Protein: Non-reducing polyketide synthase mapC' (EC 2.3.1.-) (Mycophenolic acid biosynthesis cluster protein C') (A0A0B5KU17)
Organism: Penicillium brevicompactum
Function: Non-reducing polyketide synthase; part of the gene cluster that mediates the biosynthesis of mycophenolic acid (MPA), the first isolated antibiotic natural product in the world obtained from a culture of Penicillium brevicompactum in 1893. MpaC' catalyzes the synthesis of 5-methylorsellinic acid (5MOA) via the condensation of 1 acetyl-CoA starter unit with 3 malonyl-CoA units and one methylation step. The first step of the pathway is the synthesis of 5-methylorsellinic acid (5MOA) by the cytosolic polyketide synthase mpaC. 5MOA is then converted to the phthalide compound 5,7-dihydroxy-4,6-dimethylphthalide (DHMP) by the endoplasmic reticulum-bound cytochrome P450 monooxygenase mpaDE. MpaDE first catalyzes hydroxylation of 5-MOA to 4,6-dihydroxy-2-(hydroxymethyl)-3-methylbenzoic acid (DHMB). MpaDE then acts as a lactone synthase that catalyzes the ring closure to convert DHMB into DHMP. The next step is the prenylation of DHMP by the Golgi apparatus-associated prenyltransferase mpaA to yield farnesyl-DHMP (FDHMP). The ER-bound oxygenase mpaB then mediates the oxidative cleavage the C19-C20 double bond in FDHMP to yield FDHMP-3C via a mycophenolic aldehyde intermediate. The O-methyltransferase mpaG catalyzes the methylation of FDHMP-3C to yield MFDHMP-3C. After the cytosolic methylation of FDHMP-3C, MFDHMP-3C enters into peroxisomes probably via free diffusion due to its low molecular weight. Upon a peroxisomal CoA ligation reaction, catalyzed by a beta-oxidation component enzyme acyl-CoA ligase ACL891, MFDHMP-3C-CoA would then be restricted to peroxisomes for the following beta-oxidation pathway steps. The peroxisomal beta-oxidation machinery than converts MFDHMP-3C-CoA into MPA_CoA, via a beta-oxidation chain-shortening process. Finally mpaH acts as a peroxisomal acyl-CoA hydrolase with high substrate specificity toward MPA-CoA to release the final product MPA (Probable).
Subcellular location: Cytoplasm, cytosol {ECO:0000269|PubMed:31209052}.
Sequence: MNFHKGQPKEDLRVLFGPQCPDITDSITHIRDAISKDPTGLGFLTNILDELPSLWPTIAGAWPALKNVEGENQLLALGRLFEHESEVRVEASNLMMTPITVMRHVVDFWNLQDVATHPAFPSSSLSETEMPRIVDTQGFCVGLLAAIAVACSRNTQEFQYVASNAIRLSLCIGALVDLDEILCGSTTSLAVRWESVEDFNHLEKILNNNTEIPKGYTSCYTDVKSVTITIPNDSAERVKQEIHDHGLRTKQLSLRGRFHHEAHREGIQHIMKLCMNDSRFKLPRSDALLTPLRSSQGGEIFQQEALLHTVALDSILCAKANWYDVVSALINSTEMTVDQSRLLSIGPEEFVPRSARSRSVARRELESYGMQGFANESPQPSTASLSNSVQTFDSRPQAAEASPIAITGMACRYPNADTLAQLWELLELGRCTVKSPPESRFHMSDLQREPKGPFWGHFLERPDVFDHRFFNISAREAESMDPQQRVALQVAYEAMESAGYLGWQPNRLSQDIGCYVGVGSEDYTENVASRNANAFSITGTLQSFIAGRISHHFGWSGPSISLDTACSSAAVAIHLACKALQTNDCKIALAGGVNVLTNPRVYQNLSAASFLSPSGACKPFDASADGYCRGEGAGLFVLRPLQDAIDNGDPILGVIAGSAVNQGSNNSPITVPDAEAQRSLYNKAMSLAGVSPDEVTYVEAHGTGTQVGDPIELDSLRRTFGGPHRRNNLHIGSIKGNIGHTETSSGAAGLLKTILMLQQQRIPRQANFNQLNPKVKSLTPDRLVIASESTEWVSTKRVAMVSNYGASGSNAALIVKEHAPIGSEQNGTAPEYIQNKLAYNLAMKQNRDLPLNLTFSTSSDTTSLGARLEAISTGASADLIQKRPSNEPPVVLCFGGQNGLTATISKEVFDASALLRTHLEDCEEVGRTLGLLSLFPTIFSSAPITNIIHLHFILFSIQYASAKAWLDSGLRVSRIVGHSFGQLTALSVAGSLSVRDGIHLVTERARLIESSWGPESGIMLAVEGTEIEVQQLLDQTVESIEAIENAAARTPSASNLRLTRLQNSHAFHSRLVDSIVPGIMEVAGSLVYQTPIIPIEACSASGDWSTITAAEIVEHSRMPVYFRRAVERVAEKLQAPAVWLEAGSASPIIPMVRRVLESSSVANTYHKIDLGGSSGAQNLANVTSALWAQGVHVQFWPFDRAQHASFKWMNLPPYQFAQNSHWVDFDPAAFSSAGPSSGKQSAGQEAGLLCQLSESPDERLYHVNIQDALYRACTQGHAVLNQTLCPASMYMEMVLRAAASIFPTGNASEPAMSHIEDLTISSPLVLDPQGKVFLRLTRDGAGPTRPWLFSIFSSESNDHTLVHAEGTVCLHQERSRALARFQSMDRLLDSARSKTIEADPASNGLKGSTVYAALESVTNYGDYFRGVKQVFANGREASGLVSMMPSTTETNCNPILLDNFLQVAGIHVNCLSDRQSSEVFVCNAIGETFVINSLLKQENGASPSTWKVYTSYVRPSKTEIACDIYVMDCQTDTLSAAMMGVRFTSVSIRSLTRALAKLNNNVLETAEAQSVVEAAIPAEQSVVTATPSAPAADGHAANDLATVQEMLCELFGVSVAEVSPSVSLVDIGVDSLMSTEVLSEIKKRFQVDMSYTTLVDIPNIQGLVEHIFPGHSHAAPSRPVVEKAPVQSVAPQAVSHVPTPASNGPPLVSVARQCFDTTHAAVSHTSDAHWAGFFHTTYPKQMSLLTAYILEAFRALGSSLEASEPNEVLTPIAVLPRHEQLRKHLYKILDSVGLVRQMSTGELTLRQSGFEWVDWTNNETVESNALRVIVASPTGNSSAATMSPSKPIKMETVVWGERDNLQLRADIYYPETVDTTRKQRPIALMIHGGGHVMLSRKDIRPAQTQTLLDAGFLPVSIDYRLCPEVSLAEGPMADARDALSWVRRVLPNIPLLRADIRPDGNQVVAIGWSTGGHLAMTLPFTAPAAGIPAPDAVLAFYCPTNYEDPFWSNPNFPFGQTVASNEMEYDVWEGLQSMPIAGYNPALKERPLGGWMSTRDPRSRIALHMNWTGQTLPVLLKACTIKGNTEKCSPDDLSRPTEEDIQAVSPNYQIRVGRYNTPTFLIHGTSDDLVPCAQTESTHGALTASGVEAELRVVQEAAHLFDLYPASHAGQEAKAAVAEGYEFLRTHVQL
