Protein: Non-reducing polyketide synthase gsfA (EC 2.3.1.-) (Griseofulvin synthesis protein A) (Norlichexanthone synthase) (D7PI15)
Organism: Penicillium aethiopicum
Function: Norlichexanthone synthase; part of the gene cluster that mediates the biosynthesis of griseofulvin, an important antifungal drug that has been in use for a long time for treating dermatophyte infections. The first step of the pathway is the formation of the heptaketide backbone by gsfA which is initiated by priming with acetyl-CoA, followed by sequential condensations of 6 malonyl-CoA units. The resulting benzophenone can undergo a spontaneous dehydration to form norlichexanthone. However, the true precursor for the griseofulvin biosynthesis is not norlichexanthone, but the heptaketide benzophenone that is O-methylated at 3-OH by gsfB to produce griseophenone D which is further methylated at 9-OH by gsfC to yield griseophenone C. Griseophenone C is then substrate of halogenase gsfI which is responsible for the regio-specific chlorination at the C13 position to form griseophenone B. The cytochrome P450 gsfF catalyzes the coupling of orcinol and phloroglucinol rings in griseophenone B to form desmethyl-dehydrogriseofulvin A which is further methylated at 5-OH by gsfD to yield dehydrogriseofulvin. Finally, gsfE performs stereospecific reduction of enone 18 of dehydrogriseofulvin to afford the final product griseofulvin.
Sequence: MTSAKVLYFSGEIPQGDPEGDQRTLFRKLHLLSKERDHVVLASLLECVTLTLKDECSKLSPQYRDLLPPFESVLDLTDHVVQLRKTPLGGAIERVLVLVFQLGSLVAYHEAHPLEYNFTPASTVIIGRGSGLLSAAAIGLSPSIVMVPSIAKEIARISFRFGLVVDKVCRSLEVSSDEINSDGAWVYCVHGIGEKEARDAVNQFNEIKAYPSTNGASVFNVDDAGNSVSIGGPPKTLEALFSESNIFKKTKNVAMRKIQGMWHTDRVYGPEHVEQIVPKIESARELHVPLISPVSGDPFRETEAGPLLEQIMEEILMERVRWDMIIETVSKQLKQLMPKSVQLVSIQPSHYNQNMLERWKSELPDAAVSGLTMMPAILELALEQSPPKDTRSSKIAVVGMSCRFPGSDTTEEFWERLMLGEDMHRHIPPDRFDVETHVDPTGKRHNTSKTSYGCFVDNPGLFDAMFFGMSPREAEQTDPMQRLALVTAYEALEKAGYVDGRGVIHRKRVGTFYGQASDDYREVNSGQEVGTYFIPGGCRAFGPGRINYFLNFWGPSFSVDTACSSSLAAIQAACSSLWSGDIDMAITGGMNILSNSDVYAGLSQGHFLSPTGGCKTWDEGADGYCRSDGVGSVVLKRLEDAEADNDNILAVVLSAATSHSAEAVSITHPHDAAQALLYNQIVRRAGIDPLEVGYVEMHGTGTQAGDPTEMRSVTSVFAPPHIQGSRPIPLHVGSVKANMGHGEAAAGIMAFVKTMLVFQNGIIPPHIGVKTGLNPALPDLDKAGVVIPFRAANWRPTGTKKRLAMVNNFGAAGGNTAMIIEEAKARPRLCEDIREAHAITISAKTAVSLSLNIKRLVEYIESAQDLSLADVAYTVSARRRHYEYRKSVVVRSLAEAIKHLQPHIETAKSQTPTLVKRPPVAFAFAGQGTFYVGIAAQIYRDSPFFRAQIDQFDNLARRQNFPSFLPAINKTCAHEDLPASSIHLAIVCVEVALARMCMTFGIKPCAVIGHSLGEYAALAVAEVLSDSDTVFLVGTRATILESNCSPYTHGMISVRASVDDISREADGLPFEVSCINGPNETVIGGTVENLEAVADRLSKVGYRKTRLDVPHAYHTAQMDNVVNELIRQSQGIAYNTPKIPIMSPRDSSVIETGANIDSSYLPTSLKKAVDFAGALNAAWEAGVVSKSTVWLELSHHPVCSGFINRTLPNTSLTCSTLHRDSDNWTSLLKTLSSLYEVGLNIDWNEYHRPFEHALRLVSAPTYAWNNKDYWIQYRGDWNLTKGQVLPEAELPAVSGFRTSSIHRLYSENYDSSTAHLLGECNMTDLSLKGVIEGHAMNGYGVASSFLHAEMAFTLARRIQEKASLSTFTGMGINVTNFEYHDPVVKDASSLDPYPIVVDAEANLEMGEVQIKWFNPAIEKWYCHAIAYYEDPSTWLSNWSRTTRLVTSRIDALVAMSNKGMANKLTTSLAYTLFGKLVDYSSMYHTMQWVILNEDEAVAEVVFPADTQGDWAVPPHFIDGVVSLSGFILNGGTHFDNVNNFFITPSWKSMRFAKPLAPGGRYLTYVRMIPEGVDDKGRLGSYVGDVYILQDGEIVGVVEAILFRQWPRIMLNRFFQPVGMAPPAPRVEKKRDAGRGTLPSSSSLQEKTTATAVTAKITARFPGSVITPSRSAPISKSGSSPKIVPQLDYSLLTPRTSPNSDERIEKTDSDSGFEEADGANDVTSRAVEILAEELAVDKGLLTDECEIADIGVDSLMSLVISQKLREDLGIEVRDAFYLEVTTIGDLKKLLS
