FMAH_ASPFU
ID FMAH_ASPFU Reviewed; 1017 AA.
AC Q4WAZ4;
DT 07-SEP-2016, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 94.
DE RecName: Full=Stereoselective keto-reductase af490 {ECO:0000303|PubMed:24568283};
DE EC=1.1.1.- {ECO:0000269|PubMed:24568283};
DE AltName: Full=Fumagillin biosynthesis cluster keto-reductase {ECO:0000303|PubMed:24568283};
DE Short=Fma-KR {ECO:0000303|PubMed:24568283};
GN Name=af490 {ECO:0000303|PubMed:23488861}; ORFNames=AFUA_8G00490;
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, AND INDUCTION.
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: Stereoselective keto-reductase; 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: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: Strongly decreases the production of fumagillin
CC (PubMed:24568283). {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 -!- CAUTION: Was first identified as a pseudogene since it seemed to be
CC altered polyketide synthase with only the dehydratase (DH) and
CC ketoreductase (KR) domains remaining (PubMed:23488861). Further study
CC showed it encoded indeed for a functional keto-reductase involved in
CC fumagillin biosynthesis (PubMed:24568283).
CC {ECO:0000269|PubMed:23488861, ECO:0000269|PubMed:24568283}.
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DR EMBL; AAHF01000014; EAL85118.1; -; Genomic_DNA.
DR RefSeq; XP_747156.1; XM_742063.1.
DR AlphaFoldDB; Q4WAZ4; -.
DR SMR; Q4WAZ4; -.
DR STRING; 746128.CADAFUBP00008386; -.
DR PRIDE; Q4WAZ4; -.
DR EnsemblFungi; EAL85118; EAL85118; AFUA_8G00490.
DR GeneID; 3504544; -.
DR KEGG; afm:AFUA_8G00490; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_296646_0_0_1; -.
DR InParanoid; Q4WAZ4; -.
DR OMA; YTIACES; -.
DR OrthoDB; 19161at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000002530; Chromosome 8.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF53335; SSF53335; 1.
PE 1: Evidence at protein level;
KW Oxidoreductase; Reference proteome.
FT CHAIN 1..1017
FT /note="Stereoselective keto-reductase af490"
FT /id="PRO_0000437042"
FT REGION 8..306
FT /note="Dehydratase (DH)"
FT /evidence="ECO:0000255"
FT REGION 532..720
FT /note="Ketoreductase (KR)"
FT /evidence="ECO:0000255"
SQ SEQUENCE 1017 AA; 110955 MW; 9A7514D7CD1A5CD4 CRC64;
MLGLPNELSG SQVPGATEYE PGWRRVFKVE DLPGLGDYHI DNQTAVPTSI VCVIALAAAM
DISNGKQANS IELYDVTIGR PIHLGTSPVE IETMIAIEPG KDGADSIQAE FSLNKSAGHD
ENPVSVANGR LRMTFAGHEL ELLSSRQAKP CGLRPVSISP FYDSLREVGL GYSGPFRALT
SAERRMDYAC GVIAPTTGEA SRTPALLHPA MLEACFQTLL LAFAAPRDGS LWTIFVPTQI
GRLTIFPNSS VGINTPASVT IDTHLHEFTA GHKADLPMIK GDVSVYSSEA GQLRIRLEGL
TMSPIAPSTE KQDKRLYLKR TWLPDILSGP VLERGKPVFC YELFGLSLAP KSILAATRLL
SHRYAKLKIL QVGTSSVHLV HSLCRELGSS MDSYTIACES DSSMEDMRRR LLSDALPIKY
VVLDIGKSLT EGDEPAAGEP TDLGSFDLII LLKASADDSP ILKRTRGLIK PGGFLLMTVA
ATEAIPWEAR DMTRKAIHDT LQSVGFSGVD LLQRDPEGDS SFVILSQAVD HQIRFLRAPF
DSTPPFPTRG TLLVIGGASH RAKRPIETIQ NSLRRVWAGE IVLIRSLTDL QTRGLDHVEA
VLSLTELDQS VLENLSRDTF DGLHRLLHQS KIVLWVTYSA GNLNPHQSGA IGLVRAVQAE
TPDKVLQLLD VDQIDGNDGL VAESFLRLIG GVKMKDGSSN SLWTVEPELS VQGGRLLIPR
VLFDKKRNDR LNCLRRQLKA TDSFEKQSAL ARPIDPCSLF SPNKTYVLAG LSGQMGQSIT
RWIVQSGGRH IVITSRNPDK DDLWTKELEQ RGAHIEIMAA DVTKKQEMIN VRNQILSAMP
PIGGVANGAM LQSNCFFSDL TYEALQDVLK PKVDGSLVLD EVFSSDDLDF FLLFSSISAV
VGQPFQANYD AANNFMTGLV LQRRARNLPA SVINLGPIIG LGFIQNIDSG GGSEAVIATL
RSLDYMLVSE RELHHILAEA ILIGKSDETP EIITGLETVS DNPAPFWHKS LLFSHII
