proton relay
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2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Coline Plé ◽  
Heng-Keat Tam ◽  
Anais Vieira Da Cruz ◽  
Nina Compagne ◽  
Juan-Carlos Jiménez-Castellanos ◽  
...  

AbstractEfflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump.


Author(s):  
Sarmistha Bhunia ◽  
Atanu Rana ◽  
Shabnam Hematian ◽  
Kenneth D. Karlin ◽  
Abhishek Dey

Author(s):  
Manolis M. Roubelakis ◽  
D. Kwabena Bediako ◽  
Dilek K. Dogutan ◽  
Daniel G. Nocera
Keyword(s):  

Author(s):  
Barbara Ghiglione ◽  
María Margarita Rodríguez ◽  
Florencia Brunetti ◽  
Krisztina M. Papp-Wallace ◽  
Ayumi Yoshizumi ◽  
...  

The diazabicyclooctane (DBO) inhibitor, avibactam (AVI), reversibly inactivates most serine-β-lactamases including the CTX-M β-lactamases. Currently, more than 230 CTX-M unique members distributed in five clusters with less than 5% amino acid sequence divergence within each group are described. Recently, a variant named as CTX-M-151 was isolated from a Salmonella Choleraesuis strain in Japan. This variant possesses a low degree amino acid identity with the other CTX-Ms (63.2-69.7% with respect to the mature proteins), and thus it may represent a new sub-group within the family. CTX-M-151 hydrolyzes ceftriaxone better than ceftazidime (kcat/Km values 6,000-fold higher), as observed with CTX-Ms. CTX-M-151 is well inhibited by mechanism-based inhibitors like clavulanic acid (kinact/KI = 0.15 μM−1.s−1). For AVI, Ki app (0.4 μM) was comparable to KPC-2; k2/K (37,000 M−1s−1) was lower than for CTX-M-15, while the koff (0.0015 s−1) was 2-14-fold faster than other class A β-lactamases. The structure of the CTX-M-151/AVI complex (1.32 Å) reveals that AVI adopts a chair conformation with hydrogen bonds between the AVI carbamate and Ser70 and Ser237 at the oxyanion hole. Upon acylation, the side chain of Lys73 points towards Ser130 which is associated with the protonation of Glu166, supporting the role of Lys73 in the proton-relay pathway and Glu166 as the general base in deacylation. To our knowledge, this is the first chromosomally-encoded CTX-M in Salmonella Choleraesuis that shows similar hydrolytic preference towards cefotaxime/ceftriaxone when compared to ceftazidime.


2021 ◽  
Vol 50 (14) ◽  
pp. 4783-4788
Author(s):  
Jie Yang ◽  
Shuanglin He ◽  
Qianqian Wu ◽  
Ping Zhang ◽  
Lin Chen ◽  
...  

A bio-inspired manganese molecular catalyst featuring an intramolecular aniline as a proton relay was synthesized and used for hydrogen production. Electrochemical measurements with this complex show excellent activity (turnover frequency over 104 s−1).


Author(s):  
Mojtaba Shamsipur ◽  
Moslem - Ardeshiri ◽  
Avat Taherpour ◽  
Afshin Pashabadi

Concerted or non-concerted; these are two competitive pathways that involve in proton-coupled ‎electron transfer-driven artificial water oxidation reaction (WOR). It is known that in the designed metal-based ‎electrocatalysts applied to...


IUCrJ ◽  
2021 ◽  
Vol 8 (1) ◽  
pp. 46-59
Author(s):  
Lindsay McGregor ◽  
Tamás Földes ◽  
Soi Bui ◽  
Martine Moulin ◽  
Nicolas Coquelle ◽  
...  

Cofactor-independent urate oxidase (UOX) is an ∼137 kDa tetrameric enzyme essential for uric acid (UA) catabolism in many organisms. UA is first oxidized by O2 to dehydroisourate (DHU) via a peroxo intermediate. DHU then undergoes hydration to 5-hydroxyisourate (5HIU). At different stages of the reaction both catalytic O2 and water occupy the `peroxo hole' above the organic substrate. Here, high-resolution neutron/X-ray crystallographic analysis at room temperature has been integrated with molecular dynamics simulations to investigate the hydration step of the reaction. The joint neutron/X-ray structure of perdeuterated Aspergillus flavus UOX in complex with its 8-azaxanthine (8AZA) inhibitor shows that the catalytic water molecule (W1) is present in the peroxo hole as neutral H2O, oriented at 45° with respect to the ligand. It is stabilized by Thr57 and Asn254 on different UOX protomers as well as by an O—H...π interaction with 8AZA. The active site Lys10–Thr57 dyad features a charged Lys10–NH3 + side chain engaged in a strong hydrogen bond with Thr57OG1, while the Thr57OG1–HG1 bond is rotationally dynamic and oriented toward the π system of the ligand, on average. Our analysis offers support for a mechanism in which W1 performs a nucleophilic attack on DHUC5 with Thr57HG1 central to a Lys10-assisted proton-relay system. Room-temperature crystallography and simulations also reveal conformational heterogeneity for Asn254 that modulates W1 stability in the peroxo hole. This is proposed to be an active mechanism to facilitate W1/O2 exchange during catalysis.


2020 ◽  
Vol 59 (19) ◽  
pp. 14012-14022
Author(s):  
Srijan Narayan Chowdhury ◽  
Sachidulal Biswas ◽  
Purak Das ◽  
Satadal Paul ◽  
Achintesh N. Biswas

2020 ◽  
Author(s):  
Phoolwanti Rani ◽  
Shashwath Malli Kalladi ◽  
Harsh Bansia ◽  
Sandhya Rao ◽  
Rajiv Kumar Jha ◽  
...  

AbstractTopoisomerases maintain topological homeostasis of bacterial chromosomes by catalysing changes in DNA linking number. The resolution of RNA entanglements occurring in the cell would also require catalytic action of topoisomerases. We describe RNA topoisomerase and hydrolysis activities in DNA topoisomerase I (topo I) from mycobacteria. The interaction of topo I with mRNA, tRNA and rRNA suggested its role in some aspect of RNA metabolism; the enzyme participates in rRNA maturation via its RNA hydrolysis activity. Accumulation of rRNA precursors in a topo I knockdown strain and the rescue of rRNA processing deficiency in RNaseE knockdown cells by topo I expression, indicated the enzyme’s back-up support to RNases involved in rRNA processing. We demonstrate that the active site tyrosine of the enzyme mediates catalytic reactions with both DNA/RNA substrates, and RNA topoisomerase activity can follow two reaction paths in contrast to its DNA topoisomerase activity. Mutation in the canonical proton relay pathway impacts DNA topoisomerase activity while retaining activity on RNA substrates. The mycobacterial topo I thus exemplifies the resourcefulness and parsimony of biological catalysis in harnessing the limited chemical repertoire at its disposal to find common solutions to mechanistically-related challenges of phosphodiester breakage/exchange reactions in DNA and RNA that are essential for cell survival.


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