scholarly journals Substrate Specificity of the Bacillus licheniformis Lyxose Isomerase YdaE and Its Application inIn VitroCatalysis for Bioproduction of Lyxose and Glucose by Two-Step Isomerization

2011 ◽  
Vol 77 (10) ◽  
pp. 3343-3350 ◽  
Author(s):  
Darshan H. Patel ◽  
Seung Gon Wi ◽  
Seong-Gene Lee ◽  
Dae-Seok Lee ◽  
Youn-ho Song ◽  
...  
Keyword(s):  
Bacillus Licheniformis ◽  
Thermus Thermophilus ◽  
Xylose Isomerase ◽  
Catalytic Efficiency ◽  
Sugar Production ◽  
Uncharacterized Protein ◽  
Easy Method ◽  
Content Type ◽  
Substrate Specificities

ABSTRACTEnzymatic processes are useful for industrially important sugar production, andin vitrotwo-step isomerization has proven to be an efficient process in utilizing readily available sugar sources. A hypothetical uncharacterized protein encoded byydaEofBacillus licheniformiswas found to have broad substrate specificities and has shown high catalytic efficiency ond-lyxose, suggesting that the enzyme isd-lyxose isomerase.Escherichia coliBL21 expressing the recombinant protein, of 19.5 kDa, showed higher activity at 40 to 45°C and pH 7.5 to 8.0 in the presence of 1.0 mM Mn2+. The apparentKmvalues ford-lyxose andd-mannose were 30.4 ± 0.7 mM and 26 ± 0.8 mM, respectively. The catalytic efficiency (kcat/Km) for lyxose (3.2 ± 0.1 mM−1s−1) was higher than that ford-mannose (1.6 mM−1s−1). The purified protein was applied to the bioproduction ofd-lyxose andd-glucose fromd-xylose andd-mannose, respectively, along with the thermostable xylose isomerase ofThermus thermophilusHB08. From an initial concentration of 10 mMd-lyxose andd-mannose, 3.7 mM and 3.8 mMd-lyxose andd-glucose, respectively, were produced by two-step isomerization. This two-step isomerization is an easy method forin vitrocatalysis and can be applied to industrial production.

scholarly journals A Genotype-Phenotype Correlation Study of SHV β-Lactamases Offers New Insight into SHV Resistance Profiles

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Svetlana Neubauer ◽  
Sara Madzgalla ◽  
Mike Marquet ◽  
Anne Klabunde ◽  
Bernd Büttner ◽  
...  
Keyword(s):  
Correlation Study ◽  
Gram Negative Bacteria ◽  
Promoter Mutation ◽  
Phenotype Correlation ◽  
Content Type ◽  
Substrate Specificities ◽  
Third Generation Cephalosporins ◽  
Insight Into ◽  
Lactamase Inhibitor

ABSTRACT The SHV β-lactamases (BLs) have undergone strong allele diversification that has changed their substrate specificities. Based on 147 NCBI entries for SHV alleles, in silico mathematical models predicted 5 positions as relevant for the β-lactamase inhibitor (BLI)-resistant (2br) phenotype, 12 positions as relevant for the extended-spectrum BL (ESBL) (2be) phenotype, and 2 positions as related solely to the narrow-spectrum (2b) phenotype. These positions and six additional positions described in other studies (including one promoter mutation) were systematically substituted and investigated for their substrate specificities in a BL-free Escherichia coli background, representing, to our knowledge, the most comprehensive substrate and substitution analysis for SHV alleles to date. An in vitro analysis confirmed the essentiality of positions 238 and 179 for the 2be phenotype and of position 69 for the 2br phenotype. The E240K and E240R substitutions, which do not occur alone in known 2br SHV variants, led to a 2br phenotype, indicating a latent BLI resistance potential of these substitutions. The M129V, A234G, S271I, and R292Q substitutions conferred latent resistance to cefotaxime. In addition, seven positions that were found not always to be associated with the ESBL phenotype resulted in increased resistance to ceftaroline. We also observed that coupling of a strong promoter (IS26) to an A146V mutant with the 2b phenotype resulted in highly increased resistance to BLIs, cefepime, and ceftaroline but not to third-generation cephalosporins, indicating that SHV enzymes represent an underestimated risk for empirical therapies that use piperacillin-tazobactam or cefepime to treat different infectious diseases caused by Gram-negative bacteria.

