HPM9_HYPSB
ID HPM9_HYPSB Reviewed; 628 AA.
AC B3FWS5;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 22-JUL-2008, sequence version 1.
DT 25-MAY-2022, entry version 35.
DE RecName: Full=FAD-linked oxidoreductase hmp9 {ECO:0000305};
DE EC=1.-.-.- {ECO:0000305};
DE AltName: Full=Hypothemycin biosynthesis cluster protein hpm9 {ECO:0000303|PubMed:18567690};
DE Flags: Precursor;
GN Name=hpm9 {ECO:0000303|PubMed:18567690};
OS Hypomyces subiculosus (Nectria subiculosa).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Hypocreaceae; Hypomyces.
OX NCBI_TaxID=193393;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION.
RC STRAIN=DSM11931, and DSM11932;
RX PubMed=18567690; DOI=10.1128/aem.00478-08;
RA Reeves C.D., Hu Z., Reid R., Kealey J.T.;
RT "Genes for the biosynthesis of the fungal polyketides hypothemycin from
RT Hypomyces subiculosus and radicicol from Pochonia chlamydosporia.";
RL Appl. Environ. Microbiol. 74:5121-5129(2008).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=10598882; DOI=10.1016/s0162-3109(99)00085-5;
RA Camacho R., Staruch M.J., DaSilva C., Koprak S., Sewell T., Salituro G.,
RA Dumont F.J.;
RT "Hypothemycin inhibits the proliferative response and modulates the
RT production of cytokines during T cell activation.";
RL Immunopharmacology 44:255-265(1999).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=10595743; DOI=10.1111/j.1349-7006.1999.tb00688.x;
RA Tanaka H., Nishida K., Sugita K., Yoshioka T.;
RT "Antitumor efficacy of hypothemycin, a new Ras-signaling inhibitor.";
RL Jpn. J. Cancer Res. 90:1139-1145(1999).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=10421424; DOI=10.1016/s0024-3205(99)00259-3;
RA Sonoda H., Omi K., Hojo K., Nishida K., Omura S., Sugita K.;
RT "Suppression of oncogenic transformation by hypothemycin associated with
RT accelerated cyclin D1 degradation through ubiquitin-proteasome pathway.";
RL Life Sci. 65:381-394(1999).
RN [5]
RP BIOTECHNOLOGY.
RX PubMed=18571434; DOI=10.1016/j.jsb.2008.05.002;
RA Rastelli G., Rosenfeld R., Reid R., Santi D.V.;
RT "Molecular modeling and crystal structure of ERK2-hypothemycin complexes.";
RL J. Struct. Biol. 164:18-23(2008).
RN [6]
RP BIOTECHNOLOGY.
RX PubMed=20118535; DOI=10.1248/bpb.33.168;
RA Fukazawa H., Ikeda Y., Fukuyama M., Suzuki T., Hori H., Okuda T.,
RA Uehara Y.;
RT "The resorcylic acid lactone hypothemycin selectively inhibits the mitogen-
RT activated protein kinase kinase-extracellular signal-regulated kinase
RT pathway in cells.";
RL Biol. Pharm. Bull. 33:168-173(2010).
RN [7]
RP FUNCTION.
RX PubMed=20222707; DOI=10.1021/ja100060k;
RA Zhou H., Qiao K., Gao Z., Meehan M.J., Li J.W., Zhao X., Dorrestein P.C.,
RA Vederas J.C., Tang Y.;
RT "Enzymatic synthesis of resorcylic acid lactones by cooperation of fungal
RT iterative polyketide synthases involved in hypothemycin biosynthesis.";
RL J. Am. Chem. Soc. 132:4530-4531(2010).
RN [8]
RP BIOTECHNOLOGY.
RX PubMed=23853713; DOI=10.7554/elife.00712;
RA Nishino M., Choy J.W., Gushwa N.N., Oses-Prieto J.A., Koupparis K.,
RA Burlingame A.L., Renslo A.R., McKerrow J.H., Taunton J.;
RT "Hypothemycin, a fungal natural product, identifies therapeutic targets in
RT Trypanosoma brucei [corrected].";
RL Elife 2:E00712-E00712(2013).
RN [9]
RP BIOTECHNOLOGY.
RX PubMed=24106914; DOI=10.1021/jf4030882;
RA Xu L., Xue J., Wu P., Wang D., Lin L., Jiang Y., Duan X., Wei X.;
RT "Antifungal activity of hypothemycin against Peronophythora litchii in
RT vitro and in vivo.";
RL J. Agric. Food Chem. 61:10091-10095(2013).
RN [10]
RP BIOTECHNOLOGY.
RX PubMed=26371861; DOI=10.1016/j.intimp.2015.08.030;
RA Park K.H., Yoon Y.D., Kang M.R., Yun J., Oh S.J., Lee C.W., Lee M.Y.,
RA Han S.B., Kim Y., Kang J.S.;
RT "Hypothemycin inhibits tumor necrosis factor-alpha production by
RT tristetraprolin-dependent down-regulation of mRNA stability in
RT lipopolysaccharide-stimulated macrophages.";
RL Int. Immunopharmacol. 29:863-868(2015).
CC -!- FUNCTION: FAD-linked oxidoreductase; part of the gene cluster that
CC mediates the biosynthesis of hypothemycin, a resorcylic acid lactone
CC (RAL) that irreversibly inhibits a subset of protein kinases with a
CC conserved cysteine in the ATP binding site such as human ERK2
CC (PubMed:18567690). The first step is performed by both PKSs hmp3 and
CC hmp8 and leads to the production of 7',8'-dehydrozearalenol (DHZ)
CC (PubMed:18567690, PubMed:20222707). The highly reducing PKS hpm8
CC synthesizes the reduced hexaketide (7S,11S,2E,8E)-7,11-dihydroxy-
CC dodeca-2,8-dienoate, which is transferred downstream to the non-
CC reducing PKS hpm3 (PubMed:20222707). Hpm3 then extends the reduced
CC hexaketide to a nonaketide, after which regioselective cyclization and
CC macrolactonization affords DHZ (PubMed:20222707). The next step is the
CC conversion of DHZ into aigialomycin C and is performed by the O-
CC methyltransferase hmp5, the FAD-binding monooxygenase hmp7, and the
CC cytochrome P450 monooxygenase hmp1 (PubMed:18567690). The wide
CC substrate tolerance of the hmp5 and hmp7 implies that the reactions
CC from DHZ to aigialomycin C can occur in any order (PubMed:18567690).
CC The steps from aigialomycin C to hypothemycin are less well established
CC (PubMed:18567690). The FAD-linked oxidoreductase hmp9 presumably
CC catalyzes oxidation of the C-6' hydroxyl to a ketone (PubMed:18567690).
CC The timing of this oxidation is important, since the resulting enone
CC functional group is a Michael acceptor that can react spontaneously
CC with glutathione, an abundant metabolite in fungal cells
CC (PubMed:18567690). The glutathione S-transferase hmp2 catalyzes cis-
CC trans isomerization of the 7',8' double bond with equilibrium favoring
CC the trans isomer (PubMed:18567690). The hpm6-encoded transporter might
CC preferentially pump hypothemycin out of the cell relative to the trans
CC isomer aigialomycin A. The cis-to-trans isomerization may be coupled
CC with C-4' hydroxylation, since all known hypothemycin analogs
CC containing the enone functional group also have hydroxyl groups at both
CC C-4' and C-5' (PubMed:18567690). {ECO:0000269|PubMed:18567690,
CC ECO:0000269|PubMed:20222707}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:18567690}.
CC -!- BIOTECHNOLOGY: Hypothemycin is an antifungal agent that exhibits
CC excellent activity against Peronophythora litchii, which could be
CC helpful for the storage of harvest litchi fruit (PubMed:24106914).
