Biochemical and biophysical characterization of 1,4-naphthoquinone as a dual inhibitor of two key enzymes of type II fatty acid biosynthesis from Moraxella catarrhalis

Kumar, Vijay; Sharma, Anchal; Pratap, Shivendra; Kumar, Pravindra

doi:10.1016/j.bbapap.2018.08.008

Cited by 11 publications

(11 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This activity is instead provided by the endogenous FAS MAT (12)(13)(14). The central catalytic role of PKS and FAS MATs makes them attractive candidates for metabolic engineering and as targets for the development of new therapeutics (15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Interfacial plasticity facilitates high reaction rate of E. coli FAS malonyl-CoA:ACP transacylase, FabD

Misson

Mindrebo

Davis

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Fatty acid synthases (FASs) and polyketide synthases (PKSs) iteratively elongate and often reduce two-carbon ketide units in de novo fatty acid and polyketide biosynthesis. Cycles of chain extensions in FAS and PKS are initiated by an acyltransferase (AT), which loads monomer units onto acyl carrier proteins (ACPs), small, flexible proteins that shuttle covalently linked intermediates between catalytic partners. Formation of productive ACP–AT interactions is required for catalysis and specificity within primary and secondary FAS and PKS pathways. Here, we use the Escherichia coli FAS AT, FabD, and its cognate ACP, AcpP, to interrogate type II FAS ACP–AT interactions. We utilize a covalent crosslinking probe to trap transient interactions between AcpP and FabD to elucidate the X-ray crystal structure of a type II ACP–AT complex. Our structural data are supported using a combination of mutational, crosslinking, and kinetic analyses, and long-timescale molecular dynamics (MD) simulations. Together, these complementary approaches reveal key catalytic features of FAS ACP–AT interactions. These mechanistic inferences suggest that AcpP adopts multiple, productive conformations at the AT binding interface, allowing the complex to sustain high transacylation rates. Furthermore, MD simulations support rigid body subdomain motions within the FabD structure that may play a key role in AT activity and substrate selectivity.

show abstract

mentioning

confidence: 99%

Interfacial plasticity facilitates high reaction rate of E. coli FAS malonyl-CoA:ACP transacylase, FabD

Misson

Mindrebo

Davis

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Although FabD is a vital enzyme and a potential target for ATM drug discovery [ 33 , 34 , 35 ], there is still no established inhibitor of this enzyme.…”

Section: Fas-ii Enzymes and Their Corresponding Inhibitorsmentioning

confidence: 99%

A Review of Fatty Acid Biosynthesis Enzyme Inhibitors as Promising Antimicrobial Drugs

et al. 2023

View full text Add to dashboard Cite

Resistance to antimicrobial drugs is currently a serious threat to human health. Consequently, we are facing an urgent need for new antimicrobial drugs acting with original modes of action. The ubiquitous and widely conserved microbial fatty acid biosynthesis pathway, called FAS‑II system, represents a potential target to tackle antimicrobial resistance. This pathway has been extensively studied, and eleven proteins have been described. FabI (or InhA, its homologue in mycobacteria) was considered as a prime target by many teams and is currently the only enzyme with commercial inhibitor drugs: triclosan and isoniazid. Furthermore, afabicin and CG400549, two promising compounds which also target FabI, are in clinical assays to treat Staphylococcus aureus. However, most of the other enzymes are still underexploited targets. This review, after presenting the FAS-II system and its enzymes in Escherichia coli, highlights the reported inhibitors of the system. Their biological activities, main interactions formed with their targets and structure–activity relationships are presented as far as possible.

show abstract

“…(b) Circular dichroism based studies: (a) the far‐UV and (b) near‐UV circular dichroism (CD) spectra of McFabD under the native condition and different concentrations of naphthoquinone (NPQ). (c) The far‐UV and (d) near‐UV CD spectra of McFabZ under the native condition and different amounts of naphthoquinone (NPQ) (Kumar et al., 2018a). (c) A cartoon illustration of some bacterial mechanisms for positioning Z‐ring during cell division (Hurley et al., 2016).…”

Section: Antimicrobial Mechanism Of Plant Byproduct Compoundsmentioning

confidence: 99%

Inhibitory mechanisms of promising antimicrobials from plant byproducts: A review

Qian

Ismail

et al. 2023

Comp Rev Food Sci Food Safe

View full text Add to dashboard Cite

Plant byproducts and waste present enormous environmental challenges and an opportunity for valorization and industrial application. Due to consumer demands for natural compounds, the evident paucity of novel antimicrobial agents against foodborne pathogens, and the urgent need to improve the arsenal against infectious diseases and antimicrobial resistance (AMR), plant byproduct compounds have attracted significant research interest. Emerging research highlighted their promising antimicrobial activity, yet the inhibitory mechanisms remain largely unexplored. Therefore, this review summarizes the overall research on the antimicrobial activity and inhibitory mechanisms of plant byproduct compounds. A total of 315 natural antimicrobials from plant byproducts, totaling 1338 minimum inhibitory concentrations (MIC) (in μg/mL) against a broad spectrum of bacteria, were identified, and a particular emphasis was given to compounds with high or good antimicrobial activity (typically <100 μg/mL MIC). Moreover, the antimicrobial mechanisms, particularly against bacterial pathogens, were discussed in-depth, summarizing the latest research on using natural compounds to combat pathogenic microorganisms and AMR. Furthermore, safety concerns, relevant legislation, consumer perspective, and current gaps in the valorization of plant byproducts-derived compounds were comprehensively discussed. This comprehensive review covering up-to-date information on antimicrobial activity and mechanisms represents a powerful tool for screening and selecting the most promising plant byproduct compounds and sources for developing novel antimicrobial agents. K E Y W O R D S antimicrobial resistance, bacterial pathogens, inhibitory mechanisms, natural antimicrobial agents, plant byproducts Mengyan Qian and Balarabe B. Ismail contributed equally to this work.

show abstract

Biochemical and biophysical characterization of 1,4-naphthoquinone as a dual inhibitor of two key enzymes of type II fatty acid biosynthesis from Moraxella catarrhalis

Cited by 11 publications

References 51 publications

Interfacial plasticity facilitates high reaction rate of E. coli FAS malonyl-CoA:ACP transacylase, FabD

Interfacial plasticity facilitates high reaction rate of E. coli FAS malonyl-CoA:ACP transacylase, FabD

A Review of Fatty Acid Biosynthesis Enzyme Inhibitors as Promising Antimicrobial Drugs

Inhibitory mechanisms of promising antimicrobials from plant byproducts: A review

Contact Info

Product

Resources

About