HELE_ASPFU
ID HELE_ASPFU Reviewed; 596 AA.
AC Q4WR24;
DT 25-OCT-2017, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 88.
DE RecName: Full=3-ketosteroid 1-dehydrogenase helE {ECO:0000303|PubMed:29158519};
DE EC=1.3.-.- {ECO:0000269|PubMed:29158519};
DE AltName: Full=Helvolic acid biosynthesis cluster protein E {ECO:0000303|PubMed:29158519};
GN Name=helE {ECO:0000303|PubMed:29158519}; ORFNames=AFUA_4G14850;
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 INDUCTION.
RX PubMed=17432932; DOI=10.1371/journal.ppat.0030050;
RA Perrin R.M., Fedorova N.D., Bok J.W., Cramer R.A., Wortman J.R., Kim H.S.,
RA Nierman W.C., Keller N.P.;
RT "Transcriptional regulation of chemical diversity in Aspergillus fumigatus
RT by LaeA.";
RL PLoS Pathog. 3:E50-E50(2007).
RN [3]
RP FUNCTION, AND PATHWAY.
RX PubMed=19415934; DOI=10.1021/ja8095976;
RA Mitsuguchi H., Seshime Y., Fujii I., Shibuya M., Ebizuka Y., Kushiro T.;
RT "Biosynthesis of steroidal antibiotic fusidanes: functional analysis of
RT oxidosqualene cyclase and subsequent tailoring enzymes from Aspergillus
RT fumigatus.";
RL J. Am. Chem. Soc. 131:6402-6411(2009).
RN [4]
RP FUNCTION.
RX PubMed=19216560; DOI=10.1021/ol802696a;
RA Lodeiro S., Xiong Q., Wilson W.K., Ivanova Y., Smith M.L., May G.S.,
RA Matsuda S.P.;
RT "Protostadienol biosynthesis and metabolism in the pathogenic fungus
RT Aspergillus fumigatus.";
RL Org. Lett. 11:1241-1244(2009).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=29158519; DOI=10.1038/s41467-017-01813-9;
RA Lv J.M., Hu D., Gao H., Kushiro T., Awakawa T., Chen G.D., Wang C.X.,
RA Abe I., Yao X.S.;
RT "Biosynthesis of helvolic acid and identification of an unusual C-4-
RT demethylation process distinct from sterol biosynthesis.";
RL Nat. Commun. 8:1644-1644(2017).
CC -!- FUNCTION: 3-ketosteroid 1-dehydrogenase; part of the gene cluster that
CC mediates the biosynthesis of helvolic acid, an antibacterial
CC nortriterpenoid (PubMed:19415934, PubMed:19216560, PubMed:29158519).
CC Protostadienol synthase helA cyclizes (3S)-oxidosqualene to (17Z)-
CC protosta-17(20),24-dien-3-beta-ol (protostadienol)(PubMed:19415934,
CC PubMed:19216560, PubMed:29158519). The synthesis of protostadienol is
CC followed by several steps of monooxygenation, dehydrogenation, and acyl
CC transfer to yield the final helvolic acid (PubMed:19216560). Following
CC the cyclization to the tetracyclic protostadienol by helA, cytochrome
CC P450 monooxygenases helB1-mediated and helB2-mediated oxidation at C-4
CC and C-16, acyltransferase helD2-dependent acetylation of 16-OH,
CC oxidation of C-21 by cytochrome P450 monooxygenase helB4, and short
CC chain dehydrogenase helC-dependent oxidative decarboxylation yield the
CC fusidane skeleton (PubMed:29158519). This intermediate is further
CC modified in three additional steps mediated by the cytochrome P450
CC monooxygenase helB3, the acyltransferase helD1, and the 3-ketosteroid
CC 1-dehydrogenase helE to give helvolic acid (PubMed:19415934,
CC PubMed:19216560, PubMed:29158519). Compared with the late stages in the
CC biosynthesis of helvolic acid, enzymes involved in the early stage
CC modifications act in a relatively strict order (PubMed:29158519). The
CC hydroxylation of C-16 by helB1 and subsequent acetylation by helD2
CC should occur before the helB3-mediated oxidation of C-21
CC (PubMed:29158519). C-4 demethylation in fusidane-type antibiotics
CC proceeds in an unusual manner though it is also achieved by oxidative
CC decarboxylation (PubMed:19415934, PubMed:29158519). The methyl group at
CC C-4 beta position is oxidized by helB1 and subsequently removed by the
CC short chain dehydrogenase helC (PubMed:19415934, PubMed:29158519).
