HELB3_ASPFU
ID HELB3_ASPFU Reviewed; 507 AA.
AC Q4WR20;
DT 25-OCT-2017, integrated into UniProtKB/Swiss-Prot.
DT 17-APR-2007, sequence version 2.
DT 03-AUG-2022, entry version 96.
DE RecName: Full=Cytochrome P450 monooxygenase helB3 {ECO:0000303|PubMed:29158519};
DE EC=1.-.-.- {ECO:0000269|PubMed:19415934, ECO:0000269|PubMed:29158519};
DE AltName: Full=Helvolic acid biosynthesis cluster protein B3 {ECO:0000303|PubMed:29158519};
DE Flags: Precursor;
GN Name=helB3 {ECO:0000303|PubMed:29158519};
GN Synonyms=cyp5081D1 {ECO:0000303|PubMed:19415934}; ORFNames=AFUA_4G14810;
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; EAL89314.2; -; Genomic_DNA.
DR RefSeq; XP_751352.2; XM_746259.2.
DR AlphaFoldDB; Q4WR20; -.
DR SMR; Q4WR20; -.
DR STRING; 746128.CADAFUBP00007024; -.
DR EnsemblFungi; EAL89314; EAL89314; AFUA_4G14810.
DR GeneID; 3508870; -.
DR KEGG; afm:AFUA_4G14810; -.
DR VEuPathDB; FungiDB:Afu4g14810; -.
DR eggNOG; KOG0158; Eukaryota.
DR HOGENOM; CLU_001570_14_2_1; -.
DR InParanoid; Q4WR20; -.
DR OMA; HETRRNM; -.
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; 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.
PE 1: Evidence at protein level;
KW Glycoprotein; Iron; Metal-binding; Monooxygenase; Oxidoreductase;
KW Reference proteome; Signal.
FT SIGNAL 1..25
FT /evidence="ECO:0000255"
FT CHAIN 26..507
FT /note="Cytochrome P450 monooxygenase helB3"
FT /evidence="ECO:0000255"
FT /id="PRO_0000441950"
FT BINDING 435
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 111
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 206
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 339
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 507 AA; 57678 MW; 8B8AF6C15B52DB2D CRC64;
MAVATLISIL FAVLALRLCY LLIHALFLSP LRHIPAPFMA RVTSKRPLWH LLTGKAEIAA
RQDYSTFGDI YLCKPNTVYL CDPHDACTVL SSHAFRKTDM YRVFEYEGIP NVSTFTDPAQ
AQRRRRQLHP FFNNAYLTQM EPVMLKYGIQ ALKARWDAQL ARHKKVEVNY RFDTQLAMFD
ITGALVFGRE FHALETSNLV YTKWVNNTLS YMLVSHYFPW VKRVPLSWLV RGLKQSYDDL
VAFSQESIAI RQADLQAGRP KPADLLQALL DAEDPDSKAP MTAREVQAES IAMLVGGSES
TSSVISWVIH FLLLYPEHLQ AVVAETRANF PADHTITFNE SKANLPYLEA CIYETLRCIP
TASTSFPRVS DQAIILKGYY IPAGTEIATN KCAAHLHQPS WQDPDRFYPP RFLNQETYHE
TRRNMLSFAY GTRFCIGRNL AWAVMMVTLA NLFKDYEVEL PEDSRFGPTI VDAAGRPKIM
PTKMGVATMP ADPERDCRMV LSVRITE
