The Dimer-of-Trimers Assembly Prevents Catalysis at the Transferase Site of Prokaryotic FAD Synthase

Lans, Isaías; Seco, Juan; Serrano, Ana; Burbano, Ricardo; Cossio, Pilar; Daza, Martha C.; Medina, Milagros

doi:10.1016/j.bpj.2018.08.011

Cited by 13 publications

(37 citation statements)

References 43 publications

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“…Moreover, it also leads to cross-talk between the RFK and FMNAT modules of neighboring protomers [72]. Research on energetically favored interactions of the FMNAT module of CaFADS by molecular docking and molecular dynamics simulations revealed that the RFK module negatively influences FMN binding at the interacting FMNAT module, weakening its activity [73]. Binding of FMN and ADP ligands triggers dramatic structural changes in the RFK module [71].…”

Section: Enzymes For the Biosynthesis Of Fmn And Fadmentioning

confidence: 99%

Production of riboflavin and related cofactors by biotechnological processes

Liu

Wang

et al. 2020

Microb Cell Fact

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Riboflavin (RF) and its active forms, the cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), have been extensively used in the food, feed and pharmaceutical industries. Modern commercial production of riboflavin is based on microbial fermentation, but the established genetically engineered production strains are facing new challenges due to safety concerns in the food and feed additives industry. High yields of flavin mononucleotide and flavin adenine dinucleotide have been obtained using whole-cell biocatalysis processes. However, the necessity of adding expensive precursors results in high production costs. Consequently, developing microbial cell factories that are capable of efficiently producing flavin nucleotides at low cost is an increasingly attractive approach. The biotechnological processes for the production of RF and its cognate cofactors are reviewed in this article.

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Section: Enzymes For the Biosynthesis Of Fmn And Fadmentioning

confidence: 99%

Production of riboflavin and related cofactors by biotechnological processes

Liu

Wang

et al. 2020

Microb Cell Fact

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“…Molecular modeling techniques based on force fields have been applied to study different aspects of flavins in solvent and in protein complexes . The major requirement for such computer simulations is the existence of an adequate molecular mechanics force field model.…”

Section: Introductionmentioning

confidence: 99%

A Molecular Mechanics Model for Flavins

Aleksandrov

2019

J Comput Chem

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Flavin containing molecules form a group of important cofactors that assist a wide range of enzymatic reactions. Flavins use the redox‐active isoalloxazine system, which is capable of one‐ and two‐electron transfer reactions and can exist in several protonation states. In this work, molecular mechanics force field parameters compatible with the CHARMM36 all‐atom additive force field were derived for biologically important flavins, including riboflavin, flavin mononucleotide, and flavin adenine dinucleotide. The model was developed for important protonation and redox states of the isoalloxazine group. The partial charges were derived using the CHARMM force field parametrization strategy, where quantum mechanics water–solute interactions are used to target optimization. In addition to monohydrate energies and geometries, electrostatic potential around the compound was used to provide additional restraints during the charge optimization. Taking into account the importance of flavin‐containing molecules special attention was given to the quality of bonded terms. All bonded terms, including stiff terms and torsion angle parameters, were parametrized using exhaustive potential energy surface scans. In particular, the model reproduces well the butterfly motion of isoalloxazine in the oxidized and reduced forms as predicted by quantum mechanics in gas phase. The model quality is illustrated by simulations of four flavoproteins. Overall, the presented molecular mechanics model will be of utility to model flavin cofactors in different redox states. © 2019 Wiley Periodicals, Inc.

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“…MD simulations of potential ligandreceptor complexes allows for a more accurate sampling of their conformational space. The [42]. The flexi-pharma number of votes for each molecule was used as a score to calculate the EPs.…”

Section: Plos Computational Biologymentioning

confidence: 99%

In silico discovery and biological validation of ligands of FAD synthase, a promising new antimicrobial target

et al. 2020

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New treatments for diseases caused by antimicrobial-resistant microorganisms can be developed by identifying unexplored therapeutic targets and by designing efficient drug screening protocols. In this study, we have screened a library of compounds to find ligands for the flavin-adenine dinucleotide synthase (FADS)-a potential target for drug design against tuberculosis and pneumonia-by implementing a new and efficient virtual screening protocol. The protocol has been developed for the in silico search of ligands of unexplored therapeutic targets, for which limited information about ligands or ligand-receptor structures is available. It implements an integrative funnel-like strategy with filtering layers that increase in computational accuracy. The protocol starts with a pharmacophore-based virtual screening strategy that uses ligand-free receptor conformations from molecular dynamics (MD) simulations. Then, it performs a molecular docking stage using several docking programs and an exponential consensus ranking strategy. The last filter, samples the conformations of compounds bound to the target using MD simulations. The MD conformations are scored using several traditional scoring functions in combination with a newly-proposed score that takes into account the fluctuations of the molecule with a Morse-based potential. The protocol was optimized and validated using a compound library with known ligands of the Corynebacterium ammoniagenes FADS. Then, it was used to find new FADS ligands from a compound library of 14,000 molecules. A small set of 17 in silico filtered molecules were tested experimentally. We identified five inhibitors of the activity of the flavin adenylyl transferase module of the FADS, and some of them were able to inhibit growth of three bacterial species: C. ammoniagenes, Mycobacterium tuberculosis, and Streptococcus pneumoniae, where the last two are human pathogens. Overall, the results show that the integrative VS protocol is a cost-effective solution for the discovery of ligands of unexplored therapeutic targets.

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The Dimer-of-Trimers Assembly Prevents Catalysis at the Transferase Site of Prokaryotic FAD Synthase

Cited by 13 publications

References 43 publications

Production of riboflavin and related cofactors by biotechnological processes

Production of riboflavin and related cofactors by biotechnological processes

A Molecular Mechanics Model for Flavins

In silico discovery and biological validation of ligands of FAD synthase, a promising new antimicrobial target

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