HELA_ASPFU
ID HELA_ASPFU Reviewed; 735 AA.
AC Q4WR16;
DT 22-FEB-2012, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 92.
DE RecName: Full=Protostadienol synthase helA {ECO:0000303|PubMed:29158519};
DE EC=5.4.99.32 {ECO:0000269|PubMed:19216560, ECO:0000269|PubMed:19415934, ECO:0000269|PubMed:19951700, ECO:0000269|PubMed:29158519};
DE AltName: Full=Helvolic acid biosynthesis cluster protein A {ECO:0000303|PubMed:29158519};
DE AltName: Full=Oxidosqualene cyclase {ECO:0000303|PubMed:19415934};
DE AltName: Full=Oxidosqualene:protostadienol cyclase {ECO:0000303|PubMed:19951700};
DE Short=OSPC {ECO:0000303|PubMed:19951700};
GN Name=helA {ECO:0000303|PubMed:29158519};
GN Synonyms=osc3 {ECO:0000303|PubMed:19415934},
GN pdsA {ECO:0000303|PubMed:19216560}; ORFNames=AFUA_4G14770;
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, CATALYTIC ACTIVITY, AND PATHWAY.
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, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP MUTAGENESIS OF PRO-703 AND PRO-704.
RX PubMed=19951700; DOI=10.1016/j.bbrc.2009.11.160;
RA Kimura M., Kushiro T., Shibuya M., Ebizuka Y., Abe I.;
RT "Protostadienol synthase from Aspergillus fumigatus: functional conversion
RT into lanosterol synthase.";
RL Biochem. Biophys. Res. Commun. 391:899-902(2010).
RN [6]
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 [7]
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: Protostadienol synthase; part of the gene cluster that
CC mediates the biosynthesis of helvolic acid, an antibacterial
CC nortriterpenoid (PubMed:19415934, PubMed:19216560, PubMed:19951700,
CC PubMed:29158519). Protostadienol synthase helA cyclizes (3S)-
CC oxidosqualene to (17Z)-protosta-17(20),24-dien-3-beta-ol
CC (protostadienol)(PubMed:19415934, PubMed:19216560, PubMed:19951700,
CC PubMed:29158519). The synthesis of protostadienol is followed by
CC several steps of monooxygenation, dehydrogenation, and acyl transfer to
CC yield the final helvolic acid (PubMed:19216560). Following the
CC cyclization to the tetracyclic protostadienol by helA, cytochrome P450
CC monooxygenases helB1-mediated and helB2-mediated oxidation at C-4 and
CC C-16, acyltransferase helD2-dependent acetylation of 16-OH, oxidation
CC of C-21 by cytochrome P450 monooxygenase helB4, and short chain
CC 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:19951700, ECO:0000269|PubMed:29158519}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(S)-2,3-epoxysqualene = (17Z)-protosta-17(20),24-dien-3beta-
CC ol; Xref=Rhea:RHEA:30987, ChEBI:CHEBI:15441, ChEBI:CHEBI:62457;
CC EC=5.4.99.32; Evidence={ECO:0000269|PubMed:19216560,
CC ECO:0000269|PubMed:19415934, ECO:0000269|PubMed:19951700,
CC ECO:0000269|PubMed:29158519};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=14.4 uM for 2,3-oxidosqualene {ECO:0000269|PubMed:19951700};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:19216560,
CC ECO:0000269|PubMed:19415934, ECO:0000269|PubMed:29158519}.
CC -!- INDUCTION: Expression is under the control of the secondary metabolism
CC regulator laeA (PubMed:17432932). Expression is down-regulated when
CC gliT is deleted and up-regulated upon exposure to exogenous gliotoxin
CC (PubMed:25311525). {ECO:0000269|PubMed:17432932,
CC ECO:0000269|PubMed:25311525}.
CC -!- SIMILARITY: Belongs to the terpene cyclase/mutase family.
CC {ECO:0000305}.
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DR EMBL; AAHF01000005; EAL89318.1; -; Genomic_DNA.
DR RefSeq; XP_751356.1; XM_746263.1.
DR AlphaFoldDB; Q4WR16; -.
DR SMR; Q4WR16; -.
DR STRING; 746128.CADAFUBP00007020; -.
DR EnsemblFungi; EAL89318; EAL89318; AFUA_4G14770.
DR GeneID; 3509337; -.
DR KEGG; afm:AFUA_4G14770; -.
DR VEuPathDB; FungiDB:Afu4g14770; -.
DR eggNOG; KOG0497; Eukaryota.
DR HOGENOM; CLU_009074_2_1_1; -.
DR InParanoid; Q4WR16; -.
DR OMA; SMLCCWI; -.