scholarly journals Enhancing the Promiscuous Phosphotriesterase Activity of a Thermostable Lactonase (GkaP) for the Efficient Degradation of Organophosphate Pesticides

2012 ◽  
Vol 78 (18) ◽  
pp. 6647-6655 ◽  
Author(s):  
Yu Zhang ◽  
Jiao An ◽  
Wei Ye ◽  
Guangyu Yang ◽  
Zhi-Gang Qian ◽  
...  
Keyword(s):  
Catalytic Efficiency ◽  
Dynamics Simulation ◽  
Saturation Mutagenesis ◽  
Divergent Evolution ◽  
Laboratory Evolution ◽  
Content Type ◽  
Hydrolytic Activities ◽  
Geobacillus Kaustophilus ◽  
Amidohydrolase Superfamily

ABSTRACTThe phosphotriesterase-like lactonase (PLL) enzymes in the amidohydrolase superfamily hydrolyze various lactones and exhibit latent phosphotriesterase activities. These enzymes serve as attractive templates forin vitroevolution of neurotoxic organophosphates (OPs) with hydrolytic capabilities that can be used as bioremediation tools. Here, a thermostable PLL fromGeobacillus kaustophilusHTA426 (GkaP) was targeted for joint laboratory evolution with the aim of enhancing its catalytic efficiency against OP pesticides. By a combination of site saturation mutagenesis and whole-gene error-prone PCR approaches, several improved variants were isolated. The most active variant, 26A8C, accumulated eight amino acid substitutions and demonstrated a 232-fold improvement over the wild-type enzyme in reactivity (kcat/Km) for the OP pesticideethyl-paraoxon. Concomitantly, this variant showed a 767-fold decrease in lactonase activity with δ-decanolactone, imparting a specificity switch of 1.8 × 105-fold. 26A8C also exhibited high hydrolytic activities (19- to 497-fold) for several OP pesticides, including parathion, diazinon, and chlorpyrifos. Analysis of the mutagenesis sites on the GkaP structure revealed that most mutations are located in loop 8, which determines substrate specificity in the amidohydrolase superfamily. Molecular dynamics simulation shed light on why 26A8C lost its native lactonase activity and improved the promiscuous phosphotriesterase activity. These results permit us to obtain further insights into the divergent evolution of promiscuous enzymes and suggest that laboratory evolution of GkaP may lead to potential biological solutions for the efficient decontamination of neurotoxic OP compounds.

scholarly journals In VitroStudies Indicate a High Resistance Potential for the Lantibiotic Nisin in Staphylococcus aureus and Define a Genetic Basis for Nisin Resistance

2011 ◽  
Vol 55 (5) ◽  
pp. 2362-2368 ◽  
Author(s):  
Katy L. Blake ◽  
Chris P. Randall ◽  
Alex J. O'Neill
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Infections ◽  
Fold Increase ◽  
Peptide Antibiotics ◽  
Uncharacterized Protein ◽  
Content Type ◽  
Development Of Resistance ◽  
Genes Encoding ◽  
Bacterial Fitness

ABSTRACTLantibiotics such as nisin (NIS) are peptide antibiotics that may have a role in the chemotherapy of bacterial infections. A perceived benefit of lantibiotics for clinical use is their low propensity to select resistance, although detailed resistance studies with relevant bacterial pathogens are lacking. Here we examined the development of resistance to NIS inStaphylococcus aureus, establishing that mutants, including small-colony variants, exhibiting substantial (4- to 32-fold) reductions in NIS susceptibility could be selected readily. Comparative genome sequencing of a single NISrmutant exhibiting a 32-fold increase in NIS MIC revealed the presence of only two mutations, leading to the substitutions V229G in the purine operon repressor, PurR, and A208E in an uncharacterized protein encoded by SAOUHSC_02955. Independently selected NISrmutants also harbored mutations in the genes encoding these products. Reintroduction of these mutations into theS. aureuschromosome alone and in combination revealed that SAOUHSC_02955(A208E) made the primary contribution to the resistance phenotype, conferring up to a 16-fold decrease in NIS susceptibility. Bioinformatic analyses suggested that this gene encodes a sensor histidine kinase, leading us to designate it “nisin susceptibility-associated sensor (nsaS).” Doubling-time determinations and mixed-culture competition assays between NISrand NISsstrains indicated that NIS resistance had little impact on bacterial fitness, and resistance was stable in the absence of selection. The apparent ease with whichS. aureuscan develop and maintain NIS resistancein vitrosuggests that resistance to NIS and other lantibiotics with similar modes of action would arise in the clinic if these agents are employed as chemotherapeutic drugs.

