MPAH_PENBR
ID MPAH_PENBR Reviewed; 433 AA.
AC F1DBB4;
DT 06-JUL-2016, integrated into UniProtKB/Swiss-Prot.
DT 03-MAY-2011, sequence version 1.
DT 03-AUG-2022, entry version 27.
DE RecName: Full=Type I acyl-CoA thioesterase mpaH {ECO:0000303|PubMed:21398490};
DE EC=3.1.1.- {ECO:0000305|PubMed:21398490};
DE AltName: Full=Mycophenolic acid biosynthesis cluster protein H {ECO:0000303|PubMed:21398490};
GN Name=mpaH {ECO:0000303|PubMed:21398490};
OS Penicillium brevicompactum.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=5074;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], CATALYTIC ACTIVITY, FUNCTION, AND
RP PATHWAY.
RC STRAIN=IBT 23078;
RX PubMed=21398490; DOI=10.1128/aem.03015-10;
RA Regueira T.B., Kildegaard K.R., Hansen B.G., Mortensen U.H., Hertweck C.,
RA Nielsen J.;
RT "Molecular basis for mycophenolic acid biosynthesis in Penicillium
RT brevicompactum.";
RL Appl. Environ. Microbiol. 77:3035-3043(2011).
RN [2]
RP FUNCTION.
RC STRAIN=IBT23078;
RX PubMed=22544261; DOI=10.1128/aem.07955-11;
RA Hansen B.G., Mnich E., Nielsen K.F., Nielsen J.B., Nielsen M.T.,
RA Mortensen U.H., Larsen T.O., Patil K.R.;
RT "Involvement of a natural fusion of a cytochrome p450 and a hydrolase in
RT mycophenolic acid biosynthesis.";
RL Appl. Environ. Microbiol. 78:4908-4913(2012).
CC -!- FUNCTION: Type I acyl-CoA thioesterase; part of the gene cluster that
CC mediates the biosynthesis of mycophenolic acid (MPA), the first
CC isolated antibiotic natural product in the world obtained from a
CC culture of Penicillium brevicompactum in 1893 (PubMed:21398490). MpaH
CC acts as a peroxisomal acyl-CoA hydrolase that converts MPA-CoA into the
CC final product MPA (PubMed:21398490). The first step of the pathway is
CC the synthesis of 5-methylorsellinic acid (5MOA) by the cytosolic
CC polyketide synthase mpaC. 5MOA is then converted to the phthalide
CC compound 5,7-dihydroxy-4,6-dimethylphthalide (DHMP) by the endoplasmic
CC reticulum-bound cytochrome P450 monooxygenase mpaDE. MpaDE first
CC catalyzes hydroxylation of 5-MOA to 4,6-dihydroxy-2-(hydroxymethyl)-3-
CC methylbenzoic acid (DHMB). MpaDE then acts as a lactone synthase that
CC catalyzes the ring closure to convert DHMB into DHMP. The next step is
CC the prenylation of DHMP by the Golgi apparatus-associated
CC prenyltransferase mpaA to yield farnesyl-DHMP (FDHMP). The ER-bound
CC oxygenase mpaB then mediates the oxidative cleavage the C19-C20 double
CC bond in FDHMP to yield FDHMP-3C via a mycophenolic aldehyde
CC intermediate. The O-methyltransferase mpaG catalyzes the methylation of
CC FDHMP-3C to yield MFDHMP-3C. After the cytosolic methylation of FDHMP-
CC 3C, MFDHMP-3C enters into peroxisomes probably via free diffusion due
CC to its low molecular weight. Upon a peroxisomal CoA ligation reaction,
CC catalyzed by a beta-oxidation component enzyme acyl-CoA ligase ACL891,
CC MFDHMP-3C-CoA would then be restricted to peroxisomes for the following
CC beta-oxidation pathway steps. The peroxisomal beta-oxidation machinery
CC than converts MFDHMP-3C-CoA into MPA_CoA, via a beta-oxidation chain-
CC shortening process. Finally mpaH acts as a peroxisomal acyl-CoA
CC hydrolase with high substrate specificity toward MPA-CoA to release the
CC final product MPA (PubMed:21398490, PubMed:22544261) (Probable).
CC {ECO:0000269|PubMed:21398490, ECO:0000305|PubMed:21398490,
CC ECO:0000305|PubMed:22544261}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + mycophenolyl-CoA = CoA + H(+) + mycophenolate;
CC Xref=Rhea:RHEA:66704, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:62932, ChEBI:CHEBI:167447;
CC Evidence={ECO:0000305|PubMed:21398490};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66705;
CC Evidence={ECO:0000305|PubMed:21398490};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:21398490}.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:A0A0B5LB55}.
CC -!- SUBCELLULAR LOCATION: Peroxisome matrix
CC {ECO:0000250|UniProtKB:A0A0B5LB55}. Note=The mpaH' location in
CC peroxisomes is required for the unique cooperation between biosynthetic
CC and beta-oxidation catabolism machineries to produce final MPA.
CC {ECO:0000250|UniProtKB:A0A0B5LB55}.
CC -!- SIMILARITY: Belongs to the AB hydrolase superfamily. MpaH hydrolase
CC 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; HQ731031; ADY00135.1; -; Genomic_DNA.
DR AlphaFoldDB; F1DBB4; -.
DR SMR; F1DBB4; -.
DR ESTHER; penbr-mpaH; MpaH.
DR PRIDE; F1DBB4; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0005782; C:peroxisomal matrix; ISS:GO_Central.
DR GO; GO:0016787; F:hydrolase activity; ISS:GO_Central.
DR GO; GO:0140722; P:mycophenolic acid biosynthetic process; ISS:GO_Central.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR000073; AB_hydrolase_1.
DR Pfam; PF12697; Abhydrolase_6; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
PE 1: Evidence at protein level;
KW Hydrolase; Peroxisome.
FT CHAIN 1..433
FT /note="Type I acyl-CoA thioesterase mpaH"
FT /id="PRO_0000436576"
FT REGION 58..246
FT /note="Abhydrolase domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 139
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:A0A0B5LB55"
FT ACT_SITE 163
FT /evidence="ECO:0000250|UniProtKB:A0A0B5LB55"
FT ACT_SITE 365
FT /evidence="ECO:0000250|UniProtKB:A0A0B5LB55"
FT BINDING 60
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A0A0B5LB55"
FT BINDING 140
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A0A0B5LB55"
SQ SEQUENCE 433 AA; 49121 MW; 340800BF16531D08 CRC64;
MSTEKFTITE HLVPGSHIRE YPGSTVNQQD VLKIHVKNYT PKREGPVPDD AITFIATHGV
GLPKELYEPL WDELLDQASG FHIRAIWMAD VASMNQSGIH NEDKLSMDCS WMDHARDLLL
MINHFRDQMP RPLVGIGHSF GGNIITNLAY LHPRLFTTLL LLDPLIQLSP PSLGFGTDAP
SAINYTLWRD DVWPSREEAI RANRAIMQGM DPRCLDRMTK HFFRDLPTPL YPDVEAIKAR
FGTTADSTTT PVTLTTPKYH ELVAQIRQNF NARDPKTGRI EVPRDTHADM DPLVAYIPLY
RPEPRSTFRR LETLRPSCLW VIAGATFLNI DEIREGVKIC GSGIGGSGGV PDGRVREVVL
PGFGHLMPFQ EVKTVAGTCV VWLQQEMDRF RQTERQWKED RDGKSHQAVE ENWYKVLKPI
PTGRKKRSDK GKL
