Protein: Non-reducing polyketide synthase nvfA (EC 2.3.1.-) (Novofumigatonin biosynthesis cluster protein A) (A0A2I1BSV9)
Organism: Aspergillus novofumigatus (strain IBT 16806)
Function: Non-reducing polyketide synthase; part of the gene cluster that mediates the biosynthesis of novofumigatonin, a heavily oxygenated meroterpenoid containing a unique orthoester moiety. The first step of the pathway is the synthesis of 3,5-dimethylorsellinic acid (DMOA) by the polyketide synthase nvfA via condensation of one acetyl-CoA starter unit with 3 malonyl-CoA units and 2 methylations. DMOA is then converted to farnesyl-DMOA by the farnesyltransferase nvfB. Epoxydation by FAD-dependent monooxygenase nvfK, followed by a protonation-initiated cyclization catalyzed by the terpene cyclase nvfL leads to the production of asnavolin H. The short chain dehydrogenase nvfC then as a 3-OH dehydrogenase of asnovolin H to yield chemesin D. There are two branches to synthesize asnovolin A from chemesin D. In one branch, chemesin D undergoes Baeyer-Villiger oxidation by nvfH, methylation by nvfJ, and enoyl reduction by the nvfM D enoylreductase that reduces the double bond between C-5'and C-6', to form respectively asnovolin I, asnovolin K, and asnovolin A. In the other branch, the methylation precedes the Baeyer-Villiger oxidation and the enoyl reduction to yield asnovolin A via the asnovolin J intermediate. Asnovolin A is further converted to fumigatonoid A by the Fe(II)/2-oxoglutarate-dependent dioxygenase nvfI that catalyzes an endoperoxidation reaction. The alpha/beta hydrolase nvfD then acts as an epimerase that converts fumigatonoid A to its C-5' epimer, which then undergoes spontaneous or nvfD-catalyzed lactonization. The following step utilizes the ketoreductase nvfG to produce fumigatonoid B. The dioxygenase nvfE further converts fumigatonoid B into fumigatonoid C. Finally the Fe(II)/2-oxoglutarate-dependent dioxygenase nvfF catalyzes two rounds of oxidation to transform fumigatonoid C into the end product, novofumigatonin A.
Sequence: MEPSDTERCDVGILFGPQSSDMDEALSCIRSYVLEQPAVRYLVDLVLELPSLWPEIKNAWPALSQVPGEEQLVALGRFFNGGPFPASDEAMNVITTPVTVIRHIVEFYKVKETMKGFQARDVQGFCVGFLAATAVAASCDETAFRALVSKIIRLAVCIGGLVDLDELAVHRARSMAVRWDGEEDYDRLEQVLAAHPEAYIACVTDANRATLTVPKSLAPQMIQDLANHGLSVREIRLCGRFHHPDHTAAVEQMSRLCERDCRFQLPDASSLSLPLRSNINGEVIRTGQLHTIALQSILCFRSQWLITVTAALASITMTDESIRLVSIGPHQCVPRMAQSKLIRTVTSSPVDGCYEAINGTGAAPVRPIAVTGMACRYPQANSVEELWEMLELGKCAVKPLPNDRLKMVELLREPKGPYWGHYLEEPDMFDHRFFGISAREAATMDPQQRLLLQVAYEAMESAGYCGLRSSQIPRDVGCYVGVGSDDYTDNVGSHHANAYSAPGTLQAFNTGRISHYFGWSGPSVVVDTACSSAAVAIHLACQALRTKDCSVAIAGGVNVMTSPKVTQNLAAASFLSPTGASKAFDADADGYCRGEGAGLVVLRPLEDAISDVDPILAVITGTAVNQGSNCSPITVPVSESQMSLYGKSLAASGIAPEDVTYVEAHGTGTQVGDPIEFDSIRRMFGGRHRSEELYVGSIKDNIGHTETSSGVAGLVKTILMMQKGRIPKQANFSRLNPKIPAPEGDRIVIPKQSTDWKSARRVAMVTNYGAAGSNAAIVLRQHTITTNTGSSWLSDVPVFVAAKSPESLRSYCYKMQAFLRQTAGLLGCTMRDITYNLAIKQNRDLDFLVSFPTPSQDPMTLLSQLESVAAGVTDLQQRPAQAPSVILCFGGQNGNTAHISQDLFAGCHLLQAHLADCEKICQSMGLPSLFPTIFQEEPIHDLVNLHCILFAIQYASAMCWIHSGLQVKRMLGHSFGQLTALCVAGGLTLIDAIRLVSERARLIETSWAGDHGVMLSVDASEAEVRALVNRAGDTVDLACYNGARSYVLAGDEISIQVVEKLADGMRIKRLPNTHAFHSRLVDSIVPGLRKLAQSLKYHPTTIPVEACSEDGSAWTCVTPDQIVAHSRMPVHFDSAVQRAANHVQGPVVWLEAGSASPIVSMVRRVVEESSSSRAHLYQASDLKSPQAQANLAKATSGLWANGIPTSHWTEYDPLAFLPASAPIAEASSEPMGLVQVLEKRPSECLFSVNTKDPLYRTCTQGHAVVEQNLCPASLYLEMVVSAAGCLSSAGLITAMPHLQELSISAPLVLEPDGDVLLRLSQSPAEKTAWTFSLFTQAGQKAPVSHATGRISLHPFDSTSTILSRFRSLDRLMNPSRPDSIASLPSSSGLKGSAVYQAFRRVVNYADYYRGVESVFCVSTEATGRVFVPLSLSRESACDPILIDNFVQVAGVHVNCLADVPEDEVYVCSAVGEAFIGEVFMKRDPAAPQPWRVYSNYDRLSKGQVACDVFVMDQKSGQLAIAILAATFTSVSIRALTRTLAKLNNHQPSMLATNEPSAGHKEVNSILNVVDRPPPTAATVDTNKFPAIQAMLSDLLGVGLDELSPYSSLMAIGVDSLMSTEVLTEIKKRFGVNITSAELGEIPDIQCLVQAIFPGASVAQKQATTSKMPPLSDLAESVFNGPAPPDALMLAQKAYDLFGTTQANTDYSQITKWAGFCESVFPKQMALVTAYVVEAFRALGYPLELLHAGQAVPLIPVLPQHESVRNQLYEVLKFSKLICRKDDGMFRTAEAVPSDTSLLLHEDIIKEYPHHASEHTLLRTTGSRLAECLSGSADPLALLFQNADARRVMEDVYTNAPMFKSATMHLAQYLQDLVILLRSRRDIKILEIGAGTGGTTKYLVSQLAAVPGLRFEYTFTDISTSLVTLAKKKFNGYSCIQYATLNIEQDPPDDLLGQYDIVLSTNCIHATRNIAHSCDNIRKLLRPDGILCLIELTRNLFWFDLVFGLLEGWWLFNDGRNHALATEQFWNESLRQAGYNWVNWSCNDSRESEILRLIVASPTLPHGASQILFRSPLVTEETVKYDEKDGVQLLADIYYPSEVDDAHRRRPIALLIHGGGHVMLSRKDIRSQQIKMLLNSGFLPVSIDYRLCPETSLTEGPMRDVRDALVWTRRTLPRLSLKRPDIRPNGDQVVAVGWSTGGHLAMTLSWTASLCGVRAPEAILSFYCPTDYSDPFWSQPNFPYGRDIAPQMKCTIFGMQ
InterPro domains: - IPR016035: Acyl transferase/acyl hydrolase/lysophospholipase (homologous_superfamily) [885-1170]
- IPR014031: Beta-ketoacyl synthase, C-terminal (domain) [616-732]
- IPR014043: Acyl transferase domain (domain) [888-1202]
- IPR020807: Polyketide/metazoan fatty acid synthase-like, dehydratase domain (domain) [1229-1401]
- IPR016039: Thiolase-like (homologous_superfamily) [361-800]
- IPR020841: Polyketide synthase, beta-ketoacyl synthase domain (domain) [365-784]
- IPR049492: BD-FAE-like domain (domain) [2091-2206]
- IPR016036: Malonyl-CoA ACP transacylase, ACP-binding (homologous_superfamily) [1011-1069]
- IPR001227: Acyl transferase domain superfamily (homologous_superfamily) [2-1188]
- IPR041068: Methyltransferase, fungal type, helix-turn-helix domain (domain) [1704-1783]
- IPR014030: Beta-ketoacyl synthase-like, N-terminal (domain) [366-608]
- IPR036736: ACP-like superfamily (homologous_superfamily) [1584-1673]
- IPR032088: Starter unit:ACP transacylase, SAT domain (domain) [86-242]
- IPR009081: Phosphopantetheine binding ACP domain (domain) [1581-1655]
- IPR006162: Phosphopantetheine attachment site (ptm) [1610-1625]
