Protein: Non-reducing polyketide synthase mapC (EC 2.3.1.-) (Mycophenolic acid biosynthesis cluster protein C) (W6QL47)
Organism: Penicillium roqueforti (strain FM164)
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 (By similarity). 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:0000250|UniProtKB:A0A0B5KU17}.
Sequence: MSLNTEHSKGDLRLLFGPQCSEIEDSIAHIRDAVYKDSAGLGFLSDILDELPSLWPVITSAWPALRKVQGEKQLAALGRRFENGSPDSEAEPSSLIMTPVTVMKHLVDFWNLQNVATHPAFPSSPLSRTTAPRIIDSQGFCVGILAAIAVACSQDTREFQSLASNAIRLAVCIGALVDFDEIVSGKAKSIAVRWETPADHDYLEQTLTKSPNVYISCYTDVNSVTITIPGDTAQRVKFKQELSGRGLHTKPIPLQGRFHHQQTHREGIQHIMNLCVKDPRFQLPHSNALILPLRSSHNGQVLINAAMLHTVALESILSVKADWWGTVSALLNSADMEVDESRLLSIGQEEFVPRSARGRLVARSNLDVYGAGVFANGNTSARSAVSLQNGTNTLNGSPQAAEMPPIAITGMACRYSNADTTSELWDLLELGVCTVEKAPGNRFRMPDLQREPKGPFWGHFLDRPDAFDHRFFNISAREAESMDPQQRVLLQVAYEAMESAGYCGWQHTELSDEIGCYVGVGSEDYTENVASRNANAFSATGTLQSFIAGRISHHFGWSGPSITLDTACSSAAVAIHMACKALQTKECSIAVAGGVNILTNPRVYQNLAAASFLSSTGACKSFDVSADGYCRGEGAGLVVLRPLQDAIDNGDPILGVIAGSVVNQGSNRSPITVPDAESQRSLYRKALSLAGVAPDEVTYVEAHGTGTQVGDPIELESLRKAFGNPLRSQSLHVGSIKGNIGHTETSSGVAGLLKTILMLQKQRIPKQANFRQLNPKVMPPLENDRLVIPVESTKWASARRVAMVSNYGASGSNAALIVRDHTPSLSGQGKAMAEYIRDMPILISARSEESIRAYCGALRTTLLRHPYSNTVVRELAYNVAMKQNRTLPFTLTFSTSSDPTSLSTRLEAIAAGKSADIIQKRESNEPPIVLCFGGQNGVTSSISQELYDSCVLLQTHLMACEQAGQKLGLPSLFPTIFTSDPIVNTVYLHFMLFSIQYASARAWIDSGLRVDRIVGHSFGQLTALSVAGSLSVQEGIRLVTERARLIQSNWGPESGVMLAVEGTQAEVQRVLEQTGHRAEIACYNGPQQQVLAGTGECIRAVEDALATNPLTSNVRVRRLENSHAFHSRLVDSIVPGLTELAESFVYQAPAIPIEACSATGDWSIVTPAKIVEHSRMPVHFQRAVERIAQKLQVPAVWLEAGSASPIIPMVRRVLEKSSATHTYHRVNLDGSDGSGNLATVTSALWGQGVHVQFWPFHHSQRGTFGWMNLPPYQFAKNRHWVDFDPTAFSFSGSSAEPQCGSQERAGLLRKLSDGPEEYLFAVNTQDVLYRSCTKGHAVLDQTLCPASMYMEMVLRAATSVFTLGESSTLTMSHIEDLVISSPLVLDPQGSVFVRLIPEAVASSQTWSFSIFSSSGTGNESSIHATGSVSLCNERSRALSHFQSMNRLMDPARARGIEDHLASNGLKGSTVYSALEQVTNYADYFRGVRQVFANGREAAGLVSMAPSATETTCNPILLDNFLQVAGIHVNCLSGREAEEVFVCNAIGETYVSDSLFKKEDGAIPLSWKVYTNYVRPSKNEIVCDIYVMNSQGDGLTAAIMGVRFMSVSIRSLTRALAKLNNNFPDVPQLPPTIQPAIVTADYDEASDNVNVDSDLVAVQEMLCELFGVSVEEVSPSVSLIDIGVDSLISTEVLSEIKRRFHKDISYSTLVDIPNIQGLTEHIFPGHSHLAPSQIVIKPVRQQTVIPQTVTSLPVPANAGPSLVSVAHQCFYETHAAVSHTHNADWAGFFNAIYPQQMTLITAYILEAFRALGSPLESSQADEVLPIISVLPRHEQLKKHLYTILESVNLVRQTPTGQLVRTATPISPLSSHALHAQIRDEHPPYALEHDLLQITGSRLAECLTGQADGVSLIFQDSQTRRLVGDVYTDSPVFKSGNLYLAQYLTDVIQTLGNGRQVKILEIGAGTGGTTKNLLEQLSALPGMATRMEYTFTDISPSLVAAARKKFSKYDFVRYETINVESSPPSLLHGQYDIVLSTNCVHATRNLVESCSNIRKLLRPDGILCLVELTRDIFWLDLVFGLLEGWWRFEDGRKHALATEDLWDQTLRQSGFEWVGWTNNEAVESNALRVIVASPTKAPSALEICSKPANMETVVWGERNGLQLLADIFYPDVVDTTQKRRACALMVHGGGHVMLSRKDIRPAQTQTLLDAGFLPISVDYRLCPEVSLSEGPMADVRDALGWVRRILPNIPLLRPDIRPDGNQVVAIGWSTGGHLAMTLAFTAPAVGIAAPEAILAFYCPTDYEDPFWSRPNFPFGQTVASNDIEYDVWEGVQSAPIKGYNPAFKERPLGGWMSTSDPRSRIALHMNWTGQTLPVLLGGMHKEFRIPDELPRPTDEEIQAVSPNYQIRIGRYRTPTFMVHGTSDDLVPCAQTESTYNALTQNGIEADIRVVQGAIEVLLYLQHPERARKWICSGSLTLEI
InterPro domains: - IPR016035: Acyl transferase/acyl hydrolase/lysophospholipase (homologous_superfamily) [928-1220]
- IPR014031: Beta-ketoacyl synthase, C-terminal (domain) [654-770]
- IPR014043: Acyl transferase domain (domain) [931-1245]
- IPR020807: Polyketide/metazoan fatty acid synthase-like, dehydratase domain (domain) [1305-1487]
- IPR016039: Thiolase-like (homologous_superfamily) [396-843]
- IPR020841: Polyketide synthase, beta-ketoacyl synthase domain (domain) [403-823]
- IPR016036: Malonyl-CoA ACP transacylase, ACP-binding (homologous_superfamily) [1054-1109]
- IPR001227: Acyl transferase domain superfamily (homologous_superfamily) [4-1234]
- IPR020806: Polyketide synthase-like, phosphopantetheine-binding domain (domain) [1654-1725]
- IPR041068: Methyltransferase, fungal type, helix-turn-helix domain (domain) [1779-1852]
- IPR014030: Beta-ketoacyl synthase-like, N-terminal (domain) [404-646]
- IPR036736: ACP-like superfamily (homologous_superfamily) [1636-1727]
- IPR032088: Starter unit:ACP transacylase, SAT domain (domain) [91-259]
- IPR009081: Phosphopantetheine binding ACP domain (domain) [1651-1725]
- IPR006162: Phosphopantetheine attachment site (ptm) [1680-1695]
- IPR018201: Beta-ketoacyl synthase, active site (active_site) [559-575]
- IPR013217: Methyltransferase type 12 (domain) [1958-2061]
- IPR029058: Alpha/Beta hydrolase fold (homologous_superfamily) [2067-2468]
- IPR029063: S-adenosyl-L-methionine-dependent methyltransferase superfamily (homologous_superfamily) [1889-2125]
- IPR042104: Polyketide synthase, dehydratase domain superfamily (homologous_superfamily) [1311-1611]
Interaction partners: - [acyl-carrier-protein] S-malonyltransferase
- Thioesterase domain-containing protein
- AMP-dependent synthetase/ligase
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0003824 (catalytic activity), GO:0016874 (ligase activity), GO:0016746 (acyltransferase activity), GO:0016747 (acyltransferase activity, transferring groups other than amino-acyl groups)
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)