ID   HELB4_ASPFU             Reviewed;         504 AA.
AC   Q4WR22;
DT   25-OCT-2017, integrated into UniProtKB/Swiss-Prot.
DT   05-JUL-2005, sequence version 1.
DT   03-AUG-2022, entry version 97.
DE   RecName: Full=Cytochrome P450 monooxygenase helB4 {ECO:0000303|PubMed:29158519};
DE            EC=1.-.-.- {ECO:0000269|PubMed:19415934, ECO:0000269|PubMed:29158519};
DE   AltName: Full=Helvolic acid biosynthesis cluster protein B4 {ECO:0000303|PubMed:29158519};
DE   Flags: Precursor;
GN   Name=helB4 {ECO:0000303|PubMed:29158519};
GN   Synonyms=cyp5081C1 {ECO:0000303|PubMed:19415934}; ORFNames=AFUA_4G14830;
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: 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). {ECO:0000269|PubMed:17432932}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family.
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DR   EMBL; AAHF01000005; EAL89312.1; -; Genomic_DNA.
DR   RefSeq; XP_751350.1; XM_746257.1.
DR   AlphaFoldDB; Q4WR22; -.
DR   SMR; Q4WR22; -.
DR   STRING; 746128.CADAFUBP00007026; -.
DR   EnsemblFungi; EAL89312; EAL89312; AFUA_4G14830.
DR   GeneID; 3508868; -.
DR   KEGG; afm:AFUA_4G14830; -.
DR   VEuPathDB; FungiDB:Afu4g14830; -.
DR   eggNOG; KOG0157; Eukaryota.
DR   HOGENOM; CLU_001570_14_2_1; -.
DR   InParanoid; Q4WR22; -.
DR   OMA; HRNCIGR; -.
DR   OrthoDB; 467733at2759; -.
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..23
FT                   /evidence="ECO:0000255"
FT   CHAIN           24..504
FT                   /note="Cytochrome P450 monooxygenase helB4"
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000441949"
FT   BINDING         434
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   504 AA;  58233 MW;  8F648C68F6D933D9 CRC64;
     MVEILRFIPL VLLLTLTWRI TYELFFSPLR HIPGSLLARL SSKYSILKRV LSDGPQSVQA
     DYQYYGNIYV HRPNGVSISH PDDIRTVLLS PEFRKTKVYE MLDIEGHASI FTTRDPAQAS
     RRRRQIGPYL NHGYLGRMEG LIMKYSVLAI KRKWDRLLEE SGGQQVTVNY RDHKQYATFD
     TIGALAFGRE FNALTNDDRT VIRWIEATGL YLGIRKNFPL LKLWPFSRVL RQYRERYERF
     IAYSKESVTR RKNLLSTVGE RPMDLLQAFI DAEDPENPHV KMTADEVMTE SIAMQLAGSE
     STSFVTSWVI HLLTLYPQHL AKVTEEIRSQ FSPSHLITFA ECRDKLPYLE ACVYETLRYS
     PITSGFLPRI SYTKGLTIQG HYIPPGVEIA INLHGAHINK DVWTNPHLYD PTRFLGDDQA
     KRNVFAFSYG HRNCIGRNLA MMEIMIIIAN ILKEYDIALP EDSVHGPWNV DALGRPRIMP
     TRSALFTTPK YPERDCRLVV SRRQ