ID   HELB1_ASPFU             Reviewed;         580 AA.
AC   Q4WR17;
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 helB1 {ECO:0000303|PubMed:29158519};
DE            EC=1.-.-.- {ECO:0000269|PubMed:19415934, ECO:0000269|PubMed:29158519};
DE   AltName: Full=Helvolic acid biosynthesis cluster protein B1 {ECO:0000303|PubMed:29158519};
GN   Name=helB1 {ECO:0000303|PubMed:29158519};
GN   Synonyms=cyp5081A1 {ECO:0000303|PubMed:19415934}; ORFNames=AFUA_4G14780;
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, CATALYTIC ACTIVITY, 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:19415934,
CC       ECO:0000269|PubMed:29158519}.
CC   -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC       protein {ECO:0000255}.
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.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AAHF01000005; EAL89317.1; -; Genomic_DNA.
DR   RefSeq; XP_751355.1; XM_746262.1.
DR   AlphaFoldDB; Q4WR17; -.
DR   SMR; Q4WR17; -.
DR   STRING; 746128.CADAFUBP00007021; -.
DR   EnsemblFungi; EAL89317; EAL89317; AFUA_4G14780.
DR   GeneID; 3509336; -.
DR   KEGG; afm:AFUA_4G14780; -.
DR   VEuPathDB; FungiDB:Afu4g14780; -.
DR   eggNOG; KOG0157; Eukaryota.
DR   HOGENOM; CLU_001570_14_2_1; -.
DR   InParanoid; Q4WR17; -.
DR   OMA; YLMHFGL; -.
DR   OrthoDB; 1247045at2759; -.
DR   Proteomes; UP000002530; Chromosome 4.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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   Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW   Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix.
FT   CHAIN           1..580
FT                   /note="Cytochrome P450 monooxygenase helB1"
FT                   /id="PRO_0000441947"
FT   TRANSMEM        61..81
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   REGION          1..32
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         497
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"
FT   CARBOHYD        28
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ   SEQUENCE   580 AA;  65467 MW;  D0A65791CE0AFEF0 CRC64;
     MRTYAIRPVS NRLPGPIEPK KHRRDRDNST TGSLYNALIH PVQGEKTITS TMIRVAEFQP
     FLNTISVLQV LAAIFIGALT YRLIDAFFLS PLRSIPGPLL ARLTTKRANV DTFSGKVTQT
     VDKDVARYGD VYVYKPRAVC INHPDDIRAV LGSQEFRKAA FFDIFNDGNT PNIVSLREPE
     LANRRRRQLG PFFNYAYLGR AEPLILQHGY QAIRTKWDAL IQANSGRPTE VNYRTDTQLV
     TFDIMSALAF GRNFNAISRG SSSIMKWAGL IMEMLESPAV LALLSLLPFS LIMRPWKIMY
     RELAAFSSDA VDMRKQLLAE DSTEKPLDML QAFIDAEDPE SKIKMSPHEV QAESIMMMLA
     GSETTSSAIM WTFHLLLLYP ETLRRAVHEV RSAFSLNHLV TYKDVRSSLP YVEACVYEAL
     RHSPTTAGLT PRISHSTGIT LQGYYIPPGT EIYVNLRSPS MHPSLWDDPA RFNPDRFLDS
     DNNKRLLFTF SYGPRNCLGR NLAWVEMLTI VANVLKDYDI ALTEDSLFGP HCTDENGLPV
     LMPAKCFIAS FPAKPERDCR MVITRRMAGV KACAREYSPC