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7dbl

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Current revision

Acyl-CoA hydrolase MpaH' mutant S139A in complex with MPA

Structural highlights

7dbl is a 4 chain structure with sequence from Penicillium brevicompactum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.84Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Mycophenolic acid (MPA) is a fungal natural product and first-line immunosuppressive drug for organ transplantations and autoimmune diseases. In the compartmentalized biosynthesis of MPA, the acyl-coenzyme A (CoA) hydrolase MpaH' located in peroxisomes catalyzes the highly specific hydrolysis of MPA-CoA to produce the final product MPA. The strict substrate specificity of MpaH' not only averts undesired hydrolysis of various cellular acyl-CoAs, but also prevents MPA-CoA from further peroxisomal beta-oxidation catabolism. To elucidate the structural basis for this important property, in this study, we solve the crystal structures of the substrate-free form of MpaH' and the MpaH'(S139A) mutant in complex with the product MPA. The MpaH' structure reveals a canonical alpha/beta-hydrolase fold with an unusually large cap domain and a rare location of the acidic residue D163 of catalytic triad after strand beta6. MpaH' also forms an atypical dimer with the unique C-terminal helices alpha13 and alpha14 arming the cap domain of the other protomer and indirectly participating in the substrate binding. With these characteristics, we propose that MpaH' and its homologs form a new subfamily of alpha/beta hydrolase fold protein. The crystal structure of MpaH'(S139A) /MPA complex and the modeled structure of MpaH'/MPA-CoA, together with the structure-guided mutagenesis analysis and isothermal titration calorimetry (ITC) measurements, provide important mechanistic insights into the high substrate specificity of MpaH'.

Structural basis for substrate specificity of the peroxisomal acyl-CoA hydrolase MpaH' involved in mycophenolic acid biosynthesis.,You C, Li F, Zhang X, Ma L, Zhang YZ, Zhang W, Li S FEBS J. 2021 Apr 12. doi: 10.1111/febs.15874. PMID:33843134^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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
↑ 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
↑ 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
↑ 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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7dbl"

Categories: Large Structures | Penicillium brevicompactum | Li SY | You C

@@ Line 3: / Line 3: @@
 <StructureSection load='7dbl' size='340' side='right'caption='[[7dbl]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7dbl]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Cbs_257.29 Cbs 257.29]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7DBL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DBL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7dbl]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Penicillium_brevicompactum Penicillium brevicompactum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7DBL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DBL FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MOA:MYCOPHENOLIC+ACID'>MOA</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.84&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MPA' ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5074 CBS 257.29])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MOA:MYCOPHENOLIC+ACID'>MOA</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7dbl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dbl OCA], [https://pdbe.org/7dbl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dbl RCSB], [https://www.ebi.ac.uk/pdbsum/7dbl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dbl ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/MPAH2_PENBR 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).<ref>PMID:31209052</ref> <ref>PMID:33843134</ref> <ref>PMID:31209052</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Cbs 257 29]]
 [[Category: Large Structures]]
-[[Category: Li, S Y]]
+[[Category: Penicillium brevicompactum]]
-[[Category: You, C]]
+[[Category: Li SY]]
-[[Category: Hydrolase]]
+[[Category: You C]]
-[[Category: Mpa biosynthesis]]
-[[Category: Mpahss']]
-[[Category: Peroxisomal acyl-coa hydrolase]]

7dbl

From Proteopedia

Current revision

Acyl-CoA hydrolase MpaH' mutant S139A in complex with MPA

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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