Penicillium brevicompactum. Mycophenolic acid biosynthesis cluster protein C Non-reducing polyketide synthase mapC
(from Uniprot) Non-reducing polyketide synthase\; 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. MpaC' catalyzes the synthesis of 5-methylorsellinic acid (5MOA) via the condensation of 1 acetyl-CoA starter unit with 3 malonyl-CoA units and one methylation step. 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
ETVVWGERDN LQLRADIYYP ETVDTTRKQR PIALMIHGGG HVMLSRKDIR PAQTQTLLDA GFLPVSIDYR LCPEVSLAEG PMADARDALS WVRRVLPNIP LLRADIRPDG NQVVAIGWST GGHLAMTLPF TAPAAGISAP NAVLAFYCPT NYEDPFWSNP NFPFGQTVAS NEMEYDVWEG LQSMPIAGYN PALKERPLGG WMSTRDPRSR IALHMNWTGQ TLPVLLKACT IKGNTEKCSP DDLSRPTEEE IQAVSPNYQI RVGRYNTPTF LIHGTSDDLV PCAQTESTHG ALTASGVEAE LRVVQEAAHL FDLYPASHAG QEAKAAVAEG YEFLRRHVQL
Title : Compartmentalized biosynthesis of mycophenolic acid - Zhang_2019_Proc.Natl.Acad.Sci.U.S.A_116_13305 |
Author(s) : Zhang W , Du L , Qu Z , Zhang X , Li F , Li Z , Qi F , Wang X , Jiang Y , Men P , Sun J , Cao S , Geng C , Wan X , Liu C , Li S |
Ref : Proc Natl Acad Sci U S A , 116 :13305 , 2019 |
Abstract : Zhang_2019_Proc.Natl.Acad.Sci.U.S.A_116_13305 |
ESTHER : Zhang_2019_Proc.Natl.Acad.Sci.U.S.A_116_13305 |
PubMedSearch : Zhang_2019_Proc.Natl.Acad.Sci.U.S.A_116_13305 |
PubMedID: 31209052 |
Gene_locus related to this paper: penbr-mpaH , penbr-mpac |
Title : Functional characterization of MpaG', the O-methyltransferase involved in the biosynthesis of mycophenolic acid - Zhang_2015_Chembiochem_16_565 |
Author(s) : Zhang W , Cao S , Qiu L , Qi F , Li Z , Yang Y , Huang S , Bai F , Liu C , Wan X , Li S |
Ref : Chembiochem , 16 :565 , 2015 |
Abstract : Zhang_2015_Chembiochem_16_565 |
ESTHER : Zhang_2015_Chembiochem_16_565 |
PubMedSearch : Zhang_2015_Chembiochem_16_565 |
PubMedID: 25630520 |
Gene_locus related to this paper: penbr-mpaH , penbr-mpac |
Title : Involvement of a natural fusion of a cytochrome P450 and a hydrolase in mycophenolic acid biosynthesis - Hansen_2012_Appl.Environ.Microbiol_78_4908 |
Author(s) : Hansen BG , Mnich E , Nielsen KF , Nielsen JB , Nielsen MT , Mortensen UH , Larsen TO , Patil KR |
Ref : Applied Environmental Microbiology , 78 :4908 , 2012 |
Abstract : Hansen_2012_Appl.Environ.Microbiol_78_4908 |
ESTHER : Hansen_2012_Appl.Environ.Microbiol_78_4908 |
PubMedSearch : Hansen_2012_Appl.Environ.Microbiol_78_4908 |
PubMedID: 22544261 |
Gene_locus related to this paper: penbr-mpac |
Title : Molecular basis for mycophenolic acid biosynthesis in Penicillium brevicompactum - Regueira_2011_Appl.Environ.Microbiol_77_3035 |
Author(s) : Regueira TB , Kildegaard KR , Hansen BG , Mortensen UH , Hertweck C , Nielsen J |
Ref : Applied Environmental Microbiology , 77 :3035 , 2011 |
Abstract : Regueira_2011_Appl.Environ.Microbiol_77_3035 |
ESTHER : Regueira_2011_Appl.Environ.Microbiol_77_3035 |
PubMedSearch : Regueira_2011_Appl.Environ.Microbiol_77_3035 |
PubMedID: 21398490 |
Gene_locus related to this paper: penbr-mpac |
Title : Versatile enzyme expression and characterization system for Aspergillus nidulans, with the Penicillium brevicompactum polyketide synthase gene from the mycophenolic acid gene cluster as a test case - Hansen_2011_Appl.Environ.Microbiol_77_3044 |
Author(s) : Hansen BG , Salomonsen B , Nielsen MT , Nielsen JB , Hansen NB , Nielsen KF , Regueira TB , Nielsen J , Patil KR , Mortensen UH |
Ref : Applied Environmental Microbiology , 77 :3044 , 2011 |
Abstract : Hansen_2011_Appl.Environ.Microbiol_77_3044 |
ESTHER : Hansen_2011_Appl.Environ.Microbiol_77_3044 |
PubMedSearch : Hansen_2011_Appl.Environ.Microbiol_77_3044 |
PubMedID: 21398493 |
Gene_locus related to this paper: penbr-mpac |