HPM7_HYPSB
ID HPM7_HYPSB Reviewed; 602 AA.
AC B3FWS3;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 22-JUL-2008, sequence version 1.
DT 03-AUG-2022, entry version 35.
DE RecName: Full=FAD-binding monooxygenase hmp7 {ECO:0000303|PubMed:18567690};
DE Short=FMO hmp7 {ECO:0000303|PubMed:18567690};
DE EC=1.14.13.- {ECO:0000305};
DE AltName: Full=Hypothemycin biosynthesis cluster protein hpm7 {ECO:0000303|PubMed:18567690};
GN Name=hpm7 {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-binding monooxygenase; 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 -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:H3JQW0};
CC Note=Binds 1 FAD per subunit. {ECO:0000250|UniProtKB:H3JQW0};
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 FAD-binding monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; EU520417; ACD39757.1; -; Genomic_DNA.
DR EMBL; EU520418; ACD39766.1; -; Genomic_DNA.
DR AlphaFoldDB; B3FWS3; -.
DR SMR; B3FWS3; -.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR Gene3D; 3.50.50.60; -; 2.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW FAD; Flavoprotein; Monooxygenase; NADP; Oxidoreductase.
FT CHAIN 1..602
FT /note="FAD-binding monooxygenase hmp7"
FT /id="PRO_0000437602"
FT BINDING 108..111
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:H3JQW0"
FT BINDING 118..120
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:H3JQW0"
FT BINDING 120..121
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:H3JQW0"
FT BINDING 126
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:H3JQW0"
FT BINDING 252..258
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:H3JQW0"
FT BINDING 275..276
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:H3JQW0"
FT SITE 390
FT /note="Transition state stabilizer"
FT /evidence="ECO:0000250|UniProtKB:H3JQW0"
SQ SEQUENCE 602 AA; 67806 MW; 73F09F3A7E19A089 CRC64;
MTRAILPDVS PDSIDPQFLE EKYDQERLKR INAAGYAKYS EVGDGELERF KVTHRLEDVA
SSREPVSVDT DVVIIGAGYA GILTAVRLVQ NGILNFRIVE KGNGFGGTWY WNQYPGAQCD
VESYIYMPLL EETGYVPTER YARGPEILKH INLIAKKWEL APKTHFQSEV SAADWTADRW
TVKTRQGDEF RSRYLVTAIG PFHRPKLPGV PGINSFKGNT FHSSGWDYEA SGGSATEKLT
KFSDKTIGII GTGATAVQML PFVANSAKEV LVFQRTPAPV NVRNNGPTPP DFAKFLEPGW
QLRRMDNFNK IYTGEPIDTS IVSEEWLSAT LQVLFGTESD KPSDPAELEQ LLARTDFQVM
ERIRRRVDET IKDPVTREQL KPWYATICKR PCFHDEYLEC FNRPNVRLVD TDGKGVDRIT
EDSVVVDGKE HHVDALVFCT GFEYLSGVDR HGGFTVTGKD GVTLTERWTP GPSTYHGLYV
HGFPNFFCLQ TAQAGTNPNF MYTATTGSTQ IGHVIAECLK DGVREVQPTK QAEDDWVKMI
LEGGRGMMHL MRNCTPGYMN NDGNLDEKTA RRMFYPGGPT AWRKLLEAWR EKGDFEGLQR
TY
