HPM4_HYPSB
ID HPM4_HYPSB Reviewed; 534 AA.
AC B3FWS0;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 22-JUL-2008, sequence version 1.
DT 25-MAY-2022, entry version 13.
DE RecName: Full=Hypothemycin biosynthesis cluster protein hpm4 {ECO:0000303|PubMed:18567690};
GN Name=hpm4 {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: Part of the gene cluster that mediates the biosynthesis of
CC hypothemycin, a resorcylic acid lactone (RAL) that irreversibly
CC inhibits a subset of protein kinases with a conserved cysteine in the
CC ATP binding site such as human ERK2 (PubMed:18567690). The first step
CC is performed by both PKSs hmp3 and hmp8 and leads to the production of
CC 7',8'-dehydrozearalenol (DHZ) (PubMed:18567690, PubMed:20222707). The
CC highly reducing PKS hpm8 synthesizes the reduced hexaketide
CC (7S,11S,2E,8E)-7,11-dihydroxy-dodeca-2,8-dienoate, which is transferred
CC downstream to the non-reducing PKS hpm3 (PubMed:20222707). Hpm3 then
CC extends the reduced hexaketide to a nonaketide, after which
CC regioselective cyclization and macrolactonization affords DHZ
CC (PubMed:20222707). 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 -!- 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}.
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DR EMBL; EU520417; ACD39754.1; -; Genomic_DNA.
DR EMBL; EU520418; ACD39763.1; -; Genomic_DNA.
DR AlphaFoldDB; B3FWS0; -.
PE 1: Evidence at protein level;
FT CHAIN 1..534
FT /note="Hypothemycin biosynthesis cluster protein hpm4"
FT /id="PRO_0000437613"
FT REGION 34..61
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 110..130
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 236..287
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 110..125
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 261..287
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ SEQUENCE 534 AA; 59218 MW; 281776840BC8CE20 CRC64;
MSWESPVNYS VGGEDLDLDL GAFLGSLSDF DGQIEPAHSL EDEYSGQSGQ GADDDPDSDG
PKVLTIMASI DAIHRHLENE RKKGNGKANV AIKLKDPTMR KSITFSIPEL QSPTTTASSA
GSPSCAPLRL PSPEAFDLGE AIFSHPTAGS SFPEEVTPAA EDDVLSSIAS PFATPEGLFF
PQDEDVLPSI APLLKAANLA HATEPSLGLI SPRATASESS MMPDEEAMAD VVQYRDGTGT
TPESLSPGDM EQDEWPHTVS SRQTRSRQAA RACQTPSTMS TKDKKCIDSS SCSLKQMNSQ
HQKRNSIETA PSRTIKRPRV ESPDLLTLIP NHDEYQRVQE LTAALDPLLA YKMVRNARAI
LPQSVAEDMA HSADMEVDGP LHYQNNQQSP SSQEEIMQQF CETVRRIEWV ERAAFKSMVE
YRVLFVQLYQ HYLRLQEIVV TRKGERRVTL AKEQLYRTLY PGVEKMTSSG LTSDEWEKFN
RCIRRGKQWN TIASKLGVGI LQRMPSSICH SWVEQKLQTK EQLHIWIEIV SLLA
