SYNTHESIS REPERTORY.PDF
Beatris Ninh
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Thus, laccases and/or laccase-mediator systems find potential applications in bioremediation, paper pulp bleaching, finishing of textiles, bio-fuel cells and more. Significantly, laccases can be used in organic synthesis, as they can perform exquisite transformations ranging from the oxidation of functional groups to the heteromolecular coupling for production of new antibiotics derivatives, or the catalysis of key steps in the synthesis of complex natural products. In this review, the application of fungal laccases and their engineering by rational design and directed evolution for organic synthesis purposes are discussed.
As mentioned above, many of these applications require the use of redox mediators opening a big window for new biotransformations of non-natural substrates towards which laccase alone hardly shows activity. On the other hand, in most of the cases large quantities of enzymes are required, which makes the efficient expression of laccase in heterologous systems an important issue. Moreover, the protein engineering of fungal laccases with the aim of improving several enzymatic features (such as activity towards new substrates, stability under harsh operating conditions -e.g. presence of organic cosolvents, extreme pH values-, thermostability, and others) is a critical point in the successful application of this remarkable biocatalyst. All these issues are addressed in the following lines, paying special attention to their application in organic synthesis.
It is well known that most of the laccase catalysed transformations for organic syntheses (from the oxidation of steroid hormones to the enzymatic polymerisation required for the synthesis of phenolic-based resins such as poly-α-naphtol, poly-pyrogallol and poly-catechol [1, 115]., as well as conductive water-soluble polymers [116]) must be carried out in the presence of organic solvents. However, at high concentrations of organic co-solvents laccases undergo unfolding, therefore losing their catalytic activity. Recently, our group generated a thermostable laccase-the genetic product of five rounds of directed evolution expressed in S. cerevisiae [117, 118]-that tolerates high concentrations of co-solvents. This evolved laccase mutant is capable of resisting a wide array of biotechnologically relevant miscible co-solvents at concentrations as high as 50% (v/v). Indeed, in 40% (v/v) ethanol or in 30% (v/v) acetonitrile the performance of the laccase mutant was comparable to that of the parental enzyme in aqueous solution, a capacity that has not been acquired in nature. Intrinsic electrochemical laccase features such as the redox potential at the T1 and T2/T3 sites and the geometry and electronic structure of the catalytic coppers varied slightly during the course of the in vitro evolution. Indeed, some mutations at the protein surface stabilized the evolved laccase by allowing additional electrostatic and hydrogen-bonding to occur [117]. Additionally, the protein folding in the post-translational maturation steps seemed to be modified by mutations in processing regions [119].
Organic synthesis of chemicals suffers from several drawbacks, including the high cost of chemicals, cumbersome multi-step reactions and toxicity of reagents [2, 17]. Laccases might prove to be very useful in synthetic chemistry, where they have been proposed to be applicable for production of complex polymers and medical agents [16, 121]. Indeed, the application of laccase in organic synthesis has arisen due to its broad substrate range, and the conversion of substrates to unstable free (cation) radicals that may undergo further non-enzymatic reactions such as polymerization or hydration. The list of laccases used for organic synthesis is presented in Table 2.
Enzymatic polymerization using laccases has drawn considerable attention recently since laccase or LMS are capable of generating straightforwardly polymers that are impossible to produce through conventional chemical synthesis [127].
It has been reported that laccase induced radical polymerization of acrylamide with or without mediator [146]. Laccase has been also used for the chemo-enzymatic synthesis of lignin graft-copolymers [153]. Along these lines, the potential of this enzyme for crosslinking and functionalizing lignocellulose compounds is also reported [154]. Laccases can be used in the enzymatic adhesion of fibers in the manufacturing of lignocellulose-based composite materials, such as fiber boards. In particular, laccase has been proposed to activate the fiberbound lignin during manufacturing of the composites, and boards with good mechanical properties without toxic synthetic adhesives have been obtained by using laccases [155, 156]. Another possibility is to functionalize lignocellulosic fibers by laccases in order to improve the chemical or physical properties of the fiber products. Preliminary results have shown that laccases are able to graft various phenolic acid derivatives onto kraft pulp fibers [157, 158]. This ability could be used in the future to attach chemically versatile compounds to the fiber surfaces, possibly resulting in fiber materials with completely novel properties, such as hydrophobicity or charge.
Other examples of the potential application of laccases for organic syntheses include the oxidative coupling of katarantine and vindoline to yield vinblastine. Vinblastine is an important anti-cancer drug, especially useful in the treatment of leukemia. Vinblastine is a natural product that may be extracted from the plant Catharanthus roseus. The compound is however only produced in small quantity in the plant, whereas the precursors-namely katarantine and vindoline- are at much higher concentrations, and thus are relatively inexpensive to obtain and purify. A method of synthesis has been developed through the use of laccase with preliminary results reaching 40% conversion of the precursors to vinblastine [2]. Laccase coupling has also resulted in the production of several other novel compounds that exhibit beneficial properties, e.g. antibiotic properties [163].
The use of laccases in organic synthesis does show as a promising green alternative to the classical chemical oxidation with a wide range of substrates. In the near future, the practical use of fungal laccases for troublesome transformations (digestion of lignocellulose to use as a carbon source; modifications of lignosulfonates for production of emulsifiers, surfactants and adhesives; synthesis of polymers with properties as redox films for bioelectronic devices; synthesis of antibiotics and much more) will expand the need for this biocatalyst. Meanwhile, the development of more robust fungal laccases tailored by protein engineering and the search for environment-friendly mediators along with further research on heterologous expression are significant hurdles that must be overcome.
Retrosynthesis aims to identify a set of appropriate reactants for the efficient synthesis of target molecules, which is indispensable and fundamental in computer-assisted synthetic planning1,2,3. Retrosynthetic analysis was formalized by Corey4,5,6 and solved by the Organic Chemical Simulation of Synthesis (OCSS) program. Later, driven by sizeable experimental reaction data and significantly increased computational capabilities, various machine-learning-based approaches7, especially deep-learning (DL) models, have been proposed and achieved incremental performance8.
In the early age of data-driven retrosynthesis, researchers primarily focused on developing template-based retrosynthesis approaches that rely on a reaction template to transform products into reactants9,10. Among these approaches, molecular fingerprints with the multi-layer perceptron are often used to encode molecular products and recommend reasonable templates. For instance, Segler et al.9. utilized extended-connectivity fingerprints (ECFPs)11 with an expansion policy network to guide the template search, whereas Chen et al.10. adopted a strategy similar to a single-step retrosynthesis predictor for their neural-guided multi-step planning. However, the process of constructing reaction templates currently relies on manual encoding or complex subgraph isomorphism, making it difficult to explore potential reaction templates in vast chemical space. To address these issues, template-free and semi-template methods have emerged as promising alternatives, utilizing molecular fingerprints to obtain molecular-level representations. Chen et al.12. introduced the FeedForward EBM (FF-EBM) method, complemented by template-free models. FF-EBM leverages the fingerprinting technique to prioritize potential precursors. In addition to molecular fingerprints, existing template-free and semi-template approaches can be generally categorized into two classes: (1) sequence-based approaches13,14,15 and (2) graph-based approaches16,17,18. The two classes of the method mainly differ in the strategies of molecular representations; the molecules are usually represented as linearized strings for sequence-based approaches13,14,15, and as molecular graph structures for graph-based approaches16,17,18.
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