Protein: Hybrid PKS-NRPS synthetase iccA (A0A482N9V7)
Organism: Talaromyces variabilis (Penicillium variabile)
Function: Hybrid PKS-NRPS synthetase; part of the gene cluster that mediates the biosynthesis of ilicicolin H, a 4-hydroxy-2- pyridonealkaloid that has potent and broad antifungal activities by inhibiting the mitochondrial respiration chain. IccA assembles the backbone of ilicicolin H. The PKS portion and trans-acting enoyl reductase iccB work together to construct an octaketide, and two methyl groups are introduced by the MT domain during the chain assembly. The nascent chain is then condensed with tyrosine, catalyzed by the C domain, and the resulting PKS-NRPS hybrid is offloaded by the RED domain to form an advanced tetramic acid intermediate. The biosynthesis of ilicicolin H starts with formation of the tetramic acid by the hybrid PKS-NRPS synthetase iccA with the partnering trans-enoyl reductase iccB since iccA lacks a designated enoylreductase (ER) domain. The cytochrome P450 monooxygenase iccC then catalyzes the ring expansion of the tetramate to the acyclic 2-pyridone. The pericyclase iccD further converts the acyclic 2-pyridone into 8-epi-ilicicolin H. Finally, the epimerase iccE converts 8-epi-ilicicolin H into ilicicolin H via epimerization. IccA to iccE are sufficient for ilicicolin H biosynthesis and the roles of the remaining enzymes, iccF, iccG and iccH within the pathway have still to be determined (Probable)
Sequence: MAANDSNNQTKPQLPEEPVAIVGSSCRFPGSSNSPSKLWDLLRQPRDVLKEFDPDRLNLKRFYHPDGDTHGSTDVTNKSYLLEEDSRLFDASFFTINPAEAAGMDPQQRILLETVYEAFESAGMTLEQLRGSLTAVHVGTMTNDYAGIQLRDLETIAKYNATGTANSIVSNRISYVFDLKGPSETIDTACSSSLVALHHAARGLLNGDCETAVVAGVNLIYDAASYIAESKLHMLSPDSQSRMWDKSANGYARGEGAAALLLKPLSRALRDGDHIEGVIRATGVNSDGQSPGITMPFAPTQAALIRQTYRRAGLDPVKDRPQYFECHGTGTPAGDPVEARAISEAFEPSADNPIYVGSIKTIIGHLEGCAGLAGVMKVILALKNRTIPPNMLFNELNPAIAPFYGPLQIPKKAMPWPELPENTPIRASVNSFGFGGTNAHVIIESFESSTPSSDSEKCEEGALGPLLFSAGSGASLLHTVQAYVQYLDQNPSVDLRDLSWLLQTRRSTHRVRTHFSGTSSDAILESMIKFVNNNEKTPSTEVGHQPKLINPKEVPGILGVFTGQGAQWPQMGKELIGKSPIFRRTLEDCDATLQALPSSDIPKWSLVKELMANASSSRVAEAAISQPLCTAVQLGLVNMLKASGLNFDAVVGHSSGEIAATYASGIINLQAAIQIAYYRGFHAKLAKGEKGQQGGMLAAGLTLDKAKQLCLREEFVGRLQVAASNAPQTVTLSGDLDAIEEVKKYLDEENVFARQLKVDTAYHSHHMKPCAEPYLKSLLACDIEVRKPTPGQCIWNSSVRGDTGLLKGDLSSLKGPYWVANMVQTVLFSQAVESSIWHGGPWDLAIEVGPHPALKGPTEQTLKAVYGVVPLYTGVLKRGASDVEAFSTAIGVTWSQLGPSFVDFAGYRKTFYESEPPTPKVIKDLPGYSWDHDKVYWRESRISKRYRTGRDQTHELLGRRTPDDNEFELRWRNVLKLSEMPWLRGHEVLEEVLLPGAAYVSIAVEASKHIATSKGKSIELLEVEDVDIQRPVVVPDNKEGVETLFTARLLPGSSSDKVLKALFSYYICNDQSTGTMVHTCSGRLSVHLGEAKEDVLPQRDPVPQNLVNINTDRAYGMFKDIGLNYTGVFRSIKESSRTLQYSAATGIWPEGSLSDKYLVHPAMLDVAFQTLFIARAHPASRLITSALLPSHIERIQVSPSVPILHARENSDEIKADFDCWVVHQTASSLTGDLNIYDKVSGKTFLQVEGLTTKMVGEQDASGDRPVFTKTVWGSDGSLGLDEPERDPVGDAEGLSLAEAAERMALFYMKRVVKEISPEERTKFQWYHQRMFEAFEQHLVNVGSGSHPMLKSEWLSDDSSIMDGLDRIHPTSIDLKLLRACGENMPDVVREKTQLLEVMSKDDMLNRFYMDNCAARINNDIAKVVKQISFKFPRANILEIGAGTGGTTWSILKDINDAYDSYTFTDISSGFFPKAAEKFSDFAHKMIFKTLDVEKQPSEQGFAENSYDVIVAANVLHATRSLETTLRNARSLLRPGGYLILMEITNPESLRTTFIFGGFSGWWLSEEPHRKLGPVVTAMDWDTVLNDTGYSGADMVVHDLAEESKHLTSLIVSQAVDDDFLRLREPLSNLADMSAPTESILVIGGKKLLTSKMVNEINKLLPKSWKRHISSAGSIDDIDINELKPGTEVISLQELDDPLFSTPMTAERMSTIQNLMMSAKTLLWVTTAGKSHAPRASMFHGIARIVPSELQHLQIQVLGLEAGSTPAIATRHCVEAFLRLRGTSDTTREMLWAIEPEVEIMADGQVLIPRVVPDETLNQTYNASRRVVTKTVDATDLAVEAVAGPTKMMLQTAELQAGERKTRIQVKYALHLPAMDGKGIYVVYGQRQDDTSSFVLAVSKSNSSIVDVDSKHAVSVSDNCEPATLNVLATYLIARAIATLSKQAGSVLLSEPEESLAAIVATETAKQGTQAYFLSSKKVSPVEWIKVHANASKRAIQKAVPHDVQLLIDCSGIEASGNAVMASMPLHCVERQLDAHLLFDALESTESKPESLLEEAYQYATQLITQEQVQSECEVFPASDLPLTNMLSLVHKKYVTDWQQRDSLVVSVPPLDLEGIFKADKTYLMVGAAGGLGLSICEWMIRNGAKNLIITSRKPQVDQNMIEEASRVGATVKVMAMDVSSKESVAEVVQQAQEIMPPIAGVCNAAMVLSDKMFLDMDVDQLNGTLAAKVYGTEHLDAVFADAPLDFFIVLSSTATTIGNIGQANYHVANLFMTSLVAQRRARGLAGSVIHIGYVADVGYVTRQDRERQLEQHFRNVRLMALSETDVHHAFAEAVRGGRPGNTVGSPDIIMGLEPASVPLEPERQTLWLSNPCFGHLVPSTLQNDSSQTGGTGNGSSVRRQVEEAQTEDEAVDAVLDGFCAKLEAILQLREGSVKENVQRAVIDLGIDSLVAVEIRTWFLKELGAEVPVVKILGGDTVLQICTTAAKKVMANAMKKKEEDAVAEEGGREAASKKEPAPAASAPTPAPVAPSLLDVPARAFEPDSATISEVGDDSAFSNKGSSSSATGASSPKELSDSESVPDTSKDQSHVRPETVRDERMSPAQARIWFLTKHLDDPSAYNMVFHYRVKGPLKTVRLRHALQVATGHHESLRTLFYSRLEDGQPMQGVMPASAYELKHVPGADEADLKKELALLKAREWDLENGRTFSVSVLSRAADEHDVVFGYHHIIMDVVGWYFFVRDLDRAYRMQPFDKKISGSYVDYSVMQLSQKNTAAASDDLAFWQKEFSTVPDPIPLLPIAAVSARPTDSGRKVSHHEYLELDPAQNLAVKETCEKLRISPFHFHVAVLRALIGGYTNIDDMCIGVVDANRGDERFAQTVGCFVNMLPVRVEAPSDATFADIARSASRKALMAFAHSSAPLDMILDAVKAPRSSETTPLFQVAVNYRTGGVWDLPMGDCQMKLSLTDGKDAENPFDISLGIAETGKGCVIEMHCQKTLYSSDATRTLLNTYLRLVDTFCKNTHVKLKDCVIHDQAKVSEALQIGKGPTTDFGWPSTLSHRVLETCLKSPKNAAIQFKGELLSYEQLASRIHLVAAAIVRAGASKGSRVAVLCEPSADAIISMLATLHIGGVYIPMDVSLPTARHAAMMNGGQPTLLLSHAATKHRVEDLVNETGSTISVLQVDTISSVEEKETVSCAAEPHNNAVLLFTSGSTGTPKGIMLSQANFVNHLALKTDRLQLGQENVLQQSSMGFDMSLIQMFCALANGGCLVIAPSEMRRDPVELTNLVHNSQISLTIATPSEYLAWLRYGTASLKDHTIWRHACMGGEPVSRQLKTEFWRLDLANLQLTNCYGPTEITAAATFETIRLDDQDDDNDRAQHAVGKALPNYSVRILDTAGRPQPVDHIGEICIGGASVALGYLGLPEQTKAKFTVDPVSGERLYLTGDKGKLLSDGTLLCLGRLDGDTQIKHRGLRIELQEVESALIQTANGLFSSAVVSARGSILVAHATISQSQAEPSESDLAKILSRLKLPQYFIPATIGILPTMPTTANGKLDRKAIASLPLPQKVTGEEGPQEKMNIREGELRLLWERVLPDTATTTPLGPSSDFFLCGGNSMLLMKLQAAIKESIGIEISTRVLYQASTLREMALCVDEQREEQADALEQHFDWQAETSLPKWLLDQIEDLPKTTKQPPKPNGIDILMTGATSFIGGRLLRSLVRSPSVRKVHCVAVLADEQDQLYQDEKVKCYTGSLLSSTLGLNNGERDQLARNVDVVIHAGSSGHCLNTYGSLRTPNLVSLQFLASLALPRSIPLLLLSSNRVPLLSGNTALPPTSVAAFPPATDGREGYTATKWASEVFLEKLVGAVQKKAPRPWVASVHRPCVVVSEHAPNSDALNAILRYSASMKCVPHLESATGYLDFASVESIVDSMAESAIEMATGNVTDQPSIRFQHHSGGVKVPIGDFKVHMENVYGGNFEEVHLEEWMHRAAAAGLDPLITAYMEGIIEAGAPIVFPYLGETV
InterPro domains: - IPR013217: Methyltransferase type 12 (domain) [1437-1538]
- IPR006162: Phosphopantetheine attachment site (ptm) [2443-2458]
- IPR014043: Acyl transferase domain (domain) [560-891]
- IPR016035: Acyl transferase/acyl hydrolase/lysophospholipase (homologous_superfamily) [558-865]
- IPR013120: Fatty acyl-CoA reductase-like, NAD-binding domain (domain) [3699-3924]
- IPR001227: Acyl transferase domain superfamily (homologous_superfamily) [557-873]