scholarly journals Production of l-Ribose from l-Ribulose by a Triple-Site Variant of Mannose-6-Phosphate Isomerase from Geobacillus thermodenitrificans

2012 ◽  
Vol 78 (11) ◽  
pp. 3880-3884 ◽  
Author(s):  
Yu-Ri Lim ◽  
Soo-Jin Yeom ◽  
Deok-Kun Oh
Keyword(s):  
Specific Activity ◽  
Thermus Thermophilus ◽  
Catalytic Efficiency ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Wild Type ◽  
Geobacillus Thermodenitrificans ◽  
Wild Type Enzyme ◽  
Content Type ◽  
Mannose 6 Phosphate

ABSTRACTA triple-site variant (W17Q N90A L129F) of mannose-6-phosphate isomerase fromGeobacillus thermodenitrificanswas obtained by combining variants with residue substitutions at different positions after random and site-directed mutagenesis. The specific activity and catalytic efficiency (kcat/Km) forl-ribulose isomerization of this variant were 3.1- and 7.1-fold higher, respectively, than those of the wild-type enzyme at pH 7.0 and 70°C in the presence of 1 mM Co2+. The triple-site variant produced 213 g/literl-ribose from 300 g/literl-ribulose for 60 min, with a volumetric productivity of 213 g liter−1h−1, which was 4.5-fold higher than that of the wild-type enzyme. Thekcat/Kmand productivity of the triple-site variant were approximately 2-fold higher than those of theThermus thermophilusR142N variant of mannose-6-phosphate isomerase, which exhibited the highest values previously reported.

scholarly journals N152G, -S, and -T Substitutions in CMY-2 β-Lactamase Increase Catalytic Efficiency for Cefoxitin and Inactivation Rates for Tazobactam

2013 ◽  
Vol 57 (4) ◽  
pp. 1596-1602 ◽  
Author(s):  
Marion J. Skalweit ◽  
Mei Li ◽  
Benjamin C. Conklin ◽  
Magdalena A. Taracila ◽  
Rebecca A. Hutton
Keyword(s):  
Catalytic Efficiency ◽  
Enzyme Inactivation ◽  
Inactivation Kinetics ◽  
Content Type ◽  
New Class ◽  
Fold Reduction ◽  
Class C ◽  
Functional Mutants

ABSTRACTClass C cephalosporinases are a growing threat, and clinical inhibitors of these enzymes are currently unavailable. Previous studies have explored the role of Asn152 in theEscherichia coliAmpC and P99 enzymes and have suggested that interactions between C-6′ or C-7′ substituents on penicillins or cephalosporins and Asn152 are important in determining substrate specificity and enzymatic stability. We sought to characterize the role of Asn152 in the clinically important CMY-2 cephalosporinase with substrates and inhibitors. Mutagenesis of CMY-2 at position 152 yields functional mutants (N152G, -S, and -T) that exhibit improved penicillinase activity and retain cephamycinase activity. We also tested whether the position 152 substitutions would affect the inactivation kinetics of tazobactam, a class A β-lactamase inhibitor within vitroactivity against CMY-2. Using standard assays, we showed that the N152G, -S, and -T variants possessed increased catalytic activity against cefoxitin compared to the wild type. The 50% inhibitory concentration (IC50) for tazobactam improved dramatically, with an 18-fold reduction for the N152S mutant due to higher rates of enzyme inactivation. Modeling studies have shown active-site expansion due to interactions between Y150 and S152 in the apoenzyme and the Michaelis-Menten complex with tazobactam. Substitutions at N152 might become clinically important as new class C β-lactamase inhibitors are developed.

scholarly journals A Novel Agarolytic β-Galactosidase Acts on Agarooligosaccharides for Complete Hydrolysis of Agarose into Monomers

