ID   HELB2_ASPFU             Reviewed;         507 AA.
AC   Q4WR18;
DT   25-OCT-2017, integrated into UniProtKB/Swiss-Prot.
DT   05-JUL-2005, sequence version 1.
DT   03-AUG-2022, entry version 101.
DE   RecName: Full=Cytochrome P450 monooxygenase helB2 {ECO:0000303|PubMed:25311525};
DE            EC=1.-.-.- {ECO:0000269|PubMed:19415934, ECO:0000269|PubMed:29158519};
DE   AltName: Full=Helvolic acid biosynthesis cluster protein B2 {ECO:0000303|PubMed:25311525};
DE   Flags: Precursor;
GN   Name=helB2 {ECO:0000303|PubMed:29158519};
GN   Synonyms=cyp5081B1 {ECO:0000303|PubMed:19415934}; ORFNames=AFUA_4G14790;
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   INDUCTION.
RX   PubMed=25311525; DOI=10.1186/1471-2164-15-894;
RA   O'Keeffe G., Hammel S., Owens R.A., Keane T.M., Fitzpatrick D.A.,
RA   Jones G.W., Doyle S.;
RT   "RNA-seq reveals the pan-transcriptomic impact of attenuating the gliotoxin
RT   self-protection mechanism in Aspergillus fumigatus.";
RL   BMC Genomics 15:894-894(2014).
RN   [6]
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: Cytochrome P450 monooxygenase; 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=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000250|UniProtKB:P04798};
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). Expression is completely abrogated
CC       when gliT is deleted in cells exposed to exogenous gliotoxin
CC       (PubMed:25311525). {ECO:0000269|PubMed:17432932,
CC       ECO:0000269|PubMed:25311525}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family.
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DR   EMBL; AAHF01000005; EAL89316.1; -; Genomic_DNA.
DR   RefSeq; XP_751354.1; XM_746261.1.
DR   AlphaFoldDB; Q4WR18; -.
DR   SMR; Q4WR18; -.
DR   STRING; 746128.CADAFUBP00007022; -.
DR   EnsemblFungi; EAL89316; EAL89316; AFUA_4G14790.
DR   GeneID; 3509335; -.
DR   KEGG; afm:AFUA_4G14790; -.
DR   VEuPathDB; FungiDB:Afu4g14790; -.
DR   eggNOG; KOG0156; Eukaryota.
DR   HOGENOM; CLU_001570_14_2_1; -.
DR   InParanoid; Q4WR18; -.
DR   OMA; VEWIMAT; -.
DR   OrthoDB; 702827at2759; -.
DR   Proteomes; UP000002530; Chromosome 4.
DR   GO; GO:0020037; F:heme binding; IEA:InterPro.
DR   GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR   GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR   GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR   GO; GO:1900812; P:helvolic acid biosynthetic process; IDA:GO_Central.
DR   GO; GO:0019748; P:secondary metabolic process; IGC:AspGD.
DR   Gene3D; 1.10.630.10; -; 1.
DR   InterPro; IPR001128; Cyt_P450.
DR   InterPro; IPR017972; Cyt_P450_CS.
DR   InterPro; IPR002401; Cyt_P450_E_grp-I.
DR   InterPro; IPR036396; Cyt_P450_sf.
DR   Pfam; PF00067; p450; 1.
DR   PRINTS; PR00463; EP450I.
DR   PRINTS; PR00385; P450.
DR   SUPFAM; SSF48264; SSF48264; 1.
DR   PROSITE; PS00086; CYTOCHROME_P450; 1.
PE   1: Evidence at protein level;
KW   Heme; Iron; Metal-binding; Monooxygenase; Oxidoreductase;
KW   Reference proteome; Signal.
FT   SIGNAL          1..22
FT                   /evidence="ECO:0000255"
FT   CHAIN           23..507
FT                   /note="Cytochrome P450 monooxygenase helB2"
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000441948"
FT   BINDING         436
FT                   /ligand="heme"
FT                   /ligand_id="ChEBI:CHEBI:30413"
FT                   /ligand_part="Fe"
FT                   /ligand_part_id="ChEBI:CHEBI:18248"
FT                   /note="axial binding residue"
FT                   /evidence="ECO:0000250|UniProtKB:P04798"
SQ   SEQUENCE   507 AA;  57810 MW;  16F1DE6E90612F32 CRC64;
     MALPIILCLA VILWTSWRLL DALFLSPLHR VPGPVLARLT PLRAIYARLP SRVIPAALAD
     FHSYGDIYLS KPRTITISHP RDVRAILASS EFQKIDVYHG LNDPVMANIV TFSDPKLASR
     RRRQIGPYFN PSYLAKMEEL ILRCGCRAVA DKWGRLIAQQ GHGPQKSVKV NYRHDLQLAT
     FDIMSALAFG RWLDSLKEEG ESVAIVEWIM ATAVYIGVRI NFRLLMVFPF SRLVRRWTRA
     YAEFVQFSKH AVASRKELLA QGCQKPVDLL QAFIDAEDPD SKVKMTTVEV QAESVGMQLA
     GSETTAASLT WAVHLFTLYP EYYRIAVDEV RGQFGPNHLI TYADCSRLVF LEAFVYEMLR
     YTPITSSFMP RVSFTKGTTL QGHYIPPGTE IAFNLIAMNN REDVWEEPER FLPDRFLKDP
     DLKRSVFAFS YGTRSCIGRH LAWMEMMTIL ANLLKDYDWS LPEDSLYGPH HVDEKGIPIR
     MPSKCHIVFA PTHPDRDCQL VISRPKT