- IPR018201: Beta-ketoacyl synthase, active site (active_site) [521-537]
- IPR013217: Methyltransferase type 12 (domain) [1885-1986]
- IPR029058: Alpha/Beta hydrolase fold (homologous_superfamily) [1991-2251]
- IPR029063: S-adenosyl-L-methionine-dependent methyltransferase superfamily (homologous_superfamily) [1780-2050]
- IPR042104: Polyketide synthase, dehydratase domain superfamily (homologous_superfamily) [1252-1535]
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0044877 (protein-containing complex binding), GO:0016740 (transferase activity), GO:0016746 (acyltransferase activity), GO:0005178 (integrin binding), GO:0005102 (signaling receptor binding)
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:0044281 (small molecule metabolic process), GO:0006807 (nitrogen compound metabolic process), GO:0019748 (secondary metabolic process), GO:0071704 (organic substance metabolic process), GO:0044550 (secondary metabolite biosynthetic process), GO:0042180 (cellular ketone metabolic process), GO:1901615 (organic hydroxy compound metabolic process), GO:1901360 (organic cyclic compound metabolic process), GO:1901576 (organic substance biosynthetic process), GO:1901564 (organonitrogen compound metabolic process), GO:0044283 (small molecule biosynthetic process), GO:0120254 (olefinic compound metabolic process), GO:0044249 (cellular biosynthetic process), GO:0006066 (alcohol metabolic process), GO:0009404 (toxin metabolic process), GO:0006725 (cellular aromatic compound metabolic process), GO:0034641 (cellular nitrogen compound metabolic process), GO:0043603 (amide metabolic process), GO:0018904 (ether metabolic process), GO:0030638 (polyketide metabolic process), GO:1901566 (organonitrogen compound biosynthetic process), GO:1902652 (secondary alcohol metabolic process), GO:1901503 (ether biosynthetic process), GO:1901362 (organic cyclic compound biosynthetic process), GO:0043385 (mycotoxin metabolic process), GO:0120255 (olefinic compound biosynthetic process), GO:0009403 (toxin biosynthetic process), GO:1902644 (tertiary alcohol metabolic process), GO:0019438 (aromatic compound biosynthetic process), GO:1901617 (organic hydroxy compound biosynthetic process), GO:0043604 (amide biosynthetic process), GO:0044271 (cellular nitrogen compound biosynthetic process), GO:0042181 (ketone biosynthetic process), GO:0046165 (alcohol biosynthetic process), GO:0030639 (polyketide biosynthetic process), GO:0018958 (phenol-containing compound metabolic process), GO:0043386 (mycotoxin biosynthetic process), GO:1902645 (tertiary alcohol biosynthetic process), GO:1902653 (secondary alcohol 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:0005737 (cytoplasm), GO:1902494 (catalytic complex), GO:0005622 (intracellular anatomical structure)