Protein: Polyprenyl transferase mpaA (EC 2.5.1.-) (Mycophenolic acid biosynthesis cluster protein A) (W6QIT8)
Organism: Penicillium roqueforti (strain FM164)
Function: Polyprenyl transferase; 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. MpaA is a Golgi apparatus-associated enzyme that catalyzes the prenylation of 5,7-dihydroxy-4,6-dimethylphthalide (DHMP) to yield farnesyl-DHMP (FDHMP). 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).
Subcellular location: Golgi apparatus membrane {ECO:0000250|UniProtKB:A0A0B5L778}; Multi-pass membrane protein {ECO:0000255}. Note=Membrane association is functionally relevant because mpaA must ostensibly interact with its membrane-embedded substrate FPP. {ECO:0000305}.
InterPro domains:
- IPR044878: UbiA prenyltransferase superfamily (homologous_superfamily) [29-195]
- IPR000537: UbiA prenyltransferase (family) [36-293]
- IPR039653: Prenyltransferase (family) [21-313]
- IPR030470: UbiA prenyltransferase conserved site (conserved_site) [81-103]
Sequence:
MVGSMENPGSWGLACLLISTSRFNRYMPYYTMMAAVWSTLIAGALKLQEDPASLSVEYILFKAGLCFVHCLLLCGAGNTWNDLIDRDIDARVERTKMRPLASGKVSTVEALVWMVGQYFLSVKMLDLILDNRSIWGLMLPLTASIMLYPYLKRPVFSRVFIYPQYILGLAVAYPSITGWASINGQEQSMSEIFTHCTPICLLIFFWCLYFNTAYSHQDSVDDRKMNINSAYVVAGQRIRLFLAFLGALPLAVIPYVVLKINSPWLWFSWMAVWTVSIVMQIVRFDSKKLESGGRIHWDNFLLGLWTTVACIVEVGLQKVEFWNLI
Predicted GO terms:
Molecular Function (MF): GO:0003674 (molecular function), GO:0003824 (catalytic activity), GO:0016740 (transferase activity), GO:0016765 (transferase activity, transferring alkyl or aryl (other than methyl) groups), GO:0004659 (prenyltransferase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0009987 (cellular process), GO:0009058 (biosynthetic process), GO:0044237 (cellular metabolic process), GO:0071704 (organic substance metabolic process), GO:0044281 (small molecule metabolic process), GO:0044238 (primary metabolic process), GO:0044255 (cellular lipid metabolic process), GO:0042180 (cellular ketone metabolic process), GO:0044249 (cellular biosynthetic process), GO:1901360 (organic cyclic compound metabolic process), GO:1901576 (organic substance biosynthetic process), GO:0006629 (lipid metabolic process), GO:0044283 (small molecule biosynthetic process), GO:0046483 (heterocycle metabolic process), GO:1901362 (organic cyclic compound biosynthetic process), GO:0042181 (ketone biosynthetic process), GO:0006720 (isoprenoid metabolic process), GO:0008299 (isoprenoid biosynthetic process), GO:0008610 (lipid biosynthetic process), GO:0018130 (heterocycle biosynthetic process), GO:0006721 (terpenoid metabolic process), GO:0016114 (terpenoid biosynthetic process)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005737 (cytoplasm), GO:0012505 (endomembrane system), GO:0005794 (Golgi apparatus), GO:0043229 (intracellular organelle), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle)