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      Filamentation of the bacterial bi-functional alcohol/aldehyde dehydrogenase AdhE is essential for substrate channeling and enzymatic regulation

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          Abstract

          Acetaldehyde–alcohol dehydrogenase (AdhE) enzymes are a key metabolic enzyme in bacterial physiology and pathogenicity. They convert acetyl-CoA to ethanol via an acetaldehyde intermediate during ethanol fermentation in an anaerobic environment. This two-step reaction is associated to NAD + regeneration, essential for glycolysis. The bifunctional AdhE enzyme is conserved in all bacterial kingdoms but also in more phylogenetically distant microorganisms such as green microalgae. It is found as an oligomeric form called spirosomes, for which the function remains elusive. Here, we use cryo-electron microscopy to obtain structures of Escherichia coli spirosomes in different conformational states. We show that spirosomes contain active AdhE monomers, and that AdhE filamentation is essential for its activity in vitro and function in vivo. The detailed analysis of these structures provides insight showing that AdhE filamentation is essential for substrate channeling within the filament and for the regulation of enzyme activity.

          Abstract

          Acetaldehyde–alcohol dehydrogenase (AdhE) converts acetyl-CoA to ethanol and is a key enzyme in bacterial alcoholic fermentation. AdhE forms spirosomes and, here, the authors present the cryoEM structures of compact and extended E.coli AdhE spirosomes and show that the extended conformation is the catalytically active form of the enzyme and discuss mechanistic implications.

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          Most cited references 23

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          Protein-ligand binding site recognition using complementary binding-specific substructure comparison and sequence profile alignment.

          Identification of protein-ligand binding sites is critical to protein function annotation and drug discovery. However, there is no method that could generate optimal binding site prediction for different protein types. Combination of complementary predictions is probably the most reliable solution to the problem. We develop two new methods, one based on binding-specific substructure comparison (TM-SITE) and another on sequence profile alignment (S-SITE), for complementary binding site predictions. The methods are tested on a set of 500 non-redundant proteins harboring 814 natural, drug-like and metal ion molecules. Starting from low-resolution protein structure predictions, the methods successfully recognize >51% of binding residues with average Matthews correlation coefficient (MCC) significantly higher (with P-value <10(-9) in student t-test) than other state-of-the-art methods, including COFACTOR, FINDSITE and ConCavity. When combining TM-SITE and S-SITE with other structure-based programs, a consensus approach (COACH) can increase MCC by 15% over the best individual predictions. COACH was examined in the recent community-wide COMEO experiment and consistently ranked as the best method in last 22 individual datasets with the Area Under the Curve score 22.5% higher than the second best method. These data demonstrate a new robust approach to protein-ligand binding site recognition, which is ready for genome-wide structure-based function annotations. http://zhanglab.ccmb.med.umich.edu/COACH/
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            Bacterial microcompartments: their properties and paradoxes.

            Many bacteria conditionally express proteinaceous organelles referred to here as microcompartments (Fig. 1). These microcompartments are thought to be involved in a least seven different metabolic processes and the number is growing. Microcompartments are very large and structurally sophisticated. They are usually about 100-150 nm in cross section and consist of 10,000-20,000 polypeptides of 10-20 types. Their unifying feature is a solid shell constructed from proteins having bacterial microcompartment (BMC) domains. In the examples that have been studied, the microcompartment shell encases sequentially acting metabolic enzymes that catalyze a reaction sequence having a toxic or volatile intermediate product. It is thought that the shell of the microcompartment confines such intermediates, thereby enhancing metabolic efficiency and/or protecting cytoplasmic components. Mechanistically, however, this creates a paradox. How do microcompartments allow enzyme substrates, products and cofactors to pass while confining metabolic intermediates in the absence of a selectively permeable membrane? We suggest that the answer to this paradox may have broad implications with respect to our understanding of the fundamental properties of biological protein sheets including microcompartment shells, S-layers and viral capsids.
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              Bacterial microcompartments

              Bacterial microcompartments (BMCs) are self-assembling organelles that consist of an enzymatic core that is encapsulated by a selectively permeable protein shell. The potential to form BMCs is widespread, found across the Kingdom Bacteria. BMCs have crucial roles in carbon dioxide fixation in autotrophs and the catabolism of organic substrates in heterotrophs. They contribute to the metabolic versatility of bacteria, providing a competitive advantage in specific environmental niches. Although BMCs were first visualized more than sixty years ago, it is mainly in the last decade that progress has been made in understanding their metabolic diversity and the structural basis of their assembly and function. This progress has not only heightened our understanding of their role in microbial metabolism but it is also beginning to enable their use in a variety of applications in synthetic biology. In this Review, we focus on recent insights into the structure, assembly, diversity and function of BMCs. Bacterial microcompartments are self-assembling organelles that consist of an enzymatic core that is encapsulated by a selectively permeable protein shell. In this Review, Kerfeld and colleagues discuss recent insights into the structure, assembly, diversity and function of bacterial microcompartments.
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                Author and article information

                Contributors
                esther.marza@u-bordeaux.fr
                remi.fronzes@u-bordeaux.fr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                18 March 2020
                18 March 2020
                2020
                : 11
                Affiliations
                [1 ]ISNI 0000 0001 2106 639X, GRID grid.412041.2, Structure and Function of Bacterial Nanomachines – Institut Européen de Chimie et Biologie, , University of Bordeaux, ; 2 rue Robert Escarpit, 33600 Pessac, France
                [2 ]ISNI 0000 0001 2106 639X, GRID grid.412041.2, Microbiologie fondamentale et pathogénicité, UMR 5234, CNRS, , University of Bordeaux, ; 2 rue Robert Escarpit, 33600 Pessac, France
                [3 ]ISNI 0000 0001 2172 4233, GRID grid.25697.3f, UMR 5086 Molecular Microbiology and Structural Biochemistry, , Institut de Biologie et Chimie des Protéines, CNRS-Université de Lyon, ; Lyon, France
                [4 ]ISNI 0000 0004 5903 3819, GRID grid.418727.f, Present Address: UCB Celltech, ; Slough, SL1 3WE UK
                Article
                15214
                10.1038/s41467-020-15214-y
                7080775
                32188856
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                bacteria, biochemistry, enzymes, structural biology, applied microbiology

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