{"id":4927,"date":"2020-01-07T19:22:31","date_gmt":"2020-01-07T10:22:31","guid":{"rendered":"http:\/\/163.180.4.222\/lab\/?p=4927"},"modified":"2020-01-07T19:22:31","modified_gmt":"2020-01-07T10:22:31","slug":"peptidic-catalysts-for-macrocycle-synthesis","status":"publish","type":"post","link":"https:\/\/biochemistry.khu.ac.kr\/lab\/?p=4927","title":{"rendered":"Peptidic catalysts for macrocycle synthesis"},"content":{"rendered":"

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Many structurally simplified catalysts have been synthesized that mimic the reactivity and efficiency of enzymes. In this context, the numerous transformations catalyzed by the amino acid proline as a catalytic-site mimic helped drive the field of organocatalysis (1<\/em><\/a>). Enzyme activity not only relies on the reactive site but also on the structure of the binding pocket that can orient and twist substrates for reactions. Oligopeptide catalysts, often referred to as foldamers (2<\/em><\/a>), can emulate both the reactivity and substrate positioning and folding of enzymes by using the secondary peptide structure such as \u03b1-helices or \u03b2-turns. On page 1528 of this issue, Girvin\u00a0et al.<\/em>\u00a0(3<\/em><\/a>) translate enzymatic synthesis of large rings (macrocycles) into a heptapeptide foldamer catalyst that performs an intramolecular aldol condensation (see the figure).<\/p>\n

Oligopeptides are short sequences of amino acids that can be designed to self-assemble in a stable secondary structure so that particular side chains can be positioned to become the reactive catalyst sites. The power of this foldamer-template principle has been demonstrated in ample studies from the Miller group, such as the use of chiral peptide catalysts in the site-selective structural modification of the complex natural product erythromycin A by Lewis and Miller (4<\/em><\/a>) or by M\u00fcller\u00a0et al.<\/em>\u00a0for retro aldol reactions of \u03b2-hydroxyketones (5<\/em><\/a>). Foldamer design can also take advantage of amino acids that bear unnatural side chains to introduce reactive groups beyond those in the enzymatic repertoire and thus extend the scope of addressable transformations compared with those offered by nature.<\/p>\n

The synthesis of macrocycles is an example of a very challenging reaction for chemists (6<\/em><\/a>) because it is usually disfavored entropically. Although the enzymatic reaction only takes place in a specific region of the enzyme, the entire protein plays an important role. The complex conformation of enzymes forces the linear starting material (such as molecule\u00a02<\/strong>\u00a0in the figure) into a certain conformation inside the enzyme-substrate complex. This step mitigates the energetic demand of the intramolecular reaction and favors cyclization over intermolecular processes. However, the structural complexity of proteins that enables this functionality and selectivity also makes enzymes substrate-specific and hampers their broad applicability as ring-closure catalysts.<\/p>\n

Girvin\u00a0et al.<\/em>\u00a0designed the heptapeptide\u00a01<\/strong>\u00a0macrocyclization catalyst to hold the two amine functionalities in place for an intramolecular aldol condensation reaction (see the figure). The foldamer is composed of \u03b1 and \u03b2 amino acid residues in an \u03b1\u03b2\u03b2 sequence that forms a stable three-dimensional backbone to put the reactive amine moieties in a concise orientation relative to one another. The authors examined the impact of the geometry and the spatial separation of the reactive diad on the transformation and found that the optimal geometry is a helix, with three amino acids per turn and with the catalytically active functionalities separated exactly by one turn. In this case, the amine moieties are optimally aligned for the foldamer to act as a molecular tweezer that pulls together both ends of the dialdehyde\u00a02<\/strong>.<\/p>\n

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