7dbl

Structural highlights

Function

MPAH2_PENBR 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:31209052, PubMed:33843134). MpaH' acts as a peroxisomal acyl-CoA hydrolase that converts MPA-CoA into the final product MPA (PubMed:31209052, PubMed:33843134). 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 (PubMed:31209052) (Probable).^{[1] [2] [3]}

References

1. ↑ 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, Qi F, Wan X, Liu C, Li S. Compartmentalized biosynthesis of mycophenolic acid. Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13305-13310. PMID:31209052 doi:10.1073/pnas.1821932116
2. ↑ You C, Li F, Zhang X, Ma L, Zhang YZ, Zhang W, Li S. Structural basis for substrate specificity of the peroxisomal acyl-CoA hydrolase MpaH' involved in mycophenolic acid biosynthesis. FEBS J. 2021 Apr 12. doi: 10.1111/febs.15874. PMID:33843134 doi:http://dx.doi.org/10.1111/febs.15874
3. ↑ 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, Qi F, Wan X, Liu C, Li S. Compartmentalized biosynthesis of mycophenolic acid. Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13305-13310. PMID:31209052 doi:10.1073/pnas.1821932116
4. ↑ You C, Li F, Zhang X, Ma L, Zhang YZ, Zhang W, Li S. Structural basis for substrate specificity of the peroxisomal acyl-CoA hydrolase MpaH' involved in mycophenolic acid biosynthesis. FEBS J. 2021 Apr 12. doi: 10.1111/febs.15874. PMID:33843134 doi:http://dx.doi.org/10.1111/febs.15874