The results from the previous six papers are collated so as to allow the construction of the complete free energy profile for the reaction catalyzed by proline racemase. This profile includes the step that involves the isomerization of the two forms of free enzyme, which can become rate limiting at very high substrate levels (in "oversaturation"). The mechanism of the reaction has been defined, the results being best accommodated by a route that involves a transition state or unstable intermediate in which the proline carbanion is flanked by the two catalytic thiols of the enzyme.

Download full-text PDF

Source
http://dx.doi.org/10.1021/bi00357a043DOI Listing

Publication Analysis

Top Keywords

proline racemase
8
energetics mechanism
4
mechanism proline
4
racemase previous
4
previous papers
4
papers collated
4
collated allow
4
allow construction
4
construction complete
4
complete free
4

Similar Publications

Design and evaluation of substrate-product analog inhibitors for racemases and epimerases utilizing a 1,1-proton transfer mechanism.

Methods Enzymol

October 2023

Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada; Department of Chemistry, Dalhousie University, Halifax, NS, Canada. Electronic address:

Racemases and epimerases catalyze the inversion of stereochemistry at asymmetric carbon atoms to generate stereoisomers that often play important roles in normal and pathological physiology. Consequently, there is interest in developing inhibitors of these enzymes for drug discovery. A strategy for the rational design of substrate-product analog (SPA) inhibitors of racemases and epimerases utilizing a direct 1,1-proton transfer mechanism is elaborated.

View Article and Find Full Text PDF

Microbial Proline Racemase-Proline Dehydrogenase Cascade for Efficient Production of D-proline and N-boc-5-hydroxy-L-proline from L-proline.

Appl Biochem Biotechnol

September 2022

Chongqing Key Laboratory of Big Data On Bio-Intelligence, School of Bioinformatics, Chongqing University of Posts and Telecommunications, Chongqing, 400065, People's Republic of China.

D-proline and N-boc-5-hydroxy-L-proline are key chiral intermediates in the production of eletriptan and saxagliptin, respectively. An efficient proline racemase-proline dehydrogenase cascade was developed for the enantioselective production of D-proline. It included the racemization of L-proline to DL-proline and the enantioselective dehydrogenation of L-proline in DL-proline.

View Article and Find Full Text PDF

Prodrugs as new therapies against Chagas disease: in vivo synergy between Trypanosoma cruzi proline racemase inhibitors and benznidazole.

J Glob Antimicrob Resist

March 2022

Institut Pasteur, Département Santé Globale, Laboratoire des Processus Infectieux à Trypanosomatidés, 28 rue du Dr Roux, 75015 Paris, France. Electronic address:

Objectives: Chagas disease, caused by the parasitic protozoan Trypanosoma cruzi, affects approximately 6-7 million people worldwide. There are limited available therapies and they exhibit low efficacy, often high toxicity in chronic cases and some drug resistance. In this study, our objective was to develop ester prodrugs that inhibit proline racemase (TcPRAC), a parasitic enzyme previously identified and characterised as a promising target because of its essential role in the parasite's life cycle and virulence, and to test their activity against T.

View Article and Find Full Text PDF

Irreversible inhibitors of the proline racemase unveil innovative mechanism of action as antibacterial agents against Clostridioides difficile.

Chem Biol Drug Des

April 2022

Institut Pasteur, Département Santé Globale, Laboratoire des Processus Infectieux à Trypanosomatidés, Paris, France.

Proline racemases (PRAC), catalyzing the l-proline and d-proline interconversion, are essential factors in eukaryotic pathogens such as Trypanosoma cruzi, Trypanosoma vivax, and Clostridioides difficile. If the discovery of irreversible inhibitors of T. cruzi PRAC (TcPRAC) led to innovative therapy of the Chagas disease, no inhibitors of CdPRAC have been discovered to date.

View Article and Find Full Text PDF

Background: Attenuated strain can be used as a vector to transport immunogens to the host antigen-binding sites.

Objectives: The study aimed to determine the protective efficacy of attenuated strain expressing highly conserved immunogens in goats.

Methods: Goats were vaccinated with vector expressing individually lipoprotein outer-membrane protein 19 (Omp19), lumazine synthase (BLS), proline racemase subunit A (PrpA), Cu/Zn superoxide dismutase (SOD) at 5 × 10⁹ CFU/mL and challenge of all groups was done at 6 weeks after vaccination.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!