CC {ECO:0000269|PubMed:19216560, ECO:0000269|PubMed:19415934,
CC ECO:0000269|PubMed:29158519}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:T2G6Z9};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:29158519,
CC ECO:0000305|PubMed:19415934}.
CC -!- INDUCTION: Expression is under the control of the secondary metabolism
CC regulator laeA (PubMed:17432932). {ECO:0000269|PubMed:17432932}.
CC -!- SIMILARITY: Belongs to the FAD-dependent oxidoreductase 2 family. 3-
CC oxosteroid dehydrogenase subfamily. {ECO:0000305}.
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DR EMBL; AAHF01000005; EAL89310.1; -; Genomic_DNA.
DR RefSeq; XP_751348.1; XM_746255.1.
DR AlphaFoldDB; Q4WR24; -.
DR SMR; Q4WR24; -.
DR STRING; 746128.CADAFUBP00007028; -.
DR EnsemblFungi; EAL89310; EAL89310; AFUA_4G14850.
DR GeneID; 3508866; -.
DR KEGG; afm:AFUA_4G14850; -.
DR VEuPathDB; FungiDB:Afu4g14850; -.
DR eggNOG; KOG2404; Eukaryota.
DR HOGENOM; CLU_011398_4_2_1; -.
DR InParanoid; Q4WR24; -.
DR OMA; HNEQMRV; -.
DR OrthoDB; 412868at2759; -.
DR Proteomes; UP000002530; Chromosome 4.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:1900812; P:helvolic acid biosynthetic process; IDA:GO_Central.
DR GO; GO:0019748; P:secondary metabolic process; IGC:AspGD.
DR Gene3D; 3.50.50.60; -; 2.
DR InterPro; IPR003953; FAD-binding_2.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR027477; Succ_DH/fumarate_Rdtase_cat_sf.
DR Pfam; PF00890; FAD_binding_2; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
DR SUPFAM; SSF56425; SSF56425; 1.
PE 1: Evidence at protein level;
KW FAD; Flavoprotein; Oxidoreductase; Reference proteome.
FT CHAIN 1..596
FT /note="3-ketosteroid 1-dehydrogenase helE"
FT /id="PRO_0000441954"
FT BINDING 28..31
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:T2G6Z9"
FT BINDING 46..47
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:T2G6Z9"
FT BINDING 53..55
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:T2G6Z9"
FT BINDING 410..411
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:T2G6Z9"
SQ SEQUENCE 596 AA; 64540 MW; CDB199EEA4FA493B CRC64;
MAARQLRRLS LPTHLPLPIR PHVRHLGTAQ TNCHRFDHET DILIVGSGAA GLTAALRSHF
HGLSSLVIEK DAQIGGTSAY SGGGLWIPNN PLAVEAGIID TPEQAMTYLI SVIDADTAED
TDVRRASSPP RKRAFLTHGP HMVSFLRDRG FAFRLSPGCP DYYPQAHGAL PTGGRSIEPD
VFDARLLGLG EKWTEAIRQR PGRSLPLFTY EASSVTRMGA SWRDVGTVLR VLLRGIYLSR
VRGQIPVTMG KSLVAQLLWL HMQLDQGPVL TDTALRQLIA TPEGVILGAR VATPDGERSI
RARCGVLLCA GGFAHNQGLR ERYGPVPANA EWTSAARGDN GDAIVAGVRV GAATALMDEA
WWGPTLRDPV RGMYYFALQE RARPFGVIVD SSGKRFMNEA EPYTDAGHHQ YAQKAVPAWF
VFDWNHRKRY AVGSLMPRQQ PPAQALDAGY IHRADTIAEL ARQIGVNEKG LEGTLARFNE
MADCGVDSDF ARGESAFDNY FGDPTVRPNP NLGAVRTPPF YAIPLVPGDL GTKGGLLTDE
HARVIREDGT PVQGLYAAGN TTASVMGRTY PGAGATLGPA MTFAFIAIDH IASEHV