CC Hypothemycin is a strong inhibitor of a subset of MAP kinases such as
CC human ERK2 (PubMed:18571434, PubMed:20118535, PubMed:26371861). It can
CC therefore be used as an anti-cancer drug thanks to its inhibitory
CC activity of Ras-mediated cellular signals (PubMed:10595743,
CC PubMed:10421424). It can also inhibit Trypanosoma brucei kinase TbCLK1
CC which is a good candidate as a therapeutic target for African
CC trypanosomiasis (PubMed:23853713). Finally, hypothemycin has also
CC inhibitor activity of T cell activation (PubMed:10598882).
CC {ECO:0000269|PubMed:10421424, ECO:0000269|PubMed:10595743,
CC ECO:0000269|PubMed:10598882, ECO:0000269|PubMed:18571434,
CC ECO:0000269|PubMed:20118535, ECO:0000269|PubMed:23853713,
CC ECO:0000269|PubMed:24106914, ECO:0000269|PubMed:26371861}.
CC -!- SIMILARITY: Belongs to the oxygen-dependent FAD-linked oxidoreductase
CC family. {ECO:0000305}.
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DR EMBL; EU520417; ACD39759.1; -; Genomic_DNA.
DR EMBL; EU520418; ACD39768.1; -; Genomic_DNA.
DR AlphaFoldDB; B3FWS5; -.
DR SMR; B3FWS5; -.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR Gene3D; 3.30.465.10; -; 1.
DR InterPro; IPR016166; FAD-bd_PCMH.
DR InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR InterPro; IPR006094; Oxid_FAD_bind_N.
DR Pfam; PF01565; FAD_binding_4; 1.
DR SUPFAM; SSF56176; SSF56176; 1.
DR PROSITE; PS51387; FAD_PCMH; 1.
PE 1: Evidence at protein level;
KW Glycoprotein; Oxidoreductase; Signal.
FT SIGNAL 1..29
FT /evidence="ECO:0000255"
FT CHAIN 30..628
FT /note="FAD-linked oxidoreductase hmp9"
FT /evidence="ECO:0000255"
FT /id="PRO_5007640112"
FT DOMAIN 152..337
FT /note="FAD-binding PCMH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT REGION 34..53
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 80
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 133
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 356
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 628 AA; 68958 MW; 54D18D0A7DD57277 CRC64;
MFCIIRAQLL LLLHLLVLAL LLVGTVCNAH PQHGHPSELE PLALKRGGSP RDDGNTLAPR
CRCIPGEACW PSTQIWDSFN RTIGGSLIKT APLAESCYPG PKKNTRKCAV VSRKWTDQDF
QTDSPVGRTY PYNITCAPVN YFAGQRPTTC SLGQLPVYAI DARTRQSVAQ GLRFAKDNNL
RVTVVSTGHD LLGRADGYGS LEIWLRHHRN EIRFERQYMA TDGCRESGWT GSAIDIDGAY
QWRDVHIKAR ANNVIVVGGG SVSPGAIGGW PSGGGHGPAS RNYGLGADQI LEAEVMLADG
SVVLANHCQH TDLFRALRGG GPGFGVVLKT KIKAYPNVAS VSVHHLTITP IRQTPNNSDL
LDAVAVLMQA YPKLSDDGYA GYAFWLRNCK SFFIGSAKSG YRHGIWMIGK TTEEAEHSFA
PVREALDKFK SKLTISESYM TYNDYWSFYT SESGLYESVG TTSVLTSRLI DRPAVEDYNR
VREAVEVIGG KPEDYATNVM MLVSNGQVFA DAADKSSGLN PAWRVSPYVV ISSRGIPMVV
DQASRKEVAD DITYVKGAAL QKLAPNTGGY MNEGDRNDPN YIKNFFGTIY PTHLATKKKY
DPWGLFYCPT CVGAELFEET SRGELCRR
