ID   HELC_ASPFU              Reviewed;         257 AA.
AC   Q4WR19;
DT   25-OCT-2017, integrated into UniProtKB/Swiss-Prot.
DT   05-JUL-2005, sequence version 1.
DT   03-AUG-2022, entry version 92.
DE   RecName: Full=Short chain dehydrogenase helC {ECO:0000303|PubMed:29158519};
DE            EC=1.1.1.- {ECO:0000269|PubMed:19415934, ECO:0000269|PubMed:29158519};
DE   AltName: Full=Helvolic acid biosynthesis cluster protein helC {ECO:0000303|PubMed:29158519};
DE   Flags: Precursor;
GN   Name=helC {ECO:0000303|PubMed:29158519};
GN   Synonyms=sdr1 {ECO:0000303|PubMed:19415934}; ORFNames=AFUA_4G14800;
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   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: Short chain dehydrogenase; 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   -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:19415934,
CC       ECO:0000269|PubMed:29158519}.
CC   -!- INDUCTION: Expression is under the control of the secondary metabolism
CC       regulator laeA (PubMed:17432932). Expression up-regulated upon exposure
CC       to exogenous gliotoxin (PubMed:25311525). {ECO:0000269|PubMed:17432932,
CC       ECO:0000269|PubMed:25311525}.
CC   -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC       family. {ECO:0000305}.
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DR   EMBL; AAHF01000005; EAL89315.1; -; Genomic_DNA.
DR   RefSeq; XP_751353.1; XM_746260.1.
DR   AlphaFoldDB; Q4WR19; -.
DR   SMR; Q4WR19; -.
DR   STRING; 746128.CADAFUBP00007023; -.
DR   EnsemblFungi; EAL89315; EAL89315; AFUA_4G14800.
DR   GeneID; 3508871; -.
DR   KEGG; afm:AFUA_4G14800; -.
DR   VEuPathDB; FungiDB:Afu4g14800; -.
DR   eggNOG; KOG4169; Eukaryota.
DR   HOGENOM; CLU_010194_2_10_1; -.
DR   InParanoid; Q4WR19; -.
DR   OMA; IYATQQA; -.
DR   OrthoDB; 1053465at2759; -.
DR   Proteomes; UP000002530; Chromosome 4.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0016616; F:oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor; 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   InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR   InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR   InterPro; IPR002347; SDR_fam.
DR   Pfam; PF00106; adh_short; 1.
DR   PRINTS; PR00081; GDHRDH.
DR   PRINTS; PR00080; SDRFAMILY.
DR   SUPFAM; SSF51735; SSF51735; 1.
DR   PROSITE; PS00061; ADH_SHORT; 1.
PE   1: Evidence at protein level;
KW   Glycoprotein; NAD; Oxidoreductase; Reference proteome; Signal.
FT   SIGNAL          1..22
FT                   /evidence="ECO:0000255"
FT   CHAIN           23..257
FT                   /note="Short chain dehydrogenase helC"
FT                   /id="PRO_0000441953"
FT   ACT_SITE        154
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10001"
FT   BINDING         11..34
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000250|UniProtKB:Q12634"
FT   CARBOHYD        46
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT   CARBOHYD        110
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ   SEQUENCE   257 AA;  27460 MW;  F39D2928B994A82C CRC64;
     MNTAIITGAA QGVGLCIAEA LAQRNYRIVL SDIDTEKGPA AASKLNLTHG EGTAAFFHCD
     LSNLREIDAL LSFTIETMGG FSVLINNAGY LRAPFLALSA QDIQDMITVN LTAPIYATQQ
     AIKYWDGLHQ GQAGCVVSVT SSSSFKTYAS IAPYGAAKAG AAMFTFAAGA FHPRVRVNAV
     APTAIATGFD KNRMRVETDR TGPGYTPEEE MRAMGLKRLQ PQEVAEAVVR CVEDKGLYGK
     VLYLDAVEGI KIHDGYT