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Flavin-adenine-dinucleotide gold complex nanoparticles: chemical modeling design, physico-chemical assessment and perspectives in nanomedicine.

ABSTRACT: Flavoproteins play an important role in the regulatory process of cell life, and they are involved in several redox reactions that regulate the metabolism of carbohydrates, amino acids, and lipids. The development of effective drug delivery systems is one of the major challenges in the fight against cancer. This study involves a nanomedicine pathway to encapsulate the cofactor flavin adenine dinucleotide (FAD) using polymeric gold nanoparticles (PEG-AuNPs) through two chemical methods of functionalization (chelation (IN); carbodiimide chemistry (ON)). These hybrid gold nanoparticles and their precursors were characterized by analytical techniques (Raman, UV-Vis, and H¹-NMR spectroscopy and transmission electron microscopy (TEM)) which confirmed the grafting of the cofactor agent. The results of the computational studies (Density Functional Theory (DFT)) were in agreement with the experimental observations. We also monitored the interaction of our hybrid nanoparticle systems with small aptamers (APT) in order to validate the hypotheses on the biomolecular mechanisms and also investigate their biological efficiency on pancreatic cancer cells (MIAPaCa-2 cells).

SUBMITTER: Arib C

PROVIDER: S-EPMC9418941 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Flavin-adenine-dinucleotide gold complex nanoparticles: chemical modeling design, physico-chemical assessment and perspectives in nanomedicine.

Arib Celia C Bouchemal Nadia N Barile Maria M Paleni Didier D Djaker Nadia N Dupont Nathalie N Spadavecchia Jolanda J

Nanoscale advances 20210819 21

Flavoproteins play an important role in the regulatory process of cell life, and they are involved in several redox reactions that regulate the metabolism of carbohydrates, amino acids, and lipids. The development of effective drug delivery systems is one of the major challenges in the fight against cancer. This study involves a nanomedicine pathway to encapsulate the cofactor flavin adenine dinucleotide (FAD) using polymeric gold nanoparticles (PEG-AuNPs) through two chemical methods of functio ...[more]

PMID: 36133939

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Project description:Xantholipin (compound 1), a polycyclic xanthone antibiotic, exhibited strong antibacterial activities and showed potent cytotoxicity. The biosynthetic gene cluster of compound 1 has been identified in our previous work, and the construction of xanthone nucleus has been well demonstrated. However, limited information of the halogenation involved in compound 1 biosynthesis is available. In this study, based on the genetic manipulation and biochemical assay, we characterized XanH as an indispensable flavin adenine dinucleotide (FAD)-dependent halogenase (FDH) for the biosynthesis of compound 1. XanH was found to be a bifunctional protein capable of flavin reduction and chlorination and exclusively used the NADH. However, the reduced flavin could not be fully and effectively utilized, and the presence of an extra flavin reductase (FDR) and chemical-reducing agent could promote the halogenation. XanH accepted its natural free-standing substrate with angular fused polycyclic aromatic systems. Meanwhile, it exhibited moderate halogenation activity and possessed high substrate specificity. The requirement of extra FDR for higher halogenation activity is tedious for future engineering. To facilitate efforts in engineering XanH derivative proteins, we constructed the self-sufficient FDR-XanH fusion proteins. The fusion protein E1 with comparable activities to that of XanH could be used as a good alternative for future protein engineering. Taken together, these findings reported here not only improve the understanding of polycyclic xanthones biosynthesis but also expand the substrate scope of FDH and pave the way for future engineering of biocatalysts for new active substance synthesis.IMPORTANCE Halogenation is important in medicinal chemistry and plays an essential role in the biosynthesis of active secondary metabolites. Halogenases have evolved to catalyze reactions with high efficiency and selectivity, and engineering efforts have been made to engage the selective reactivity in natural product biosynthesis. The enzymatic halogenations are an environmentally friendly approach with high regio- and stereoselectivity, which make it a potential complement to organic synthesis. FDHs constitute one of the most extensively elucidated class of halogenases; however, the inventory awaits to be expanded for biotechnology applications and for the generation of halogenated natural product analogues. In this study, XanH was found to reduce flavin and halogenated the freely diffusing natural substrate with an angular fused hexacyclic scaffold, findings which were different from those for the exclusively studied FDHs. Moreover, the FDR-XanH fusion protein E1 with comparable reactivity to that of XanH serves as a successful example of genetic fusions and sets an important stage for future protein engineering.

Dataset Information

Flavin-adenine-dinucleotide gold complex nanoparticles: chemical modeling design, physico-chemical assessment and perspectives in nanomedicine.

Publications

Flavin-adenine-dinucleotide gold complex nanoparticles: chemical modeling design, physico-chemical assessment and perspectives in nanomedicine.

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