HPM8_HYPSB
ID HPM8_HYPSB Reviewed; 2349 AA.
AC B3FWT3;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 22-JUL-2008, sequence version 1.
DT 03-AUG-2022, entry version 71.
DE RecName: Full=Reducing polyketide synthase hmp8 {ECO:0000303|PubMed:18567690};
DE Short=R-PKS hmp8 {ECO:0000303|PubMed:18567690};
DE EC=2.3.1.- {ECO:0000269|PubMed:18567690, ECO:0000269|PubMed:20222707, ECO:0000269|PubMed:22406519, ECO:0000269|PubMed:23356934};
DE AltName: Full=Hypothemycin biosynthesis cluster protein hpm8 {ECO:0000303|PubMed:18567690};
GN Name=hpm8 {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], FUNCTION, AND CATALYTIC ACTIVITY.
RC STRAIN=DSM11931;
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, AND CATALYTIC ACTIVITY.
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 FUNCTION, CATALYTIC ACTIVITY, AND DOMAIN.
RX PubMed=22406519; DOI=10.1038/nchembio.912;
RA Zhou H., Gao Z., Qiao K., Wang J., Vederas J.C., Tang Y.;
RT "A fungal ketoreductase domain that displays substrate-dependent
RT stereospecificity.";
RL Nat. Chem. Biol. 8:331-333(2012).
RN [9]
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 [10]
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 [11]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=23356934; DOI=10.1021/ja4001823;
RA Gao Z., Wang J., Norquay A.K., Qiao K., Tang Y., Vederas J.C.;
RT "Investigation of fungal iterative polyketide synthase functions using
RT partially assembled intermediates.";
RL J. Am. Chem. Soc. 135:1735-1738(2013).
RN [12]
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: Reducing polyketide synthase; 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, PubMed:20222707, PubMed:22406519, PubMed:23356934).
CC The first step is performed by both PKSs hmp3 and hmp8 and leads to the
CC production of 7',8'-dehydrozearalenol (DHZ) (PubMed:18567690,
CC PubMed:20222707). The highly reducing PKS hpm8 synthesizes the reduced
CC hexaketide (7S,11S,2E,8E)-7,11-dihydroxy-dodeca-2,8-dienoate, which is
CC transferred downstream to the non-reducing PKS hpm3 (PubMed:20222707,
CC PubMed:22406519, PubMed:23356934). Hpm3 then extends the reduced
CC hexaketide to a nonaketide, after which regioselective cyclization and
CC macrolactonization affords DHZ (PubMed:20222707, PubMed:22406519,
CC PubMed:23356934). The next step is the conversion of DHZ into
CC aigialomycin C and is performed by the O-methyltransferase hmp5, the
CC FAD-binding monooxygenase hmp7, and the cytochrome P450 monooxygenase
CC hmp1 (PubMed:18567690). The wide substrate tolerance of the hmp5 and
CC hmp7 implies that the reactions from DHZ to aigialomycin C can occur in
CC any order (PubMed:18567690). The steps from aigialomycin C to
CC hypothemycin are less well established (PubMed:18567690). The FAD-
CC linked oxidoreductase hmp9 presumably catalyzes oxidation of the C-6'
CC hydroxyl to a ketone (PubMed:18567690). The timing of this oxidation is
CC important, since the resulting enone functional group is a Michael
CC acceptor that can react spontaneously with glutathione, an abundant
CC metabolite in fungal cells (PubMed:18567690). The glutathione S-
CC transferase hmp2 catalyzes cis-trans isomerization of the 7',8' double
CC bond with equilibrium favoring the trans isomer (PubMed:18567690). The
CC hpm6-encoded transporter might preferentially pump hypothemycin out of
CC the cell relative to the trans isomer aigialomycin A. The cis-to-trans
CC isomerization may be coupled with C-4' hydroxylation, since all known
CC hypothemycin analogs containing the enone functional group also have
CC hydroxyl groups at both C-4' and C-5' (PubMed:18567690).
CC {ECO:0000269|PubMed:18567690, ECO:0000269|PubMed:20222707,
CC ECO:0000269|PubMed:22406519, ECO:0000269|PubMed:23356934}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:18567690}.
CC -!- DOMAIN: The ketoreductase domain catalyzes five beta-ketoreduction
CC steps involving substrates ranging in size from diketide to hexaketide
CC and possesses a previously unrecognized ability to reduce the beta-
CC ketoacyl intermediates with different stereochemical outcomes based on
CC substrate chain length (PubMed:22406519).
CC {ECO:0000269|PubMed:22406519}.
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}.
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DR EMBL; EU520418; ACD39767.1; -; Genomic_DNA.
DR AlphaFoldDB; B3FWT3; -.
DR SMR; B3FWT3; -.
DR GO; GO:0016746; F:acyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0009058; P:biosynthetic process; IEA:UniProt.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR InterPro; IPR001227; Ac_transferase_dom_sf.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR013154; ADH_N.
