5 Key excerpts on "Enzyme Stereospecificity"

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  eBook - ePub

  Chemistry of Biomolecules, Second Edition

  • S. P. Bhutani(Author)
  • 2019(Publication Date)
  • CRC Press

    (Publisher)

  Enzymes permit reactions to take place in the living organisms which otherwise would not take place at an appreciable rate at ordinary temperature and may thereby exert a directive effect on the metabolism of the cell. For example, by accelerating certain pathways to a greater extent than others, they may virtually direct the mechanism along one of the possible routes.

  D.  Stereospecificity

  Many enzymes show stereospecificity, i.e., some enzymes act on only one of a pair of optical isomers. In addition some enzymes are involved in asymmetric syntheses producing only one of the two possible optical isomers. The following examples show stereospecificity among enzymes:

  (i)

  Arginase catalyses the hydrolysis of L-arginine to ornithine and urea.

  Arginase has, however, no effect on the rate of hydrolysis of D-arginine.

  (ii)

  Pyruvic acid is converted to lactic acid by two different enzymes, each producing only one of the optical isomers.

  (iii)

  Fumarase catalyses addition of water to fumarate to give malate whereas maleate remains unaffected.

  (iv)

  Glycerol is converted to L -phosphoglycerol by the enzyme glycerolkinase. Phosphate group comes from the ATP molecule.

  (v)

  During citric acid metabolism, a series of enzymatic reactions occur in which we observe the selective action of an enzyme on only one of two chemically identical groups in a compound. For example, oxaloacetic acid is converted to citric acid by the condensing enzyme. If the carboxyl group adjacent to the —CH2

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  eBook - ePub

  Asymmetric Synthesis of Drugs and Natural Products

  • Ahindra Nag, Ahindra Nag(Authors)
  • 2018(Publication Date)
  • CRC Press

    (Publisher)

  6 Use of Specific New Artificial or Semisynthetic Biocatalysts for Synthesis of Regio- and Enantioselective Compounds Marco Filice, Oscar Romero, and Jose M. Palomo

  CONTENTS 6.1Introduction 6.2Regioselective Preparation of Monodeprotected Esters 6.2.1Regioselective Monodeprotection of Peracetylated Carbohydrates 6.2.2Regioselective Preparation of Monodeprotected Nucleosides 6.3Regio- and Enantioselective Preparation of Chiral Alcohols and Amines 6.4Regioselective Artificial Hydrolase-Catalyzed C–C Bond Formation References

  6.1Introduction

  Enzymes are versatile biocatalysts and find increasing application in many areas, including organic synthesis. The major advantages of using enzymes in biotransformations are their chemo-, regio-, and stereoselectivity as well as the very mild reaction conditions that can be used, where the generation of the side products is minimized.1 , 2 , 3 Their stereoselectivity (the ability to selectively act on a single enantiomer) their regioselectivity (the possibility to recognize one position in a molecule), and, finally, their selectivity toward defined functional group among others quite similar in reactivity allowed distinguishing them precisely. Each type of selectivity shows advantages that can accrue to chemical processes because of the special properties of the enzymes.

  Indeed, regioselective and enantiomerically pure molecules are key compounds for many industrially relevant processes. The application of biocatalysts ranges from the synthesis of regio- and chiral intermediates (usually building blocks in drug chemistry), via

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  eBook - ePub

  Directory of Therapeutic Enzymes

  • Barry M. McGrath, Gary Walsh, Barry M. McGrath, Gary Walsh(Authors)
  • 2005(Publication Date)
  • CRC Press

    (Publisher)

  99 ]. These reports, suggest that evolving novel substrate specificities can be achieved using directed evolution in particular.

  2.3.3.4    Stereoselectivity

  The use of biocatalysts is increasing rapidly in many key industrial processes [14 ,32 ,174 ,193 ,194 ]. The ability to obtain high stereoselectivities, and hence enantiomerically pure compounds with biocatalysts is of key importance in the production of chemicals and key ingredients and products in the pharmaceutical and agrochemical industries. Large-scale industrial applications of biocatalysts include using lipases for the production of enantiopure alcohols and amides, esterases and amidases for enantiopure aas, nitrilases for the production of enantiopure carboxylic acids, and acylases for the production of new semisynthetic β-lactam antibiotics [8 ,9 ,16 ,164 ]. Many new developments are expected in this area in the years ahead [4 ,13 ,15 ].

