HPM3_HYPSB
ID HPM3_HYPSB Reviewed; 2049 AA.
AC B3FWS8;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 22-JUL-2008, sequence version 1.
DT 25-MAY-2022, entry version 58.
DE RecName: Full=Non-reducing polyketide synthase hmp3 {ECO:0000303|PubMed:18567690};
DE Short=NR-PKS hmp3 {ECO:0000303|PubMed:18567690};
DE EC=2.3.1.- {ECO:0000269|PubMed:18567690, ECO:0000269|PubMed:20222707};
DE AltName: Full=Hypothemycin biosynthesis cluster protein hpm3 {ECO:0000303|PubMed:18567690};
GN Name=hpm3 {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, CATALYTIC ACTIVITY, MUTAGENESIS OF SER-121, AND DOMAIN.
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: Non-reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of hypothemycin, a resorcylic acid
CC lactone (RAL) that irreversibly inhibits a subset of protein kinases
CC with a 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, ECO:0000269|PubMed:20222707}.
CC -!- DOMAIN: Multidomain protein; including a starter unit:ACP transacylase
CC (SAT) that selects the starter unit; a ketosynthase (KS) that catalyzes
CC repeated decarboxylative condensation to elongate the polyketide
CC backbone; a malonyl-CoA:ACP transacylase (MAT) that selects and
CC transfers the extender unit malonyl-CoA; a product template (PT) domain
CC that controls the immediate cyclization regioselectivity of the
CC reactive polyketide backbone; and an acyl-carrier protein (ACP) that
CC serves as the tether of the growing and completed polyketide via its
CC phosphopantetheinyl arm (By similarity).
CC {ECO:0000250|UniProtKB:Q5B0D0}.
CC -!- DOMAIN: The SAT domain at the N-terminus facilitates crosstalk between
CC the two PKSs hmp3 and hmp8 encoded by the cluster (PubMed:20222707).
CC {ECO:0000269|PubMed:20222707}.
CC -!- DOMAIN: The release of the polyketide chain from the non-reducing
CC polyketide synthase is mediated by the thioesterase (TE) domain
CC localized at the C-ter of the protein (By similarity).
CC {ECO:0000250|UniProtKB:Q5ATJ7}.
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; ACD39762.1; -; Genomic_DNA.
DR AlphaFoldDB; B3FWS8; -.
DR SMR; B3FWS8; -.
DR PRIDE; B3FWS8; -.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
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 Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
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; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR030918; PT_fungal_PKS.
DR InterPro; IPR032088; SAT.
DR InterPro; IPR001031; Thioesterase.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR Pfam; PF16073; SAT; 1.
DR Pfam; PF00975; Thioesterase; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR TIGRFAMs; TIGR04532; PT_fungal_PKS; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Multifunctional enzyme; Phosphopantetheine;
KW Phosphoprotein; Transferase.
FT CHAIN 1..2049
FT /note="Non-reducing polyketide synthase hmp3"
FT /id="PRO_0000437584"
FT DOMAIN 1626..1704
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 9..246
FT /note="N-terminal acylcarrier protein transacylase (SAT)
FT domain"
FT /evidence="ECO:0000255"
FT REGION 368..796
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 887..1146
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1269..1572
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1700..1747
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1761..1951
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000255"
FT COMPBIAS 1700..1729
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1730..1744
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 538
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 978
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 1663
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MUTAGEN 121
FT /note="S->A: Abolishes the synthesis of hypothemycin."
