ID MPADE_PENRF Reviewed; 932 AA. AC W6QRN8; DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot. DT 16-APR-2014, sequence version 1. DT 26-FEB-2020, entry version 28. DE RecName: Full=Cytochrome P450 monooxygenase mpaDE {ECO:0000303|PubMed:26751579}; DE EC=1.-.-.- {ECO:0000305|PubMed:26751579}; DE AltName: Full=Mycophenolic acid biosynthesis cluster fusion protein DE {ECO:0000303|PubMed:26751579}; GN Name=mpaDE {ECO:0000303|PubMed:26751579}; ORFNames=PROQFM164_S05g000557; OS Penicillium roqueforti (strain FM164). OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes; OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium. OX NCBI_TaxID=1365484; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=FM164; RX PubMed=24407037; DOI=10.1038/ncomms3876; RA Cheeseman K., Ropars J., Renault P., Dupont J., Gouzy J., Branca A., RA Abraham A.L., Ceppi M., Conseiller E., Debuchy R., Malagnac F., Goarin A., RA Silar P., Lacoste S., Sallet E., Bensimon A., Giraud T., Brygoo Y.; RT "Multiple recent horizontal transfers of a large genomic region in cheese RT making fungi."; RL Nat. Commun. 5:2876-2876(2014). RN [2] RP FUNCTION, DISRUPTION PHENOTYPE, AND PATHWAY. RX PubMed=26751579; DOI=10.1371/journal.pone.0147047; RA Del-Cid A., Gil-Duran C., Vaca I., Rojas-Aedo J.F., Garcia-Rico R.O., RA Levican G., Chavez R.; RT "Identification and Functional Analysis of the Mycophenolic Acid Gene RT Cluster of Penicillium roqueforti."; RL PLoS ONE 11:E0147047-E0147047(2016). CC -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that CC mediates the biosynthesis of mycophenolic acid (MPA), the first CC isolated antibiotic natural product in the world (PubMed:26751579). The CC first step of the pathway is the synthesis of 5-methylorsellinic acid CC (5MOA) by the polyketide synthase mpaC (PubMed:26751579). 5MOA is then CC converted to the phthalide compound 5,7-dihydroxy-4,6-dimethylphthalide CC (DHDMP) by mpaDE (PubMed:26751579). MpaDE first catalyzes hydroxylation CC of 5-MOA to 4,6-dihydroxy-2-(hydroxymethyl)-3-methylbenzoic acid (DHMB) CC (PubMed:26751579). MpaDE then acts as a lactone synthase that catalyzes CC the ring closure to convert DHMB is then converted to DHMP CC (PubMed:26751579). The next step is the prenylation of DHMP by the CC prenyltransferase mpaA to yield farnesyl-DHDMP (PubMed:26751579). CC Farnesyl-DHDMP might be a substrate of mpaH for transformation into CC demethylmycophenolic acid (DMMPA) (PubMed:26751579). Finally, the O- CC methyltransferase mpaG catalyzes the methylation DMMPA to form MPA CC (PubMed:26751579). {ECO:0000269|PubMed:26751579}. CC -!- COFACTOR: CC Name=heme; Xref=ChEBI:CHEBI:30413; CC Evidence={ECO:0000250|UniProtKB:P04798}; CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis. CC {ECO:0000269|PubMed:26751579}. CC -!- DISRUPTION PHENOTYPE: Results in dramatic reduction in MPA production CC and leads to the accumulation of 5-MOA. {ECO:0000269|PubMed:26751579}. CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; HG792019; CDM36724.1; -; Genomic_DNA. DR EnsemblFungi; CDM36724; CDM36724; PROQFM164_S05g000557. DR OrthoDB; 467733at2759; -. DR UniPathway; UPA00213; -. DR Proteomes; UP000030686; Unassembled WGS sequence. DR GO; GO:0020037; F:heme binding; IEA:InterPro. DR GO; GO:0005506; F:iron ion binding; IEA:InterPro. DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW. DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro. DR Gene3D; 1.10.630.10; -; 1. DR Gene3D; 3.60.15.10; -; 1. DR InterPro; IPR001128; Cyt_P450. DR InterPro; IPR017972; Cyt_P450_CS. DR InterPro; IPR002403; Cyt_P450_E_grp-IV. DR InterPro; IPR036396; Cyt_P450_sf. DR InterPro; IPR001279; Metallo-B-lactamas. DR InterPro; IPR036866; RibonucZ/Hydroxyglut_hydro. DR Pfam; PF00753; Lactamase_B; 1. DR Pfam; PF00067; p450; 1. DR PRINTS; PR00465; EP450IV. DR PRINTS; PR00385; P450. DR SMART; SM00849; Lactamase_B; 1. DR SUPFAM; SSF48264; SSF48264; 1. DR SUPFAM; SSF56281; SSF56281; 1. DR PROSITE; PS00086; CYTOCHROME_P450; 1. PE 3: Inferred from homology; KW Heme; Iron; Metal-binding; Monooxygenase; Oxidoreductase; KW Reference proteome. FT CHAIN 1..932 FT /note="Cytochrome P450 monooxygenase mpaDE" FT /id="PRO_0000449216" FT METAL 528 FT /note="Iron (heme axial ligand)" FT /evidence="ECO:0000250|UniProtKB:P04798" SQ SEQUENCE 932 AA; 105594 MW; B891279647754F58 CRC64; MRVEAGGDMR DKLMWIRLYI LGNVGQTFGD MKRYIGMWSG MLFPISTKHT RRLISILKVY FIFILNPPAQ VYVQDINLYT MDYLIIIRIT AVAVVLYLTR YVCCLYLHLQ DVPGPLFAKF TNLQRVWWVK SGRAHEYHRR MHAVYGPAVR FGPNMVSISD PRTIPAIYPS RPGFPKSDFY RTQKPYTPNK GAMPAVFNSQ DEDLHKRLRS PIAPLYSMTN VVKLESFVDQ TLAVLLEQLD GRFLGSNDVP FDLGSWLQYF AFDSMGTLTF SRRYGFLEQG RDMNGILGEI WKFMKRVSVM GQIPWFDEFC NTNPFIALFR SPTGFGVLKV VDKFILQRLA PREKDEVSDE KDMLSQFLNI QASNPDVMPW APRAWTFSNI MAGSDSTANV MRTIMYNLLV HRDTLSRLQD ELLESESSNG LSRTCPSWEK VRDLPYLDAC VLEALRLHPP FCLPFERVVP GGGLTVCETY LPAGTIVGIS PYMANRDKET FGNDADEWRP ERWLGLSHED RKRLENSLLT FGAGRRTCLG KNIAILEIKK LIPVLLLNYD IQIVNPENYK TENAWFFKQT GLQAVIRKRA KMERGSSNKD KPTLPPVLNI PPSSSTVDVR VIDPGTLLDL RPDLFWQPEL PGLRKVTAPT YCFLISVGTR HVLFDLGVRQ DWERLPPSVV AMIKSQTTIQ NPRNISDILD SDASSLGIRS TDIEAIIWSH AHFDHIGDPS TFPLSTELVV GPGIRDSHWP GFPTNPDAIN LNSDIQGRKV REISFERTEK EAIKIGSFDA LDYFGDGSFY LLNAAGHSIG HIGALARVTT SPDSFVFMGG DSCHHAGVLR PSKYLPCPSH SRHIPLSSES ESVFTLSPVL PSDYDAALKT VDNIKELDAY DNVFLILAHD STLKGNMDFY PLTINDWKAK GYGKQTKWLF YKDLEDAMEG TK //