2014 ◽  
Vol 80 (19) ◽  
pp. 5965-5973 ◽  
Author(s):  
Chan Hyoung Lee ◽  
Hee Taek Kim ◽  
Eun Ju Yun ◽  
Ah Reum Lee ◽  
Sa Rang Kim ◽  
...  
Keyword(s):  
Marine Bacterium ◽  
Catalytic Efficiency ◽  
Sugar Production ◽  
Biomass Feedstock ◽  
Fermentable Sugar ◽  
Content Type ◽  
Renewable Biomass ◽  
Red Macroalgae ◽  
Optimum Ph ◽  
Hydrolysis Of

ABSTRACTMarine red macroalgae have emerged to be renewable biomass for the production of chemicals and biofuels, because carbohydrates that form the major component of red macroalgae can be hydrolyzed into fermentable sugars. The main carbohydrate in red algae is agarose, and it is composed ofd-galactose and 3,6-anhydro-l-galactose (AHG), which are alternately bonded by β1-4 and α1-3 linkages. In this study, a novel β-galactosidase that can act on agarooligosaccharides (AOSs) to release galactose was discovered in a marine bacterium (Vibriosp. strain EJY3); the enzyme is annotated asVibriosp. EJY3 agarolytic β-galactosidase (VejABG). Unlike thelacZ-encoded β-galactosidase fromEscherichia coli,VejABG does not hydrolyze common substrates like lactose and can act only on the galactose moiety at the nonreducing end of AOS. The optimum pH and temperature ofVejABG on an agarotriose substrate were 7 and 35°C, respectively. Its catalytic efficiency with agarotriose was also similar to that with agaropentaose or agaroheptaose. Since agarotriose lingers as the unreacted residual oligomer in the currently available saccharification system using β-agarases and acid prehydrolysis, the agarotriose-hydrolyzing capability of this novel β-galactosidase offers an enormous advantage in the saccharification of agarose or agar in red macroalgae for its use as a biomass feedstock for fermentable sugar production.

scholarly journals Roles of Two Glutathione-Dependent 3,6-Dichlorogentisate Dehalogenases inRhizorhabdus dicambivoransNdbn-20 in the Catabolism of the Herbicide Dicamba

2018 ◽  
Vol 84 (17) ◽  
Author(s):  
Na Li ◽  
Ren-Lei Tong ◽  
Li Yao ◽  
Qing Chen ◽  
Xin Yan ◽  
...  
Keyword(s):  
Large Scale ◽  
Catalytic Efficiency ◽  
Catabolic Pathway ◽  
High Identity ◽  
Content Type ◽  
Phylogenetic Status ◽  
Sphingobium Chlorophenolicum ◽  
Sequence Identities

ABSTRACTThe herbicide dicamba is initially demethylated to 3,6-dichlorosalicylate (3,6-DCSA) inRhizorhabdus dicambivoransNdbn-20 and is subsequently 5-hydroxylated to 3,6-dichlorogentisate (3,6-DCGA). In the present study, two glutathione-dependent 3,6-DCGA dehalogenases, DsmH1 and DsmH2, were identified in strain Ndbn-20. DsmH2 shared a low identity (only 31%) with the tetrachlorohydroquinone (TCHQ) dehalogenase PcpC fromSphingobium chlorophenolicumATCC 39723, while DsmH1 shared a high identity (79%) with PcpC. In the phylogenetic tree of related glutathioneS-transferases (GSTs), DsmH1 and DsmH2, together with PcpC and the 2,5-dichlorohydroquinone dehalogenase LinD, formed a separate clade. DsmH1 and DsmH2 were synthesized inEscherichia coliBL21 and purified as His-tagged enzymes. Both enzymes required glutathione (GSH) as a cofactor and could 6-dechlorinate 3,6-DCGA to 3-chlorogentisatein vitro. DsmH2 had a significantly higher catalytic efficiency toward 3,6-DCGA than DsmH1. Transcription and disruption analysis revealed that DsmH2 but not DsmH1 was responsible for the 6-dechlorination of 3,6-DCGA in strain Ndbn-20in vivo. Furthermore, we propose a novel eta class of GSTs to accommodate the four bacterial dehalogenases PcpC, LinD, DsmH1, and DsmH2.IMPORTANCEDicamba is an important herbicide, and its use and leakage into the environment have dramatically increased since the large-scale planting of genetically modified (GM) dicamba-resistant crops in 2015. However, the complete catabolic pathway of dicamba has remained unknown, which limits ecotoxicological studies of this herbicide. Our previous study revealed that 3,6-DCGA was an intermediate of dicamba degradation in strain Ndbn-20. In this study, we identified two glutathione-dependent 3,6-DCGA dehalogenases, DsmH1 and DsmH2, and demonstrated that DsmH2 is physiologically responsible for the 6-dechlorination of 3,6-DCGA in strain Ndbn-20. GSTs play an important role in the detoxification and degradation of a variety of endogenous and exogenous toxic compounds. On the basis of their sequence identities, phylogenetic status, and functions, the four bacterial GSH-dependent dehalogenases (PcpC, LinD, DsmH1, and DsmH2) were reclassified as a new eta class of GSTs. This study helps us to elucidate the microbial catabolism of dicamba and enhances our understanding of the diversity and functions of GSTs.

scholarly journals Recycling of Overactivated Acyls by a Type II Thioesterase during Calcimycin Biosynthesis in Streptomyces chartreusis NRRL 3882

2018 ◽  
Vol 84 (12) ◽  
pp. e00587-18
Author(s):  
Hao Wu ◽  
Jingdan Liang ◽  
Lixia Gou ◽  
Qiulin Wu ◽  
Wei-Jun Liang ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Divalent Cations ◽  
Catalytic Efficiency ◽  
Biosynthetic Gene Cluster ◽  
Type Ii ◽  
Acyl Carrier Proteins ◽  
Content Type ◽  
Biosynthetic Precursor ◽  
Hydrolysis Of

ABSTRACT Type II thioesterases typically function as editing enzymes, removing acyl groups that have been misconjugated to acyl carrier proteins during polyketide secondary metabolite biosynthesis as a consequence of biosynthetic errors. Streptomyces chartreusis NRRL 3882 produces the pyrrole polyether ionophoric antibiotic, and we have identified the presence of a putative type II thioesterase-like sequence, calG, within the biosynthetic gene cluster involved in the antibiotic's synthesis. However, targeted gene mutagenesis experiments in which calG was inactivated in the organism did not lead to a decrease in calcimycin production but rather reduced the strain's production of its biosynthetic precursor, cezomycin. Results from in vitro activity assays of purified, recombinant CalG protein indicated that it was involved in the hydrolysis of cezomycin coenzyme A (cezomycin-CoA), as well as other acyl CoAs, but was not active toward 3-S-N-acetylcysteamine (SNAC; the mimic of the polyketide chain-releasing precursor). Further investigation of the enzyme's activity showed that it possessed a cezomycin-CoA hydrolysis Km of 0.67 mM and a kcat of 17.77 min−1 and was significantly inhibited by the presence of Mn2+ and Fe2+ divalent cations. Interestingly, when S. chartreusis NRRL 3882 was cultured in the presence of inorganic nitrite, NaNO2, it was observed that the production of calcimycin rather than cezomycin was promoted. Also, supplementation of S. chartreusis NRRL 3882 growth medium with the divalent cations Ca2+, Mg2+, Mn2+, and Fe2+ had a similar effect. Taken together, these observations suggest that CalG is not responsible for megasynthase polyketide precursor chain release during the synthesis of calcimycin or for retaining the catalytic efficiency of the megasynthase enzyme complex as is supposed to be the function for type II thioesterases. Rather, our results suggest that CalG is a dedicated thioesterase that prevents the accumulation of cezomycin-CoA when intracellular nitrogen is limited, an apparently new and previously unreported function of type II thioesterases. IMPORTANCE Type II thioesterases (TEIIs) are generally regarded as being responsible for removing aberrant acyl groups that block polyketide production, thereby maintaining the efficiency of the megasynthase involved in this class of secondary metabolites' biosynthesis. Specifically, this class of enzyme is believed to be involved in editing misprimed precursors, controlling initial units, providing key intermediates, and releasing final synthetic products in the biosynthesis of this class of secondary metabolites. Our results indicate that the putative TEII CalG present in the calcimycin (A23187)-producing organism Streptomyces chartreusis NRRL 3882 is not important either for the retention of catalytic efficiency of, or for the release of the product compound from, the megasynthase involved in calcimycin biosynthesis. Rather, the enzyme is involved in regulating/controlling the pool size of the calcimycin biosynthetic precursor, cezomycin, by hydrolysis of its CoA derivative. This novel function of CalG suggests a possible additional activity for enzymes belonging to the TEII protein family and promotes better understanding of the overall biosynthetic mechanisms involved in the production of this class of secondary metabolites.

scholarly journals Engineering the Substrate Specificity of a Thermophilic Penicillin Acylase from Thermus thermophilus

2012 ◽  
Vol 79 (5) ◽  
pp. 1555-1562 ◽  
Author(s):  
Leticia L. Torres ◽  
Ángel Cantero ◽  
Mercedes del Valle ◽  
Anabel Marina ◽  
Fernando López-Gallego ◽  
...  
Keyword(s):  
Thermus Thermophilus ◽  
Three Dimensional ◽  
Catalytic Efficiency ◽  
Binding Pocket ◽  
Penicillin Acylase ◽  
Penicillin G ◽  
Content Type ◽  
Marked Preference ◽  
Three Dimensional Models ◽  
Phenylalanine Residue

ABSTRACTA homologue of theEscherichia colipenicillin acylase is encoded in the genomes of several thermophiles, including in differentThermus thermophilusstrains. Although the natural substrate of this enzyme is not known, this acylase shows a marked preference for penicillin K over penicillin G. Three-dimensional models were created in which the catalytic residues and the substrate binding pocket were identified. Through rational redesign, residues were replaced to mimic the aromatic binding site of theE. colipenicillin G acylase. A set of enzyme variants containing between one and four amino acid replacements was generated, with altered catalytic properties in the hydrolyses of penicillins K and G. The introduction of a single phenylalanine residue in position α188, α189, or β24 improved theKmfor penicillin G between 9- and 12-fold, and the catalytic efficiency of these variants for penicillin G was improved up to 6.6-fold. Structural models, as well as docking analyses, can predict the positioning of penicillins G and K for catalysis and can demonstrate how binding in a productive pose is compromised when more than one bulky phenylalanine residue is introduced into the active site.

scholarly journals Characterization of DprE1-Mediated Benzothiazinone Resistance in Mycobacterium tuberculosis

2016 ◽  
Vol 60 (11) ◽  
pp. 6451-6459 ◽  
Author(s):  
Caroline Shi-Yan Foo ◽  
Benoit Lechartier ◽  
Gaëlle S. Kolly ◽  
Stefanie Boy-Röttger ◽  
João Neres ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Ex Vivo ◽  
Covalent Binding ◽  
Catalytic Efficiency ◽  
Site Directed Mutagenesis ◽  
Lower Growth ◽  
Content Type ◽  
Covalent Inhibitors ◽  
Killing Action

ABSTRACTBenzothiazinones (BTZs) are a class of compounds found to be extremely potent against both drug-susceptible and drug-resistantMycobacterium tuberculosisstrains. The potency of BTZs is explained by their specificity for their target decaprenylphosphoryl-d-ribose oxidase (DprE1), in particular by covalent binding of the activated form of the compound to the critical cysteine 387 residue of the enzyme. To probe the role of C387, we used promiscuous site-directed mutagenesis to introduce other codons at this position intodprE1ofM. tuberculosis. The resultant viable BTZ-resistant mutants were characterizedin vitro,ex vivo, and biochemically to gain insight into the effects of these mutations on DprE1 function and onM. tuberculosis. Five different mutations (C387G, C387A, C387S, C387N, and C387T) conferred various levels of resistance to BTZ and exhibited different phenotypes. The C387G and C387N mutations resulted in a lower growth rate of the mycobacterium on solid medium, which could be attributed to the significant decrease in the catalytic efficiency of the DprE1 enzyme. All five mutations rendered the mycobacterium less cytotoxic to macrophages. Finally, differences in the potencies of covalent and noncovalent DprE1 inhibitors in the presence of C387 mutations were revealed by enzymatic assays. As expected from the mechanism of action, the covalent inhibitor PBTZ169 only partially inhibited the mutant DprE1 enzymes compared to the near-complete inhibition with a noncovalent DprE1 inhibitor, Ty38c. This study emphasizes the importance of the C387 residue for DprE1 activity and for the killing action of covalent inhibitors such as BTZs and other recently identified nitroaromatic inhibitors.

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