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      Demystifying racemic natural products in the homochiral world

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          Abstract

          Natural products possess structural complexity, diversity and chirality with attractive functions and biological activities that have significantly impacted drug discovery initiatives. Chiral natural products are abundant in nature but rarely occur as racemates. The occurrence of natural products as racemates is very intriguing from a biosynthetic point of view; as enzymes are chiral molecules, enzymatic reactions generating natural products should be stereospecific and lead to single-enantiomer products. Despite several reports in the literature describing racemic mixtures of stereoisomers isolated from natural sources, there has not been a comprehensive review of these intriguing racemic natural products. The discovery of many more natural racemates and their potential enzymatic sources in recent years allows us to describe the distribution and chemical diversity of this ‘class of natural products’ to enrich discussions on biosynthesis. In this Review, we describe the chemical classes, occurrence and distribution of pairs of enantiomers in nature and provide insights about recent advances in analytical methods used for their characterization. Special emphasis is on the biosynthesis, including plausible enzymatic and non-enzymatic formation of natural racemates, and their pharmacological significance.

          Abstract

          Racemic natural products display a wealth of bioactivities and chemical diversity. Their derivation from intriguing racemization processes, through enzymatic or non-enzymatic pathways, are discussed here, as well as their pharmacological properties and the analytical techniques developed for their identification, resolution and characterization.

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          Most cited references180

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          X-ray analysis on the nanogram to microgram scale using porous complexes.

          X-ray single-crystal diffraction (SCD) analysis has the intrinsic limitation that the target molecules must be obtained as single crystals. Here we report a protocol for SCD analysis that does not require the crystallization of the sample. In our method, tiny crystals of porous complexes are soaked in a solution of the target, such that the complexes can absorb the target molecules. Crystallographic analysis clearly determines the absorbed guest structures along with the host frameworks. Because the SCD analysis is carried out on only one tiny crystal of the complex, the required sample mass is of the nanogram-microgram order. We demonstrate that as little as about 80 nanograms of a sample is enough for the SCD analysis. In combination with high-performance liquid chromatography, our protocol allows the direct characterization of multiple fractions, establishing a prototypical means of liquid chromatography SCD analysis. Furthermore, we unambiguously determined the structure of a scarce marine natural product using only 5 micrograms of the compound.
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            Stereoselective bimolecular phenoxy radical coupling by an auxiliary (dirigent) protein without an active center.

            The regio- and stereospecificity of bimolecular phenoxy radical coupling reactions, of especial importance in lignin and lignan biosynthesis, are clearly controlled in some manner in vivo; yet in vitro coupling by oxidases, such as laccases, only produce racemic products. In other words, laccases, peroxidases, and comparable oxidases are unable to control regio- or stereospecificity by themselves and thus some other agent must exist. A 78-kilodalton protein has been isolated that, in the presence of an oxidase or one electron oxidant, effects stereoselective bimolecular phenoxy radical coupling in vitro. Itself lacking a catalytically active (oxidative) center, its mechanism of action is presumed to involve capture of E-coniferyl alcohol-derived free-radical intermediates, with consequent stereoselective coupling to give (+)-pinoresinol.
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              High-resolution structure determination by continuous rotation data collection in MicroED

              MicroED uses very small three-dimensional protein crystals and electron diffraction for structure determination. An improved data collection protocol for MicroED called “continuous rotation” is presented. Here microcrystals are continuously rotated during data collection yielding improved data, and allowing data processing with MOSFLM resulting in improved resolution for the model protein lysozyme. These improvements pave the way for the implementation and application of MicroED with wide applicability in structural biology.
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                Author and article information

                Contributors
                s.fobofou@tu-braunschweig.de
                Journal
                Nat Rev Chem
                Nat Rev Chem
                Nature Reviews. Chemistry
                Nature Publishing Group UK (London )
                2397-3358
                14 October 2022
                : 1-17
                Affiliations
                [1 ]Agrobiosciences, Mohamed IV Polytechnic University, Ben-Guerir, Morocco
                [2 ]GRID grid.418374.d, ISNI 0000 0001 2227 9389, Plant Sciences and Bioeconomy, , Rothamsted Research, ; Harpenden, UK
                [3 ]GRID grid.8201.b, ISNI 0000 0001 0657 2358, Department of Chemistry, , University of Dschang, ; Dschang, Cameroon
                [4 ]GRID grid.10604.33, ISNI 0000 0001 2019 0495, Department of Chemistry, , University of Nairobi, ; Nairobi, Kenya
                [5 ]GRID grid.11348.3f, ISNI 0000 0001 0942 1117, Institute of Chemistry, , University of Potsdam, ; Potsdam-Golm, Germany
                [6 ]GRID grid.6738.a, ISNI 0000 0001 1090 0254, Institute of Pharmaceutical Biology, , Technische Universität Braunschweig, ; Braunschweig, Germany
                [7 ]GRID grid.39382.33, ISNI 0000 0001 2160 926X, Department of Pathology and Immunology, , Baylor College of Medicine, ; Houston, TX USA
                [8 ]GRID grid.416975.8, ISNI 0000 0001 2200 2638, Texas Children’s Microbiome Center, Department of Pathology, , Texas Children’s Hospital, ; Houston, TX USA
                Article
                431
                10.1038/s41570-022-00431-4
                9562063
                36259059
                cf8809aa-f59f-49f8-a715-7be97c184742
                © Springer Nature Limited 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                Categories
                Review Article

                structure elucidation,biosynthesis,natural products,pharmacology

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