DR InterPro; IPR011032; GroES-like_sf.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020843; PKS_ER.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR002364; Quin_OxRdtase/zeta-crystal_CS.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF08240; ADH_N; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
DR PROSITE; PS01162; QOR_ZETA_CRYSTAL; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Multifunctional enzyme; NADP; Oxidoreductase;
KW Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2349
FT /note="Reducing polyketide synthase hmp8"
FT /id="PRO_0000437585"
FT DOMAIN 2267..2344
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 12..438
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 551..856
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 932..1244
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1641..1953
FT /note="Enoyl reductase (ER) domain"
FT /evidence="ECO:0000255"
FT REGION 1977..2157
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255"
FT MOD_RES 2304
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2349 AA; 253569 MW; 91A83FAB705FD201 CRC64;
MPSTSNPSHV PVAIIGLACR FPGEATSPSK FWDLLKNGRD AYSPNTDRYN ADAFYHPKAS
NRQNVLATKG GHFLKQDPYV FDAAFFNITA AEAISFDPKQ RIAMEVVYEA LENAGKTLPK
VAGTQTACYI GSSMSDYRDA VVRDFGNSPK YHILGTCEEM ISNRVSHFLD IHGPSATIHT
ACSSSLVATH LACQSLQSGE SEMAIAGGVG MIITPDGNMH LNNLGFLNPE GHSRSFDENA
GGYGRGEGCG ILILKRLDRA LEDGDSIRAV IRASGVNSDG WTQGVTMPSS QAQSALIKYV
YESHGLDYGA TQYVEAHGTG TKAGDPAEIG ALHRTIGQGA SKSRRLWIGS VKPNIGHLEA
AAGVAGIIKG VLSMEHGMIP PNIYFSKPNP AIPLDEWNMA VPTKLTPWPA SQTGRRMSVS
GFGMGGTNGH VVLEAYKPQG KLTNGHTNGI TNGIHKTRHS GKRLFVLSAQ DQAGFKRLGN
ALVEHLDALG PAAATPEFLA NLSHTLAVGR SGLAWRSSII AESAPDLREK LATDPGEGAA
RSSGSEPRIG FVFTGQGAQW ARMGVELLER PVFKASVIKS AETLKELGCE WDPIVELSKP
QAESRLGVPE ISQPICTVLQ VALVDELKHW GVSPSKVVGH SSGEIGAAYS IGALSHRDAV
AAAYFRGKSS NGAKKLGGGM MAVGCSREDA DKLLSETKLK GGVATVACVN SPSSVTISGD
AAALEELRVI LEEKSVFARR LKVDVAYHSA HMNAVFAEYS AAIAHIEPAQ AVEGGPIMVS
SVTGSEVDSE LLGPYYWTRN LISPVLFADA VKELVTPADG DGQNTVDLLI EIGPHSALGG
PVEQILSHNG IKNVAYRSAL TRGENAVDCS LKLAGELFLL GVPFELQKAN GDSGSRMLTN
LPPYPWNHSK SFRADSRLHR EHLEQKFPTR SLIGAPVPMM AESEYTWRNF IRLADEPWLR
GHTVGTTVLF PGAGIVSIIL EAAQQLVDTG KTVRGFRMRD VNLFAAMALP EDLATEVIIH
IRPHLISTVG STAPGGWWEW TVSSCVGTDQ LRDNARGLVA IDYEESRSEQ INAEDKALVA
SQVADYHKIL SECPEHYAHD KFYQHMTKAS WSYGELFQGV ENVRPGYGKT IFDIRVIDIG
ETFSKGQLER PFLINAATLD AVFQSWLGST YNNGAFEFDK PFVPTSIGEL EISVNIPGDG
DYLMPGHCRS ERYGFNELSA DIAIFDKDLK NVFLSVKDFR TSELDMDSGK GDGDAAHVDP
ADINSEVKWN YALGLLKSEE ITELVTKVAS NDKLAELLRL TLHNNPAATV IELVSDESKI
SGASSAKLSK GLILPSQIRY VVVNPEAADA DSFFKFFSLG EDGAPVAAER GPAELLIASS
EVTDAAVLER LITLAKPDAS ILVAVNNKTT AAALSAKAFR VVTSIQDSKS IALYTSKKAP
AADTSKLEAI ILKPTTAQPA AQNFASILQK ALELQGYSVV SQPWGTDIDV NDAKGKTYIS
LLELEQPLLD NLSKSDFENL RAVVLNCERL LWVTAGDNPS FGMVDGFARC IMSEIASTKF
QVLHLSAATG LKYGSSLATR ILQSDSTDNE YREVDGALQV ARIFKSYNEN ESLRHHLEDT
TSVVTLADQE DALRLTIGKP GLLDTLKFVP DERMLPPLQD HEVEIQVKAT GLNFRDIMAC
MGLIPVRSLG QEASGIVLRT GAKATNFKPG DRVCTMNVGT HATKIRADYR VMTKIPDSMT
FEEAASVAVV HTTAYYAFIT IAKLRKGQSV LIHAAAGGVG QAAIQLAKHL GLITYVTVGT
EDKRQLIREQ YGIPDEHIFN SRDASFVKGV QRVTNGRGVD CVLNSLSGEL LRASWGCLAT
FGHFIEIGLR DITNNMRLDM RPFRKSTSFT FINTHTLFEE DPAALGDILN ESFKLMFAGA
LTAPSPLNAY PIGQVEEAFR TMQQGKHRGK MVLSFSDDAK APVLRKAKDS LKLDPDATYL
FVGGLGGLGR SLAKEFVASG ARNIAFLSRS GDTTAQAKAI VDELAGQGIQ VKAYRGDIAS
EASFLQAMEQ CSQDLPPVKG VIQMAMVLRD IVFEKMSYDE WTVPVGPKVQ GSWNLHKYFS
HERPLDFMVI CSSSSGIYGY PSQAQYAAGN TYQDALAHYR RSQGLNAISV NLGIMRDVGV
LAETGTTGNI KLWEEVLGIR EPAFHALMKS LINHQQRGSG DYPAQVCTGL GTADIMATHG
LARPEYFNDP RFGPLAVTTV ATDASADGQG SAVSLASRLS KVSTKDEAAE IITDALVNKT
ADILQMPPSE VDPGRPLYRY GVDSLVALEV RNWITREMKA NMALLEILAA VPIESFAVKI
AEKSKLVTV
