Protein: HPM3_HYPSB
Sequence: MVTVPQTILYFGDQTDSWVDSLDQLYRQAATIPWLQTFLDDLVKVFKEESRGMDRALQDSVGEYSTLLDLADRYRHGTDEIGMVRAVLLHAARGGMLLQWVKKESQLVDLNGSKPEALGISGGLTNLAALAISTDFESLYDAVIEAARIFVRLCRFTSVRSRAMEDRPGVWGWAVLGITPEELSKVLEQFQSSMGIPAIKRAKVGVTGDRWSTVIGPPSVLDLFIHQCPAVRNLPKNELSIHALQHTVTVTEADLDFIVGSAELLSHPIVPDFKVWGMDDPVASYQNWGEMLRAIVTQVLSKPLDITKVIAQLNTHLGPRHVDVRVIGPSSHTPYLASSLKAAGSKAIFQTDKTLEQLQPKKLPPGRIAIVGMAGRGPGCENVDEFWDVIMAKQDRCEEIPKDRFDINEFYCTEHGEGCTTTTKYGCFMNKPGNFDSRFFHVSPREALLMDPGHRQFMMSTYEALETAGYSDGQTRDVDPNRIAAFYGQSNDDWHMVSHYTLGCDAYTLQGAQRAFGAGRIAFHFKWEGPTYSLDSACASTSSAIHLACVSLLSKDVDMAVVGAANVVGYPHSWTSLSKSGVLSDTGNCKTYCDDADGYCRADFVGSVVLKRLEDAVEQNDNILAVVAGSGRNHSGNSSSITTSDAGAQERLFHKIMHSARVSPDEISYVEMHGTGTQIGDPAEMSAVTNVFRKRKANNPLTVGGIKANVGHAEASAGMASLLKCIQMFQKDIMPPQARMPHTLNPKYPSLSELNIHIPSEPKEFKAIGERPRRILLNNFDAAGGNASLILEDFPSTVKENADPRPSHVIVSSAKTQSSYHANKRNLLKWLRKNKDAKLEDVAYTTTARRMHHPLRFSCSASTTEELISKLEADTADATASRGSPVVFVFTGQGSHYAGMGAELYKTCPAFREEVNLCASISEEHGFPPYVDIITNKDVDITTKDTMQTQLAVVTLEIALAAFWKASGIQPSAVMGHSLGEYVALQVAGVLSLADLLYLVGNRARLLLERCEADTCAMLAVSSSAASIRELIDQRPQSSFEIACKNSPNATVISGSTDEISELQSSFTASRARALSVPYGFHSFQMDPMLEDYIVLAGGVTYSPPKIPVASTLLASIVESSGVFNASYLGQQTRQAVDFVGALGALKEKFADPLWLEIGPSQICNSFVRATLSPSPGKILSTLEANTNPWASIAKCLAGAYKDGVAVDWLAVHAPFKGGLKLVKLPAYAWDLKDFWIVYSEANKAARALAPAPSFETQRISTCAQQIVEESSSPSLHVSARAAISDPGFMALVDGHRMRDVSICPGSVFCEAGLAVSKYALKYSGRKDTVETRLTINNLSLKRPLTKSLVGTDGELLTTVVADKASSDTLQVSWKASSSHASYDLGSCEITICDAQTLQTSWNRSSYFVKARMNELIKNVKSGNGHRMLPSILYTLFASTVDYDPTFKSVKEAFISNEFDEAAAEVVLQKNPAGTQFFASPYWGESVVHLAGFLVNSNPARKTASQTTFMMQSLESVEQTADLEAGRTYYTYARVLHEEEDTVSCDLFVFDSEKMVMQCSGLSFHEVSNNVLDRLLGKASPPVKQVSHQKAPVLVPAESKPALKAAVEAAPKAPEPVKTEVKKISSSESELFHTILESIAKETGTQVSDFTDDMELAELGVDSIMGIEIAAGVSSRTGLDVLLPSFVVDYPTIGDLRNEFARSSTSTPPSKTFSEFSIVDATPESTRSSSRAPSEKKEPAPASEKSEELVIVPSAVVEDSSPLPSARITLIQGRSSSGKQPFYLIADGAGSIATYIHLAPFKDKRPVYGIDSPFLRCPSRLTTQVGIEGVAKIIFEALIKCQPEGPFDLGGFSGGAMLSYEVSRQLAAAGRVVSSLLLIDMCSPRPLGVEDTIEVGWKVYETIASQDKLWNASSNTQQHLKAVFACVAAYHPPPITPAQRPKRTAIIWAKKGMVDRCSRDEKVMKFLADKGIPTESYPGFMEDPKLGAVAWGLPHKSAADLGPNGWDKFLGETLCLSIDSDHLDMPMPGHVHLLQAAMEESFKYFSEAN
What is the function of this protein?
Non-reducing polyketide synthase; part of the gene cluster that mediates the biosynthesis of hypothemycin, a resorcylic acid lactone (RAL) that irreversibly inhibits a subset of protein kinases with a conserved cysteine in the ATP binding site such as human ERK2 (PubMed:18567690).  The first step is performed by both PKSs hmp3 and hmp8 and leads to the production of 7',8'-dehydrozearalenol (DHZ) (PubMed:18567690, PubMed:20222707).  The highly reducing PKS hpm8 synthesizes the reduced hexaketide (7S,11S,2E,8E)-7,11-dihydroxy-dodeca-2,8-dienoate, which is transferred downstream to the non-reducing PKS hpm3 (PubMed:20222707).  Hpm3 then extends the reduced hexaketide to a nonaketide, after which regioselective cyclization and macrolactonization affords DHZ (PubMed:20222707).  The next step is the conversion of DHZ into aigialomycin C and is performed by the O-methyltransferase hmp5, the FAD-binding monooxygenase hmp7, and the cytochrome P450 monooxygenase hmp1 (PubMed:18567690).  The wide substrate tolerance of the hmp5 and hmp7 implies that the reactions from DHZ to aigialomycin C can occur in any order (PubMed:18567690).  The steps from aigialomycin C to hypothemycin are less well established (PubMed:18567690).  The FAD-linked oxidoreductase hmp9 presumably catalyzes oxidation of the C-6' hydroxyl to a ketone (PubMed:18567690).  The timing of this oxidation is important, since the resulting enone functional group is a Michael acceptor that can react spontaneously with glutathione, an abundant metabolite in fungal cells (PubMed:18567690).  The glutathione S-transferase hmp2 catalyzes cis-trans isomerization of the 7',8' double bond with equilibrium favoring the trans isomer (PubMed:18567690).  The hpm6-encoded transporter might preferentially pump hypothemycin out of the cell relative to the trans isomer aigialomycin A.  The cis-to-trans isomerization may be coupled with C-4' hydroxylation, since all known hypothemycin analogs containing the enone functional group also have hydroxyl groups at both C-4' and C-5' (PubMed:18567690).
What are the official names of this protein?
Non-reducing polyketide synthase hmp3, NR-PKS hmp3, Hypothemycin biosynthesis cluster protein hpm3.