DR OrthoDB; 365003at2759; -.
DR BioCyc; MetaCyc:MON-16527; -.
DR Proteomes; UP000002530; Chromosome 4.
DR GO; GO:0005811; C:lipid droplet; IBA:GO_Central.
DR GO; GO:0000250; F:lanosterol synthase activity; IMP:AspGD.
DR GO; GO:1900581; P:(17Z)-protosta-17(20),24-dien-3beta-ol biosynthetic process; IMP:AspGD.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IBA:GO_Central.
DR GO; GO:1900812; P:helvolic acid biosynthetic process; IDA:GO_Central.
DR GO; GO:0019748; P:secondary metabolic process; IGC:AspGD.
DR CDD; cd02892; SQCY_1; 1.
DR InterPro; IPR032696; SQ_cyclase_C.
DR InterPro; IPR032697; SQ_cyclase_N.
DR InterPro; IPR018333; Squalene_cyclase.
DR InterPro; IPR008930; Terpenoid_cyclase/PrenylTrfase.
DR PANTHER; PTHR11764; PTHR11764; 1.
DR Pfam; PF13243; SQHop_cyclase_C; 1.
DR Pfam; PF13249; SQHop_cyclase_N; 1.
DR SFLD; SFLDG01016; Prenyltransferase_Like_2; 1.
DR SUPFAM; SSF48239; SSF48239; 2.
DR TIGRFAMs; TIGR01787; squalene_cyclas; 1.
PE 1: Evidence at protein level;
KW Isomerase; Lipid biosynthesis; Lipid metabolism; Reference proteome;
KW Repeat; Steroid biosynthesis; Virulence.
FT CHAIN 1..735
FT /note="Protostadienol synthase helA"
FT /id="PRO_0000415495"
FT REPEAT 132..173
FT /note="PFTB 1"
FT REPEAT 490..531
FT /note="PFTB 2"
FT REPEAT 567..607
FT /note="PFTB 3"
FT REPEAT 616..663
FT /note="PFTB 4"
FT ACT_SITE 463
FT /note="Proton donor"
FT /evidence="ECO:0000305"
FT MUTAGEN 702..708
FT /note="APPGGMR->NKSCAIS: Changes its
FT oxidosqualene:protostadienol cyclase (OSPC) activity to
FT oxidosqualene:lanosterol cyclase (OSLC) activity."
FT /evidence="ECO:0000269|PubMed:19951700"
FT MUTAGEN 703
FT /note="P->K: Impairs catalytic activity; when associated
FT with S-704."
FT /evidence="ECO:0000269|PubMed:19951700"
FT MUTAGEN 704
FT /note="P->S: Impairs catalytic activity; when associated
FT with K-703."
FT /evidence="ECO:0000269|PubMed:19951700"
SQ SEQUENCE 735 AA; 83091 MW; AA0AC92A8A6E36F8 CRC64;
MATDSSMPGT VIGKAEFSDT KAASEFGTDL SRWRLNVDNG RHMWEYLESE DEARKRPQSF
LEKYWLGLPY ELPARPRATC ALEAVENGWE FFKRLQTADG HWGCNDDGPL FVTSGMVIAR
YIVGIPIDSH MKQEMCRYLL NVVNEDGGWG LFIQSPSTVF GTVMNYCMLR ILGLGPEHPA
MAKARNTLHR LGSARATPTW GKFWLCVLGV YEWEGMVPLP PEPLLVPASL PFNPGKWWVH
TRNVYISMSY LYGHRFSMPP NKLVQALRDE LYDIPYQQIN WPAQRTNVSA ADRLTDPTWI
QRSFTSALTM YETFKIPFLR RRALNEALFQ IETETRNTHY LCIAPVSFAS NMLALYHAHG
RDSHWIRGMR DRFIDPMWLC REGLAASGTN GTSLWDTALT VQATIDAGLA ARPENQAILR
KALEFIDNSQ IREDPLGVHH VYRQPTRGAW PFSTRDQSYA VSDTTAEAVK VIVLLQRIEG
FPSRISDERL QQAIDLILGM ENAGGGFSAY EPVRGPKFLE LLNITELYEN VMTDNLYPEC
TSSVIMCLTT FAREYPTYRP RDIQACLSRS IDYLLRSQYP NGGWFASWGV CFTYATMFAL
QGLACMGWNE SNCAACQRAC SFLLQHQNPD GGWGESLDTV RFKQYLPHPD GSQVTNTAYA
VIGLLAARCG NHEAIRRGVA YLVKEQQDTG EWLPGPLEGV FAPPGGMRYP NYKFHFTLMA
LGRYVAIHGN ECLAI