InterPro domains: - IPR016035: Acyl transferase/acyl hydrolase/lysophospholipase (homologous_superfamily) [890-1162]
- IPR014031: Beta-ketoacyl synthase, C-terminal (domain) [652-768]
- IPR014043: Acyl transferase domain (domain) [893-1190]
- IPR020807: Polyketide/metazoan fatty acid synthase-like, dehydratase domain (domain) [1246-1427]
- IPR016039: Thiolase-like (homologous_superfamily) [398-823]
- IPR001375: Peptidase S9, prolyl oligopeptidase, catalytic domain (domain) [2098-2187]
- IPR020841: Polyketide synthase, beta-ketoacyl synthase domain (domain) [401-820]
- IPR049492: BD-FAE-like domain (domain) [1866-1978]
- IPR001227: Acyl transferase domain superfamily (homologous_superfamily) [4-1176]
- IPR020806: Polyketide synthase-like, phosphopantetheine-binding domain (domain) [1600-1671]
- IPR041068: Methyltransferase, fungal type, helix-turn-helix domain (domain) [1723-1797]
- IPR014030: Beta-ketoacyl synthase-like, N-terminal (domain) [402-644]
- IPR036736: ACP-like superfamily (homologous_superfamily) [1581-1677]
- IPR032088: Starter unit:ACP transacylase, SAT domain (domain) [136-259]
- IPR009081: Phosphopantetheine binding ACP domain (domain) [1597-1671]
- IPR006162: Phosphopantetheine attachment site (ptm) [1626-1641]
- IPR049551: Polyketide synthase, dehydratase domain, C-terminal (domain) [1393-1549]
- IPR018201: Beta-ketoacyl synthase, active site (active_site) [557-573]
- IPR029058: Alpha/Beta hydrolase fold (homologous_superfamily) [1840-2187]
- IPR042104: Polyketide synthase, dehydratase domain superfamily (homologous_superfamily) [1249-1551]
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0003824 (catalytic activity), GO:0016491 (oxidoreductase 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:0016999 (antibiotic metabolic process), GO:0044281 (small molecule metabolic process), GO:0019748 (secondary metabolic process), GO:0071704 (organic substance metabolic process), GO:0044550 (secondary metabolite biosynthetic process), GO:0017000 (antibiotic biosynthetic process), GO:1901615 (organic hydroxy compound metabolic process), GO:1901360 (organic cyclic compound metabolic process), GO:1901576 (organic substance biosynthetic process), GO:0044283 (small molecule biosynthetic process), GO:0046483 (heterocycle metabolic process), GO:0006082 (organic acid metabolic process), GO:0044249 (cellular biosynthetic process), GO:0009404 (toxin metabolic process), GO:0006725 (cellular aromatic compound metabolic process), GO:0030638 (polyketide metabolic process), GO:1901334 (lactone metabolic process), GO:1901362 (organic cyclic compound biosynthetic process), GO:0043385 (mycotoxin metabolic process), GO:0009403 (toxin biosynthetic process), GO:0016053 (organic acid biosynthetic process), GO:0043436 (oxoacid metabolic process), GO:0019438 (aromatic compound biosynthetic process), GO:0018130 (heterocycle biosynthetic process), GO:1901617 (organic hydroxy compound biosynthetic process), GO:0030639 (polyketide biosynthetic process), GO:0018958 (phenol-containing compound metabolic process), GO:0019752 (carboxylic acid metabolic process), GO:0043386 (mycotoxin biosynthetic process), GO:1901336 (lactone biosynthetic process), GO:0046394 (carboxylic acid biosynthetic process), GO:0046189 (phenol-containing compound biosynthetic process), GO:0072330 (monocarboxylic acid biosynthetic process), GO:0032787 (monocarboxylic acid metabolic 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)