You_2021_FEBS.J_288_5768

Reference

Title : Structural basis for substrate specificity of the peroxisomal acyl-CoA hydrolase MpaH' involved in mycophenolic acid biosynthesis - You_2021_FEBS.J_288_5768
Author(s) : You C , Li F , Zhang X , Ma L , Zhang YZ , Zhang W , Li S
Ref : Febs J , 288 :5768 , 2021
Abstract :

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 homologues form a new subfamily of alpha/beta hydrolase fold protein. The crystal structure of MpaH'(S139A) /MPA complex and the modelled 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'.

PubMedSearch : You_2021_FEBS.J_288_5768
PubMedID: 33843134
Gene_locus related to this paper: penbr-mpaH

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Citations formats

You C, Li F, Zhang X, Ma L, Zhang YZ, Zhang W, Li S (2021)
Structural basis for substrate specificity of the peroxisomal acyl-CoA hydrolase MpaH' involved in mycophenolic acid biosynthesis
Febs J 288 :5768

You C, Li F, Zhang X, Ma L, Zhang YZ, Zhang W, Li S (2021)
Febs J 288 :5768