FT /evidence="ECO:0000269|PubMed:20222707"
SQ SEQUENCE 2049 AA; 222890 MW; B59D9EF2578A8464 CRC64;
MVTVPQTILY FGDQTDSWVD SLDQLYRQAA TIPWLQTFLD DLVKVFKEES RGMDRALQDS
VGEYSTLLDL ADRYRHGTDE IGMVRAVLLH AARGGMLLQW VKKESQLVDL NGSKPEALGI
SGGLTNLAAL AISTDFESLY DAVIEAARIF VRLCRFTSVR SRAMEDRPGV WGWAVLGITP
EELSKVLEQF QSSMGIPAIK RAKVGVTGDR WSTVIGPPSV LDLFIHQCPA VRNLPKNELS
IHALQHTVTV TEADLDFIVG SAELLSHPIV PDFKVWGMDD PVASYQNWGE MLRAIVTQVL
SKPLDITKVI AQLNTHLGPR HVDVRVIGPS SHTPYLASSL KAAGSKAIFQ TDKTLEQLQP
KKLPPGRIAI VGMAGRGPGC ENVDEFWDVI MAKQDRCEEI PKDRFDINEF YCTEHGEGCT
TTTKYGCFMN KPGNFDSRFF HVSPREALLM DPGHRQFMMS TYEALETAGY SDGQTRDVDP
NRIAAFYGQS NDDWHMVSHY TLGCDAYTLQ GAQRAFGAGR IAFHFKWEGP TYSLDSACAS
TSSAIHLACV SLLSKDVDMA VVGAANVVGY PHSWTSLSKS GVLSDTGNCK TYCDDADGYC
RADFVGSVVL KRLEDAVEQN DNILAVVAGS GRNHSGNSSS ITTSDAGAQE RLFHKIMHSA
RVSPDEISYV EMHGTGTQIG DPAEMSAVTN VFRKRKANNP LTVGGIKANV GHAEASAGMA
SLLKCIQMFQ KDIMPPQARM PHTLNPKYPS LSELNIHIPS EPKEFKAIGE RPRRILLNNF
DAAGGNASLI LEDFPSTVKE NADPRPSHVI VSSAKTQSSY HANKRNLLKW LRKNKDAKLE
DVAYTTTARR MHHPLRFSCS ASTTEELISK LEADTADATA SRGSPVVFVF TGQGSHYAGM
GAELYKTCPA FREEVNLCAS ISEEHGFPPY VDIITNKDVD ITTKDTMQTQ LAVVTLEIAL
AAFWKASGIQ PSAVMGHSLG EYVALQVAGV LSLADLLYLV GNRARLLLER CEADTCAMLA
VSSSAASIRE LIDQRPQSSF EIACKNSPNA TVISGSTDEI SELQSSFTAS RARALSVPYG
FHSFQMDPML EDYIVLAGGV TYSPPKIPVA STLLASIVES SGVFNASYLG QQTRQAVDFV
GALGALKEKF ADPLWLEIGP SQICNSFVRA TLSPSPGKIL STLEANTNPW ASIAKCLAGA
YKDGVAVDWL AVHAPFKGGL KLVKLPAYAW DLKDFWIVYS EANKAARALA PAPSFETQRI
STCAQQIVEE SSSPSLHVSA RAAISDPGFM ALVDGHRMRD VSICPGSVFC EAGLAVSKYA
LKYSGRKDTV ETRLTINNLS LKRPLTKSLV GTDGELLTTV VADKASSDTL QVSWKASSSH
ASYDLGSCEI TICDAQTLQT SWNRSSYFVK ARMNELIKNV KSGNGHRMLP SILYTLFAST
VDYDPTFKSV KEAFISNEFD EAAAEVVLQK NPAGTQFFAS PYWGESVVHL AGFLVNSNPA
RKTASQTTFM MQSLESVEQT ADLEAGRTYY TYARVLHEEE DTVSCDLFVF DSEKMVMQCS
GLSFHEVSNN VLDRLLGKAS PPVKQVSHQK APVLVPAESK PALKAAVEAA PKAPEPVKTE
VKKISSSESE LFHTILESIA KETGTQVSDF TDDMELAELG VDSIMGIEIA AGVSSRTGLD
VLLPSFVVDY PTIGDLRNEF ARSSTSTPPS KTFSEFSIVD ATPESTRSSS RAPSEKKEPA
PASEKSEELV IVPSAVVEDS SPLPSARITL IQGRSSSGKQ PFYLIADGAG SIATYIHLAP
FKDKRPVYGI DSPFLRCPSR LTTQVGIEGV AKIIFEALIK CQPEGPFDLG GFSGGAMLSY
EVSRQLAAAG RVVSSLLLID MCSPRPLGVE DTIEVGWKVY ETIASQDKLW NASSNTQQHL
KAVFACVAAY HPPPITPAQR PKRTAIIWAK KGMVDRCSRD EKVMKFLADK GIPTESYPGF
MEDPKLGAVA WGLPHKSAAD LGPNGWDKFL GETLCLSIDS DHLDMPMPGH VHLLQAAMEE
SFKYFSEAN
