MPAG_PENRF
ID MPAG_PENRF Reviewed; 398 AA.
AC W6R4H4;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 34.
DE RecName: Full=O-methyltransferase mpaG {ECO:0000303|PubMed:26751579};
DE EC=2.1.1.- {ECO:0000305|PubMed:26751579};
DE AltName: Full=Mycophenolic acid biosynthesis cluster protein G {ECO:0000303|PubMed:26751579};
GN Name=mpaG {ECO:0000303|PubMed:26751579}; ORFNames=PROQFM164_S05g000555;
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, CATALYVITY, 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: O-methyltransferase; part of the gene cluster that mediates
CC the biosynthesis of mycophenolic acid (MPA), the first isolated
CC antibiotic natural product in the world obtained from a culture of
CC Penicillium brevicompactum in 1893 (PubMed:26751579). MpaC methylates
CC farnesyl-DHMP-3C (FDHMP-3C) to yield MFDHMP-3C (By similarity). The
CC first step of the pathway is the synthesis of 5-methylorsellinic acid
CC (5MOA) by the cytosolic polyketide synthase mpaC. 5MOA is then
CC converted to the phthalide compound 5,7-dihydroxy-4,6-dimethylphthalide
CC (DHMP) by the endoplasmic reticulum-bound cytochrome P450 monooxygenase
CC mpaDE. MpaDE first catalyzes hydroxylation of 5-MOA to 4,6-dihydroxy-2-
CC (hydroxymethyl)-3-methylbenzoic acid (DHMB). MpaDE then acts as a
CC lactone synthase that catalyzes the ring closure to convert DHMB into
CC DHMP. The next step is the prenylation of DHMP by the Golgi apparatus-
CC associated prenyltransferase mpaA to yield farnesyl-DHMP (FDHMP). The
CC ER-bound oxygenase mpaB then mediates the oxidative cleavage the C19-
CC C20 double 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:26751579) (Probable).
CC {ECO:0000250|UniProtKB:A0A0B5L781, ECO:0000269|PubMed:26751579,
CC ECO:0000305|PubMed:26751579}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(4E,8E)-10-(4,6-dihydroxy-7-methyl-3-oxo-1,3-dihydro-2-
CC benzofuran-5-yl)-4,8-dimethyldeca-4,8-dienoate + S-adenosyl-L-
CC methionine = (4E,8E)-10-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-
CC dihydro-2-benzofuran-5-yl)-4,8-dimethyldeca-4,8-dienoate + H(+) + S-
CC adenosyl-L-homocysteine; Xref=Rhea:RHEA:66696, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:167389,
CC ChEBI:CHEBI:167390; Evidence={ECO:0000250|UniProtKB:A0A0B5L781};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66697;
CC Evidence={ECO:0000250|UniProtKB:A0A0B5L781};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:26751579}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:A0A0B5L781}.
CC -!- DISRUPTION PHENOTYPE: Results in dramatic reduction in MPA production
CC and leads to the accumulation of DMMPA. {ECO:0000269|PubMed:26751579}.
CC -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase
CC superfamily. Cation-independent O-methyltransferase family. COMT
CC subfamily. {ECO:0000305}.
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DR EMBL; HG792019; CDM36722.1; -; Genomic_DNA.
DR AlphaFoldDB; W6R4H4; -.
DR SMR; W6R4H4; -.
DR EnsemblFungi; CDM36722; CDM36722; PROQFM164_S05g000555.
DR OrthoDB; 817726at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000030686; Unassembled WGS sequence.
DR GO; GO:0005829; C:cytosol; ISS:GO_Central.
DR GO; GO:0008168; F:methyltransferase activity; ISS:GO_Central.
DR GO; GO:0008171; F:O-methyltransferase activity; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
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; 1.10.10.10; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR016461; COMT-like.
DR InterPro; IPR001077; O_MeTrfase_dom.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR InterPro; IPR036390; WH_DNA-bd_sf.
DR Pfam; PF00891; Methyltransf_2; 1.
DR PIRSF; PIRSF005739; O-mtase; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR PROSITE; PS51683; SAM_OMT_II; 1.
PE 3: Inferred from homology;
KW Cytoplasm; Methyltransferase; S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..398
FT /note="O-methyltransferase mpaG"
FT /id="PRO_0000449218"
FT ACT_SITE 306
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01020"
FT ACT_SITE 335
FT /evidence="ECO:0000250|UniProtKB:F1DBB3"
FT ACT_SITE 362
FT /evidence="ECO:0000250|UniProtKB:F1DBB3"
FT BINDING 264
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01020"
SQ SEQUENCE 398 AA; 44077 MW; 00FD1BE57107E05F CRC64;
MLTKSVTSIL QGITLAAKEF ENNEAGARES LIAHSRALIS ALEVPSEFIQ HTFWSQPALS
AIIRLAADVN MFQHLKDAAG KGIDCEALSM KTGVDASLLS RLARHLVAMN VITFQNGAFH
GTDLSDSLAA ENYQHSIRFC HDVSRPSFNE FPEFFKSNGY KTPTLSGTDG PFQAAHKTEL
TFLQWLVNTH PYLQYFHSYM SVYRAGKQNW CDTGFYPVSE RLLSGFDASV SDVVLVDVGG
GRGHDLETFA SKFSPLPGRL VLQDREQTIA SMPADESRQF EATAHNIFTP QPVKYARAYY
MHSVPHGFGD EDAIKIMANL VPALAKGYSR VLLNEIVVSE ENPILAATNM DMIMLAHLAV
KERTEAEWRY IFTQAGLKVV NIYSYPGVAE SLIEAELA
