W6QRN8 · MPADE_PENRF
- ProteinCytochrome P450 monooxygenase mpaDE
- GenempaDE
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids852 (go to sequence)
- Protein existenceInferred from homology
- Annotation score4/5
Function
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 (PubMed:26751579).
MpaDE is an endoplasmic reticulum-bound enzyme that catalyzes the conversion of 5-methylorsellinic acid (5MOA) into the phthalide compound 5,7-dihydroxy-4,6-dimethylphthalide (DHMP) (PubMed:26751579).
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 (PubMed:26751579).
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) (PubMed:26751579).
MpaDE is an endoplasmic reticulum-bound enzyme that catalyzes the conversion of 5-methylorsellinic acid (5MOA) into the phthalide compound 5,7-dihydroxy-4,6-dimethylphthalide (DHMP) (PubMed:26751579).
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 (PubMed:26751579).
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) (PubMed:26751579).
Catalytic activity
- 5-methylorsellinate + O2 + reduced [NADPH--hemoprotein reductase] = 4,6-dihydroxy-2-(hydroxymethyl)-3-methylbenzoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- 4,6-dihydroxy-2-(hydroxymethyl)-3-methylbenzoate + H+ = 5,7-dihydroxy-4-methylphthalide + H2OThis reaction proceeds in the forward direction.
Cofactor
Pathway
Secondary metabolite biosynthesis; terpenoid biosynthesis.
Features
Showing features for binding site.
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | endoplasmic reticulum membrane | |
Molecular Function | heme binding | |
Molecular Function | iron ion binding | |
Molecular Function | monooxygenase activity | |
Molecular Function | oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen | |
Biological Process | mycophenolic acid biosynthetic process | |
Biological Process | terpenoid biosynthetic process |
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameCytochrome P450 monooxygenase mpaDE
- EC number
- Alternative names
Gene names
Organism names
- Strain
- Taxonomic lineageEukaryota > Fungi > Dikarya > Ascomycota > Pezizomycotina > Eurotiomycetes > Eurotiomycetidae > Eurotiales > Aspergillaceae > Penicillium
Accessions
- Primary accessionW6QRN8
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Endoplasmic reticulum membrane ; Single-pass membrane protein
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-6 | Lumenal | ||||
Sequence: MDYLII | ||||||
Transmembrane | 7-29 | Helical | ||||
Sequence: IRITAVAVVLYLTRYVCCLYLHL | ||||||
Topological domain | 30-852 | Cytoplasmic | ||||
Sequence: QDVPGPLFAKFTNLQRVWWVKSGRAHEYHRRMHAVYGPAVRFGPNMVSISDPRTIPAIYPSRPGFPKSDFYRTQKPYTPNKGAMPAVFNSQDEDLHKRLRSPIAPLYSMTNVVKLESFVDQTLAVLLEQLDGRFLGSNDVPFDLGSWLQYFAFDSMGTLTFSRRYGFLEQGRDMNGILGEIWKFMKRVSVMGQIPWFDEFCNTNPFIALFRSPTGFGVLKVVDKFILQRLAPREKDEVSDEKDMLSQFLNIQASNPDVMPWAPRAWTFSNIMAGSDSTANVMRTIMYNLLVHRDTLSRLQDELLESESSNGLSRTCPSWEKVRDLPYLDACVLEALRLHPPFCLPFERVVPGGGLTVCETYLPAGTIVGISPYMANRDKETFGNDADEWRPERWLGLSHEDRKRLENSLLTFGAGRRTCLGKNIAILEIKKLIPVLLLNYDIQIVNPENYKTENAWFFKQTGLQAVIRKRAKMERGSSNKDKPTLPPVLNIPPSSSTVDVRVIDPGTLLDLRPDLFWQPELPGLRKVTAPTYCFLISVGTRHVLFDLGVRQDWERLPPSVVAMIKSQTTIQNPRNISDILDSDASSLGIRSTDIEAIIWSHAHFDHIGDPSTFPLSTELVVGPGIRDSHWPGFPTNPDAINLNSDIQGRKVREISFERTEKEAIKIGSFDALDYFGDGSFYLLNAAGHSIGHIGALARVTTSPDSFVFMGGDSCHHAGVLRPSKYLPCPSHSRHIPLSSESESVFTLSPVLPSDYDAALKTVDNIKELDAYDNVFLILAHDSTLKGNMDFYPLTINDWKAKGYGKQTKWLFYKDLEDAMEGTK |
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
Results in dramatic reduction in MPA production and leads to the accumulation of 5-MOA.
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000449216 | 1-852 | Cytochrome P450 monooxygenase mpaDE | |||
Sequence: MDYLIIIRITAVAVVLYLTRYVCCLYLHLQDVPGPLFAKFTNLQRVWWVKSGRAHEYHRRMHAVYGPAVRFGPNMVSISDPRTIPAIYPSRPGFPKSDFYRTQKPYTPNKGAMPAVFNSQDEDLHKRLRSPIAPLYSMTNVVKLESFVDQTLAVLLEQLDGRFLGSNDVPFDLGSWLQYFAFDSMGTLTFSRRYGFLEQGRDMNGILGEIWKFMKRVSVMGQIPWFDEFCNTNPFIALFRSPTGFGVLKVVDKFILQRLAPREKDEVSDEKDMLSQFLNIQASNPDVMPWAPRAWTFSNIMAGSDSTANVMRTIMYNLLVHRDTLSRLQDELLESESSNGLSRTCPSWEKVRDLPYLDACVLEALRLHPPFCLPFERVVPGGGLTVCETYLPAGTIVGISPYMANRDKETFGNDADEWRPERWLGLSHEDRKRLENSLLTFGAGRRTCLGKNIAILEIKKLIPVLLLNYDIQIVNPENYKTENAWFFKQTGLQAVIRKRAKMERGSSNKDKPTLPPVLNIPPSSSTVDVRVIDPGTLLDLRPDLFWQPELPGLRKVTAPTYCFLISVGTRHVLFDLGVRQDWERLPPSVVAMIKSQTTIQNPRNISDILDSDASSLGIRSTDIEAIIWSHAHFDHIGDPSTFPLSTELVVGPGIRDSHWPGFPTNPDAINLNSDIQGRKVREISFERTEKEAIKIGSFDALDYFGDGSFYLLNAAGHSIGHIGALARVTTSPDSFVFMGGDSCHHAGVLRPSKYLPCPSHSRHIPLSSESESVFTLSPVLPSDYDAALKTVDNIKELDAYDNVFLILAHDSTLKGNMDFYPLTINDWKAKGYGKQTKWLFYKDLEDAMEGTK |
Interaction
Protein-protein interaction databases
Structure
Sequence
- Sequence statusComplete
- Length852
- Mass (Da)96,209
- Last updated2021-02-10 v2
- ChecksumC48E72CDD5344FA2
Sequence caution
Keywords
- Technical term