InterPro domains: - IPR020841: Polyketide synthase, beta-ketoacyl synthase domain (domain) [392-825]
- IPR018201: Beta-ketoacyl synthase, active site (active_site) [554-570]
- IPR016035: Acyl transferase/acyl hydrolase/lysophospholipase (homologous_superfamily) [920-1214]
- IPR014030: Beta-ketoacyl synthase-like, N-terminal (domain) [393-641]
- IPR030918: Polyketide product template domain (domain) [1298-1616]
- IPR036736: ACP-like superfamily (homologous_superfamily) [1718-1789]
- IPR014031: Beta-ketoacyl synthase, C-terminal (domain) [649-769]
- IPR032088: Starter unit:ACP transacylase, SAT domain (domain) [20-255]
- IPR049900: Polyketide synthase, dehydratase domain (domain) [1302-1611]
- IPR014043: Acyl transferase domain (domain) [922-1223]
- IPR050091: Polyketide and Nonribosomal Peptide Biosynthesis Enzymes (family) [379-1571]
- IPR009081: Phosphopantetheine binding ACP domain (domain) [1716-1790]
- IPR016036: Malonyl-CoA ACP transacylase, ACP-binding (homologous_superfamily) [1049-1109]
- IPR001227: Acyl transferase domain superfamily (homologous_superfamily) [6-1224]
- IPR016039: Thiolase-like (homologous_superfamily) [389-829]
- IPR042104: Polyketide synthase, dehydratase domain superfamily (homologous_superfamily) [1296-1615]
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0003824 (catalytic activity), GO:0016491 (oxidoreductase activity), GO:0016679 (oxidoreductase activity, acting on diphenols and related substances as donors), GO:0016682 (oxidoreductase activity, acting on diphenols and related substances as donors, oxygen as acceptor)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0009987 (cellular process), GO:0009058 (biosynthetic process), GO:0044237 (cellular metabolic process), GO:0019748 (secondary metabolic process), GO:0071704 (organic substance metabolic process), GO:0044281 (small molecule metabolic process), GO:0044550 (secondary metabolite biosynthetic process), GO:1901615 (organic hydroxy compound metabolic process), GO:0044249 (cellular biosynthetic process), GO:0009404 (toxin metabolic process), GO:1901360 (organic cyclic compound metabolic process), GO:1901576 (organic substance biosynthetic process), GO:0006725 (cellular aromatic compound metabolic process), GO:0018904 (ether metabolic process), GO:0030638 (polyketide metabolic process), GO:1901617 (organic hydroxy compound biosynthetic process), GO:1901503 (ether biosynthetic process), GO:1901362 (organic cyclic compound biosynthetic process), GO:0043385 (mycotoxin metabolic process), GO:0009403 (toxin biosynthetic process), GO:0019438 (aromatic compound biosynthetic process), GO:0030639 (polyketide biosynthetic process), GO:0018958 (phenol-containing compound metabolic process), GO:0043386 (mycotoxin biosynthetic process), GO:0046189 (phenol-containing compound biosynthetic process)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0032991 (protein-containing complex), GO:1902494 (catalytic complex), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005737 (cytoplasm), GO:0043229 (intracellular organelle), GO:1990204 (oxidoreductase complex), GO:0005739 (mitochondrion), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle)