Multisubstrate adduct inhibitors: Drug design and biological tools

Calvez, P.B. Le; Scott, Christopher J.; Migaud, Marie E.

doi:10.3109/14756360902843809

Cited by 9 publications

(8 citation statements)

References 213 publications

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“…Moreover, the multienzyme complex provides the opportunity to make a multiligand inhibitor that incorporates both biotin carboxylase and carboxyltransferase inhibitors. Not only would an acetyl-CoA carboxylase multiligand inhibitor be potentially more potent than either of the individual ligands, but a multiligand antibacterial agent would also lower the likelihood of pathogenic bacteria developing resistance. − …”

Section: Discussionmentioning

confidence: 99%

Complex Formation and Regulation of Escherichia coli Acetyl-CoA Carboxylase

et al. 2013

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Acetyl-CoA carboxylase is a biotin-dependent enzyme that catalyzes the regulated step in fatty acid synthesis. The bacterial form has three separate components: biotin carboxylase, biotin carboxyl carrier protein (BCCP), and carboxyltransferase. Catalysis by acetyl-CoA carboxylase proceeds via two half-reactions. In the first half-reaction, biotin carboxylase catalyzes the ATP-dependent carboxylation of biotin, which is covalently attached to BCCP, to form carboxybiotin. In the second half-reaction, carboxyltransferase transfers the carboxyl group from carboxybiotin to acetyl-CoA to form malonyl-CoA. All biotin-dependent carboxylases are proposed to have a two-site ping-pong mechanism in which the carboxylase and transferase activities are separate and do not interact. This posits two hypotheses: either biotin carboxylase and BCCP undergo the first half-reaction, BCCP dissociates, and then BCCP binds to carboxyltransferase, or all three constituents form an enzyme complex. To determine which hypothesis is correct, a steady-state enzyme kinetic analysis of Escherichia coli acetyl-CoA carboxylase was conducted. The results indicated the two active sites of acetyl-CoA carboxylase interact. Both in vitro and in vivo pull-down assays demonstrated that the three components of E. coli acetyl-CoA carboxylase form a multimeric complex and that complex formation is unaffected by acetyl-CoA, AMPPNP, and mRNA encoding carboxyltransferase. The implications of these findings for the regulation of acetyl-CoA carboxylase and fatty acid biosynthesis are discussed.

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Section: Discussionmentioning

confidence: 99%

Complex Formation and Regulation of Escherichia coli Acetyl-CoA Carboxylase

et al. 2013

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“…The reaction proceeds via nucleophilic attack by the 5'-phosphate of the mononucleotide (NMN or NaMN) on the -phosphate of ATP, resulting in a pentacoordinated transition state that ultimately gives rise to NAD/NaAD and inorganic pyrophosphate (PPi) [30,31].…”

Section: Introductionmentioning

confidence: 99%

NMN/NaMN Adenylyltransferase (NMNAT) and NAD Kinase (NADK) Inhibitors: Chemistry and Potential Therapeutic Applications

Petrelli

Felczak

Cappellacci

2011

CMC

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Nicotinamide adenine dinucleotide (NAD(+)) has a crucial role in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Thus, enzymes involved in NAD(+) metabolism are attractive targets for drug discovery against a variety of human diseases. Herein we focus on two of them: NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK). NMNAT is a key enzyme in all organisms catalyzing coupling of ATP and NMN or NaMN yielding NAD or NaAD, respectively. NADKs are ubiquitous enzymes involved in the last step of the biosynthesis of NADP. They phosphorylate NAD to produce NADP using ATP (or inorganic polyphosphates) in the presence of Mg(2+). No other pathway of NADP biosynthesis has been found in prokaryotic or eukaryotic cells. In this review we provide a comprehensive summary of NMNAT and NADK inhibitors highlighting their chemical modifications by different synthetic approaches, and structure-activity relationships depending on their potential therapeutic applications.

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“…We identified a list of compounds including ZINC95543764 and ZINC20057784, which can efficiently bind to the active site of the enzyme. It is important to note that a scarce number of KdsA inhibitors have so far been reported (Du et al, 1999;Birck et al, 2000;Grison et al, 2005;Le Calvez et al, 2009;Harrison et al, 2012;Smyth and Marchant, 2013). We provided an insight on the molecular nature of binding interactions.…”

Section: Resultsmentioning

confidence: 84%

“…The KdsA from different pathogens has been so far proposed as the putative drug targets through in silico studies such as metabolic pathway analysis (Perumal et al, 2007;Rath et al, 2016), multi-omics approach (Ramos et al, 2018), subtractive genomics (Amineni et al, 2010), and subtractive proteomics (Ahmad et al, 2018b) as well as through in vitro studies (Perumal et al, 2010). Moreover, several Kdo inhibitors with a limited in vivo activity, despite their promising in vitro applications, have been developed (Du et al, 1999;Birck et al, 2000;Grison et al, 2005;Le Calvez et al, 2009;Harrison et al, 2012;Smyth and Marchant, 2013). These inhibitors were reported to be useful for inhibition of the KdsA activity in different bacteria.…”

Section: Analysis Of the Prioritized Drug Targetsmentioning

confidence: 99%

Network-Based Metabolism-Centered Screening of Potential Drug Targets in Klebsiella pneumoniae at Genome Scale

Cesur

Siraj

Uddin

et al. 2020

Front. Cell. Infect. Microbiol.

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Klebsiella pneumoniae is an opportunistic bacterial pathogen leading to life-threatening nosocomial infections. Emergence of highly resistant strains poses a major challenge in the management of the infections by healthcare-associated K. pneumoniae isolates. Thus, despite intensive efforts, the current treatment strategies remain insufficient to eradicate such infections. Failure of the conventional infection-prevention and treatment efforts explicitly indicates the requirement of new therapeutic approaches. This prompted us to systematically analyze the K. pneumoniae metabolism to investigate drug targets. Genome-scale metabolic networks (GMNs) facilitating the systematic analysis of the metabolism are promising platforms. Thus, we used a GMN of K. pneumoniae MGH 78578 to determine putative targets through gene-and metabolite-centric approaches. To develop more realistic infection models, we performed the bacterial growth simulations within different host-mimicking media, using an improved biomass formation reaction. We selected more suitable targets based on several property-based prioritization procedures. KdsA was identified as the high-ranked putative target satisfying most of the target prioritization criteria specified under the gene-centric approach. Through a structure-based virtual screening protocol, we identified potential KdsA inhibitors. In addition, the metabolite-centric approach extended the drug target list based on synthetic lethality. This revealed the importance of combined metabolic analyses for a better understanding of the metabolism. To our knowledge, this is the first comprehensive effort on the investigation of the K. pneumoniae metabolism for drug target prediction through the constraint-based analysis of its GMN in conjunction with several bioinformatic approaches. This study can guide the researchers for the future drug designs by providing initial findings regarding crucial components of the Klebsiella metabolism.

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Multisubstrate adduct inhibitors: Drug design and biological tools

Cited by 9 publications

References 213 publications

Complex Formation and Regulation of Escherichia coli Acetyl-CoA Carboxylase

Complex Formation and Regulation of Escherichia coli Acetyl-CoA Carboxylase

NMN/NaMN Adenylyltransferase (NMNAT) and NAD Kinase (NADK) Inhibitors: Chemistry and Potential Therapeutic Applications

Network-Based Metabolism-Centered Screening of Potential Drug Targets in Klebsiella pneumoniae at Genome Scale

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