  Many strategies have been used to control stereoselectivity during biocatalysis, including modifying the substrate or through solvent engineering, by changing the reaction conditions or by a combination of chemocatalysis and biocatalysis (reviewed in [195 ,196 ]). All these strategies do not involve modification of the biocatalyst. In contrast, genetic engineering approaches (rational design and directed evolution) alter the primary structure of the enzyme. Subtle changes in enzyme structure and even changes in reaction conditions can influence enantioselectivity [110 ]. Such changes are very difficult to predict however, and thus attempts at rationally engineering enantioselectivity are rare (see [174 ], for a review of rationally designed enantioselective enzymes). In contrast, directed evolution approaches have proven extremely successful in altering enantioselectivity [193 ], aided by the recent developments in high-throughput enantioselective screening systems [197 ,198 ,199 ]. Table 2.4 highlights some recent examples of altering enzyme enantioselectivity using a directed evolution approach together with high-throughput screening systems (see [193 ,200

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  eBook - ePub

  Protein Engineering Handbook

  • Stefan Lutz, Uwe Theo Bornscheuer(Authors)
  • 2012(Publication Date)
  • Wiley-VCH

    (Publisher)

  Chapter 13

  Assessing and Exploiting the Persistence of Substrate Ambiguity in Modern Protein Catalysts

  Kevin K. Desai and Brian G. Miller

  13.1 Quantitative Description of Enzyme Specificity

  A widely accepted tenet of biochemistry is that protein catalysts possess a remarkable level of specificity for their physiological substrates. Indeed, enzymes encounter a surfeit of potential substrates during their normal cellular lifespan, many of which possess overlapping functional groups. Common moieties such as phosphoryl groups, carboxylate side chains and hydroxyl substituents have the potential to complicate molecular recognition inside an active site. Despite the structural and electrostatic similarities of the multitude of metabolites found within a cell, enzymes are capable of selecting from this pool a single substrate for chemical transformation. In so doing, protein catalysts often recognize single atom differences between individual substrates. The discriminatory power of enzymes, which is a hallmark of biological catalysis, is rarely observed in the small-molecule catalytic counterparts that synthetic chemists employ on a daily basis. As a result, chemists and engineers have begun to explore the possibility that Nature’s own catalyst of choice could be subverted for the needs of humankind.

  The ability of enzymes to catalyze the chemical transformations of two competing substrates can be represented by the simple reaction schemes and corresponding rate equations shown below:

  (13.1)

  In Equation 13.1 , E is the enzyme, S1 and S2 are competing substrates, and P1 and P2 are the products of the enzymatic transformations of S1 and S2 , respectively. Similarly, and

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  eBook - ePub

  Pharmaceutical Process Chemistry

  • Takayuki Shioiri, Kunisuke Izawa, Toshiro Konoike(Authors)
  • 2010(Publication Date)
  • Wiley-VCH

    (Publisher)

  Indeed, biocatalysis is receiving an increasing attention not only because it can very well address the above described needs for sustainable manufacturing solutions with respect to cost, quality, and ecologic footprint but also because of the groundbreaking technological breakthroughs in enabling technologies that happened during the last 10 years. For example, our ability to clone DNA from environmental samples (metagenome) [4], breakthroughs in enzyme engineering by evolutionary design [5], exponentially reduced cost, and increased speed of DNA sequencing [6] and synthesis [7] led to an exponential increasing number of available enzymes and an accelerated development speed as well as reduced development costs.

  This chapter focuses on enzymatic concepts enabling the synthesis of chiral molecules in up to a theoretical 100% yield and >99% ee. Such concepts are very much preferred, from an economic as well as ecologic perspective, over resolution concepts which generate either 50% waste or requiring costly and waste generating recycling steps. The discussed concepts are divided into (i) asymmetric synthesis, (ii) desymmetrization, (iii) deracemization, and (iv) dynamic kinetic resolution (DKR) concepts. Asymmetric introduction of oxygen by oxygenases which also enables 100% yield and 100% ee concepts is, however, beyond the scope of this chapter. The interested reader is referred to some excellent reviews that have been published elsewhere (8, 9, 10).

  The aim of this chapter is not to be comprehensive but to provide an overview on some general concepts, discuss recent progress, and highlight industrially relevant examples of processes that are operated on a significant scale to demonstrate the practical use of the described approaches.

  16.2 Asymmetric Synthesis Asymmetric synthesis

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