- IPR020845: AMP-binding, conserved site (conserved_site) [3203-3214]
- IPR010071: Amino acid adenylation domain (domain) [3079-3483]
- IPR020841: Polyketide synthase, beta-ketoacyl synthase domain (domain) [16-448]
- IPR016039: Thiolase-like (homologous_superfamily) [15-524]
- IPR020807: Polyketide/metazoan fatty acid synthase-like, dehydratase domain (domain) [954-1132]
- IPR018201: Beta-ketoacyl synthase, active site (active_site) [181-197]
- IPR014031: Beta-ketoacyl synthase, C-terminal (domain) [277-391]
- IPR016036: Malonyl-CoA ACP transacylase, ACP-binding (homologous_superfamily) [693-759]
- IPR001242: Condensation domain (domain) [2599-3032]
- IPR009081: Phosphopantetheine binding ACP domain (domain) [2409-3651]
- IPR020806: Polyketide synthase-like, phosphopantetheine-binding domain (domain) [2415-3651]
- IPR014030: Beta-ketoacyl synthase-like, N-terminal (domain) [17-268]
- IPR000873: AMP-dependent synthetase/ligase domain (domain) [3061-3417]
- IPR013968: Polyketide synthase-like, ketoreductase domain (domain) [2121-2295]
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0003824 (catalytic activity), GO:0016740 (transferase activity), GO:0016491 (oxidoreductase activity), GO:0016746 (acyltransferase activity), GO:0016741 (transferase activity, transferring one-carbon groups), GO:0016747 (acyltransferase activity, transferring groups other than amino-acyl groups), GO:0008168 (methyltransferase activity), GO:0008757 (S-adenosylmethionine-dependent methyltransferase activity)
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:0046483 (heterocycle metabolic process), GO:0044249 (cellular biosynthetic process), GO:0009404 (toxin metabolic process), GO:0006725 (cellular aromatic compound metabolic process), GO:0034641 (cellular nitrogen compound metabolic process), GO:0030638 (polyketide metabolic process), GO:1901566 (organonitrogen compound biosynthetic process), GO:1901362 (organic cyclic compound biosynthetic process), GO:0043385 (mycotoxin metabolic process), GO:0009403 (toxin biosynthetic process), GO:0009821 (alkaloid biosynthetic process), GO:0019438 (aromatic compound biosynthetic process), GO:0018130 (heterocycle biosynthetic process), GO:0009820 (alkaloid metabolic process), GO:1901617 (organic hydroxy compound biosynthetic process), GO:0044271 (cellular nitrogen compound biosynthetic process), GO:0042181 (ketone biosynthetic process), GO:0072524 (pyridine-containing compound metabolic process), GO:0030639 (polyketide biosynthetic process), GO:0018958 (phenol-containing compound metabolic process), GO:0043386 (mycotoxin biosynthetic process), GO:0072525 (pyridine-containing compound biosynthetic process), GO:0046189 (phenol-containing compound biosynthetic process)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005737 (cytoplasm), GO:0043229 (intracellular organelle), GO:0043227 (membrane-bounded organelle), GO:0009536 (plastid), GO:0009507 (chloroplast), GO:0043231 (intracellular membrane-bounded organelle)