC backbone; a malonyl-CoA:ACP transacylase (MAT) that selects and
CC transfers the extender unit malonyl-CoA; a product template (PT) domain
CC that controls the immediate cyclization regioselectivity of the
CC reactive polyketide backbone; and an acyl-carrier protein (ACP) that
CC serves as the tether of the growing and completed polyketide via its
CC phosphopantetheinyl arm (By similarity).
CC {ECO:0000250|UniProtKB:Q5B0D0}.
CC -!- DOMAIN: The release of the polyketide chain from the non-reducing
CC polyketide synthase is mediated by the thioesterase (TE) domain
CC localized at the C-ter of the protein (By similarity).
CC {ECO:0000250|UniProtKB:Q5ATJ7}.
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 -!- SEQUENCE CAUTION:
CC Sequence=EAL85129.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; KC407775; AGI05041.1; -; mRNA.
DR EMBL; AAHF01000014; EAL85129.1; ALT_SEQ; Genomic_DNA.
DR RefSeq; XP_747167.1; XM_742074.1.
DR AlphaFoldDB; Q4WAY3; -.
DR SMR; Q4WAY3; -.
DR STRING; 746128.CADAFUBP00008398; -.
DR GeneID; 3504549; -.
DR KEGG; afm:AFUA_8G00370; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_31_0_1; -.
DR InParanoid; Q4WAY3; -.
DR OrthoDB; 19161at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000002530; Chromosome 8.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0004312; F:fatty acid synthase activity; IBA:GO_Central.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:InterPro.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IBA:GO_Central.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IBA:GO_Central.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR InterPro; IPR001227; Ac_transferase_dom_sf.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR011032; GroES-like_sf.
DR InterPro; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020843; PKS_ER.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF51735; SSF51735; 3.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 1: Evidence at protein level;
KW Multifunctional enzyme; Phosphopantetheine; Phosphoprotein;
KW Reference proteome; Transferase.
FT CHAIN 1..2435
FT /note="Fumagillin dodecapentaenoate synthase"
FT /id="PRO_0000437039"
FT DOMAIN 2355..2431
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 20..203
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 338..698
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 887..1155
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1221..1519
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 2057..2398
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 188
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 188
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 672
FT /note="For malonyltransferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 999
FT /note="For beta-hydroxyacyl dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 2336
