HPM1_HYPSB
ID HPM1_HYPSB Reviewed; 502 AA.
AC B3FWR7;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 22-JUL-2008, sequence version 1.
DT 03-AUG-2022, entry version 41.
DE RecName: Full=Cytochrome P450 monooxygenase hmp1 {ECO:0000303|PubMed:18567690};
DE EC=1.-.-.- {ECO:0000305|PubMed:18567690};
DE AltName: Full=Hypothemycin biosynthesis cluster protein hpm1 {ECO:0000303|PubMed:18567690};
GN Name=hpm1 {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;
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: Cytochrome P450 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=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:18567690}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
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 cytochrome P450 family. {ECO:0000305}.
CC -!- CAUTION: In contrast to other members of the family, it is shorter at
CC the C-terminus and lacks the heme-binding sites. {ECO:0000305}.
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DR EMBL; EU520417; ACD39751.1; -; Genomic_DNA.
DR AlphaFoldDB; B3FWR7; -.
DR SMR; B3FWR7; -.
DR PRIDE; B3FWR7; -.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
PE 1: Evidence at protein level;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Transmembrane; Transmembrane helix.
FT CHAIN 1..502
FT /note="Cytochrome P450 monooxygenase hmp1"
FT /id="PRO_0000437593"
FT TRANSMEM 18..38
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 447
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P04798"
FT CARBOHYD 300
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 451
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 502 AA; 56351 MW; EB521DF49D4CB64E CRC64;
MAVLPQVDLG HLANRDTAFV IVGAFFAWVF VVNPIYLLYF HPLSKFPGPK FWAVTRWGVS
LAIISGKSHD IILDLHKKYG PILRIAPDEL AFQSVSAWND IGGHRKPGQP EMTKEPIFNE
AFKDNLLGVT TREDHSRMRR ILSRGFSAAT FQKQEPLLKG YVDLLLSELR KRCEGGQKLI
DIQTWYSFTA FDIIGDLTFG ESFGSLDSGG HHPWASLIFE TTRFVILANC LKRINRAFLP
VLLFITPKGF GRRLKENQQL TDAKIAKRRA LGASRPDYMT AMLGNDEKGA KLSDTEITSN
CTALILGGAE TISSALSGTT YYLTKNPEAM AKVIEEVRSA FSSEDEITLT GTGHLKYLNA
VITESLRMFP PFAGASPRQV PRGGATIAGE FIPAGTSVGI WHWSMARCPD FFTHANEFHP
ERWLDDPRFD NDKKDASQPF AVGPRNCIGM NLTYVELRLI LARLFWNFDI KLDKSCDNWV
DDMVEYFGWE KIPLMVSLTP RS
