Protein: Cytochrome P450 monooxygenase mpaDE (EC 1.-.-.-) (Mycophenolic acid biosynthesis cluster fusion protein DE) (W6QRN8)
Organism: Penicillium roqueforti (strain FM164)
Function: Cytochrome P450 monooxygenase; 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. MpaDE is an endoplasmic reticulum-bound entyme that catalyzes the conversion of 5-methylorsellinic acid (5MOA) into the phthalide compound 5,7-dihydroxy-4,6-dimethylphthalide (DHMP). MpaDE first catalyzes hydroxylation of 5-MOA to 4,6-dihydroxy-2-(hydroxymethyl)-3-methylbenzoic acid (DHMB), and then acts as a lactone synthase that catalyzes the ring closure to convert DHMB into DHMP. 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: Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:A0A0B5KYT4}; Single-pass membrane protein {ECO:0000255}.
Interaction partners:
- Nitrate reductase
Sequence:
MDYLIIIRITAVAVVLYLTRYVCCLYLHLQDVPGPLFAKFTNLQRVWWVKSGRAHEYHRRMHAVYGPAVRFGPNMVSISDPRTIPAIYPSRPGFPKSDFYRTQKPYTPNKGAMPAVFNSQDEDLHKRLRSPIAPLYSMTNVVKLESFVDQTLAVLLEQLDGRFLGSNDVPFDLGSWLQYFAFDSMGTLTFSRRYGFLEQGRDMNGILGEIWKFMKRVSVMGQIPWFDEFCNTNPFIALFRSPTGFGVLKVVDKFILQRLAPREKDEVSDEKDMLSQFLNIQASNPDVMPWAPRAWTFSNIMAGSDSTANVMRTIMYNLLVHRDTLSRLQDELLESESSNGLSRTCPSWEKVRDLPYLDACVLEALRLHPPFCLPFERVVPGGGLTVCETYLPAGTIVGISPYMANRDKETFGNDADEWRPERWLGLSHEDRKRLENSLLTFGAGRRTCLGKNIAILEIKKLIPVLLLNYDIQIVNPENYKTENAWFFKQTGLQAVIRKRAKMERGSSNKDKPTLPPVLNIPPSSSTVDVRVIDPGTLLDLRPDLFWQPELPGLRKVTAPTYCFLISVGTRHVLFDLGVRQDWERLPPSVVAMIKSQTTIQNPRNISDILDSDASSLGIRSTDIEAIIWSHAHFDHIGDPSTFPLSTELVVGPGIRDSHWPGFPTNPDAINLNSDIQGRKVREISFERTEKEAIKIGSFDALDYFGDGSFYLLNAAGHSIGHIGALARVTTSPDSFVFMGGDSCHHAGVLRPSKYLPCPSHSRHIPLSSESESVFTLSPVLPSDYDAALKTVDNIKELDAYDNVFLILAHDSTLKGNMDFYPLTINDWKAKGYGKQTKWLFYKDLEDAMEGTK