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT MOD_RES 2391
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2435 AA; 263577 MW; 7789A57F35764FCF CRC64;
MTLTYGHKRL QDAPEPIAIV SAACRLPGHV NGPHKLWELL QSGGTAVSNE VPQSRFSSEG
HFDGSGRPGT MKALSGMFIE DIDPAAFDAA FFNLTRADAI AMDPQQRQLL EVVYECFENG
GIPIEKVRGK QIGCYVGSLN GDYHDMQMRD PEQRVSGHAV GTGRAILSNR ISHFFDLRGS
SFTIDTACSS GLVGVDVACK NLRAGTLTGA VVAGVNLWLS PEHTEERGTM RAAYSASGKC
HTFDAKADGY CRAEAVNAVY LKRLSDAVRD GDPIRAVIRG TASNSDGWTP GINSPSAQAQ
AAMIREAYAN AGIDSSEYAE TGYLECHGTG TPAGDPTEVK GAASVLAHMR PPASPLIIGS
VKSNIGHSEP GAGLSGLIKA MLVVEEGEIP GNPTFLNPNP AIDFDNLRVY ATRIRIPWPK
ESSHYRRASV NSFGFGGSNA HAVLDNAEHY LGKYWASLEI PRSHLSSYIN LSDMLSLFDG
RRSSKTVTRR PQVLVFSAND MDSLKRQIST LSAHLLNPRV KVKLSDLSYT LSERRSRHFC
RAFLLSYPAK SGHASKIAVE EAQFSKISQE ATRIGFVFTG QGAQWSQMGL ELVRTFPGVV
KPILEQLDNV LQELPADLKS EWSLLQELTE ARSSEHLSRP EFSQPLVTAL QLAQLAVLQS
WGVRAEAVIG HSSGEIAAAC SAGLLTPRQA ILNAYFRGLA GKSALATSPK GMMAVGLGAQ
DVQPYLEGVS ADVVIACHNS PASVTLSGSA STLAELEGTI KAAGHFARML RVEVAYHSPH
MAKIANRYEE LLKEHGRLDD GSKTNKRSNR MISTVTEDEV TGAQVCDAAY WKANMLSPVR
FDGACNKLLT NTQLAPNFLI ELGPSNTLAG PVTQIARAAK VDNLTYAAAN KRGPDESSRA
IFDVAGHLFL QNADISLDKV NLGDNTPDKA KPAVIVDLPN YQWKHSTHYW HESLASKDWR
FKKFPSHDLL GSKVIGTLWQ SPSWHKMLRL SDVPWLRDHR IGSEILFPAA GYLAMAMEAV
RQAALSTATA EARELLKTRH YRYCLRDVQF PRGLVLEDDA EVHIMLLLVP MAKLGQGWWE
YKITSLAESD SVASSSSSTL SPEKWNINST GLVRLETILE ASSSRAPEHT CSLPLDNPTP
GQMWYKSLRD AGYSYGPSFQ RLVAVESTEG KSATRSLISL EPPRSKWEPQ SEYPLHPAPL
DSVLQSMFPS LHRGNRTKLD QLLVPRGIGE LTVSGDIWKS GEAISVTTWN KVSGDASLYD
PASRSLIMQL NSVSFSPMLD GRDSLYMSHV YTQLTWKPDF QLLDTDEKLQ QALSGGDGAA
SSLVQDLLDL AAHKAPNLRV LEFNLVPGSS ESLWLAGHPT PRAVRTALTE FHFAANSADT
ALAAQEEYAE WPAARTARFS VLDPFSKALA VPAGSSQFDL VIIRRPQHAD LGELDILVGN
LRRLTSDGGS VIFYDSKQSS LSGGRGLANG HNHFPAALQR FGLTKVRQTR DGSCIVAEVS
PAQNLSLRND FRVVIVRFST ARSTIIDHTI SQLRQFGWTL TEICIYNESG TGLPQLPPKS
TVLVLDELDR PLLATATDHE WTALQAIIQS ECNLLWVTEG SQVRPTAPLK AVAHGIFRTV
RAEVPMMRIV TLDVESATTE SLGTNASAIN MALREITLAD RSSLPIECEI AERGGLLHVS
RIWPDAGVNK RKVEDNAGGA PPVLTNLHDS KSTIRLMASR PGSLEALHFA EQGRDVCSRQ
DMGPDDVEVE IFAAGCNSRD IDVAMGDISG DLDGLGLEGA GVVVRVGACV SARCVGQRVA
VFGKGCFANR VTVSCKATFP LPDAMSFEQA ATLPIALLTA LYAVGRLAHV QGDDRVLVHS
PCTDVGIACI RLCQRSGSTP FATVDNLEQR HFLTHELGLP EDHIFMSEPA AFPRALRHAT
KGHGLDVIIS QPANRNLDNE NMRLLAPGGR LIGIANGGAD VGNLLPTGSL APNCSFQRLD
VTALPEKTIE SVFLELSRLV TDGSVQPLSP STLLGYEEIP KALQLLREGT HIGKIVISDP
RGTKLAVLTR PATTLAQSMI NPSHCYLLVG GLKGICGSLA IHLASHGAKN IAVMSRSGGG
DQVSQGIARN IRALGCSLDL LQGDVTSISD VRRAFSQISV PLGGIIQGAA VFRDRTFESM
SHEDYHAAVS SKVTGTCNLH TVSLETNQPI SFFTMLSSIS GVIGQKGQAN YAGGNAFQDA
FAEYRRALGL PAISIDLGPV EDVGVIHGNE DLQNRFDGST LLSINEGLLR RIFDYSILQQ
HPDPQHRLNV TSQGQMITSI LVPQPEDSDL LRDCRFRGLR ALGEHSPRSR RDPTKDKEIQ
SLLFLAQSQD PDRAALRAAA ITVVGARLAK QLRLTDAVDP ARPLSYYGLD SLAAVELRTW
VRMTLAIELT TLDVMNAASL GELCEKVIGK MGFGM
