W6QL41 · MPAH_PENRF
- ProteinType I acyl-CoA thioesterase mpaH
- GenempaH
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids433 (go to sequence)
- Protein existenceInferred from homology
- Annotation score4/5
Function
function
Type I acyl-CoA thioesterase; 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).
MpaH acts as a peroxisomal acyl-CoA hydrolase that converts MPA-CoA into the final product MPA (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) (PubMed:26751579).
MpaH acts as a peroxisomal acyl-CoA hydrolase that converts MPA-CoA into the final product MPA (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) (PubMed:26751579).
Catalytic activity
- H2O + mycophenolyl-CoA = CoA + H+ + mycophenolateThis reaction proceeds in the forward direction.
Pathway
Secondary metabolite biosynthesis; terpenoid biosynthesis.
Features
Showing features for binding site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 60 | substrate | ||||
Sequence: V | ||||||
Active site | 139 | Nucleophile | ||||
Sequence: S | ||||||
Binding site | 140 | substrate | ||||
Sequence: F | ||||||
Active site | 163 | |||||
Sequence: D | ||||||
Active site | 365 | |||||
Sequence: H |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | peroxisomal matrix | |
Molecular Function | hydrolase activity | |
Biological Process | mycophenolic acid biosynthetic process | |
Biological Process | terpenoid biosynthetic process |
Keywords
- Molecular function
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameType I acyl-CoA thioesterase mpaH
- EC number
- Alternative names
Gene names
Organism names
- Strain
- Taxonomic lineageEukaryota > Fungi > Dikarya > Ascomycota > Pezizomycotina > Eurotiomycetes > Eurotiomycetidae > Eurotiales > Aspergillaceae > Penicillium
Accessions
- Primary accessionW6QL41
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Note: The mpaH' location in peroxisomes is required for the unique cooperation between biosynthetic and beta-oxidation catabolism machineries to produce final MPA.
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
Results in dramatic reduction in MPA production.
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000449214 | 1-433 | Type I acyl-CoA thioesterase mpaH | |||
Sequence: MSSEKFTVTEHLVPGSYIREYPGSTVTQEDVLKIHVKQYTPKHEGPVPADAITFIAAHGVGLPKELYEPLWDELLERTNGFHIHGIWVADVASMNQSGIQNEDKLSMDCSWMDHPRDLFLMINHFREQMPRPLVGVGHSFGGNIITNLAYLHPRLFTTLLLIDPLIQLSPPSMGFGTDPPGPINYTLWRNDVWPSREAAIRANRGLIHGWDPRCVDRMAKYFFRDLPTPLYPDVEAVKARFDAAADTTATPVTLATPKYHELIAQIRQNFNARDPTTGRIEIPRATHADMDPLVASIPLYRPEPRSTFRRLGTLRPSCLWIVGGATFLNVDEIHEGVKICGSGIGGSGGVSEGRVKEVILPGLGHLMPFQEIGTVVGPCVAWLQQEMDRFRQMEREWGEERKGKSHLVLEKNWYKVLKPMPSGRGKGGRKEKL |
Interaction
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 58-246 | Abhydrolase domain | ||||
Sequence: HGVGLPKELYEPLWDELLERTNGFHIHGIWVADVASMNQSGIQNEDKLSMDCSWMDHPRDLFLMINHFREQMPRPLVGVGHSFGGNIITNLAYLHPRLFTTLLLIDPLIQLSPPSMGFGTDPPGPINYTLWRNDVWPSREAAIRANRGLIHGWDPRCVDRMAKYFFRDLPTPLYPDVEAVKARFDAAAD |
Sequence similarities
Belongs to the AB hydrolase superfamily. MpaH hydrolase family.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length433
- Mass (Da)48,633
- Last updated2014-04-16 v1
- ChecksumDC67088F2174D14E
Keywords
- Technical term