Biocatalysis

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Three dimensional structure of an enzyme. Biocatalysis utilizes these biological macromolecules to catalyze small molecule transformations. PDB 3bl7 EBI.png
Three dimensional structure of an enzyme. Biocatalysis utilizes these biological macromolecules to catalyze small molecule transformations.

Biocatalysis refers to the use of living (biological) systems or their parts to speed up (catalyze) chemical reactions. In biocatalytic processes, natural catalysts, such as enzymes, perform chemical transformations on organic compounds. Both enzymes that have been more or less isolated and enzymes still residing inside living cells are employed for this task. [1] [2] [3] Modern biotechnology, specifically directed evolution, has made the production of modified or non-natural enzymes possible. This has enabled the development of enzymes that can catalyze novel small molecule transformations that may be difficult or impossible using classical synthetic organic chemistry. Utilizing natural or modified enzymes to perform organic synthesis is termed chemoenzymatic synthesis; the reactions performed by the enzyme are classified as chemoenzymatic reactions.

Contents

History

Biocatalysis underpins some of the oldest chemical transformations known to humans, for brewing predates recorded history. The oldest records of brewing are about 6000 years old and refer to the Sumerians.

The employment of enzymes and whole cells have been important for many industries for centuries. The most obvious uses have been in the food and drink businesses where the production of wine, beer, cheese etc. is dependent on the effects of the microorganisms.

More than one hundred years ago, biocatalysis was employed to do chemical transformations on non-natural man-made organic compounds, with the last 30 years seeing a substantial increase in the application of biocatalysis to produce fine chemicals, especially for the pharmaceutical industry. [4]

Since biocatalysis deals with enzymes and microorganisms, it is historically classified separately from "homogeneous catalysis" and "heterogeneous catalysis". However, mechanistically speaking, biocatalysis is simply a special case of heterogeneous catalysis. [5]

Advantages of chemoenzymatic synthesis

-Enzymes are environmentally benign, being completely degraded in the environment.

-Most enzymes typically function under mild or biological conditions, which minimizes problems of undesired side-reactions such as decomposition, isomerization, racemization and rearrangement, which often plague traditional methodology.

-Enzymes selected for chemoenzymatic synthesis can be immobilized on a solid support. These immobilized enzymes demonstrate improved stability and re-usability.

-Through the development of protein engineering, specifically site-directed mutagenesis and directed evolution, enzymes can be modified to enable non-natural reactivity. Modifications may also allow for a broader substrate range, enhance reaction rate or catalyst turnover.

-Enzymes exhibit extreme selectivity towards their substrates. Typically enzymes display three major types of selectivity:

These reasons, and especially the latter, are the major reasons why synthetic chemists have become interested in biocatalysis. This interest in turn is mainly due to the need to synthesize enantiopure compounds as chiral building blocks for Pharmaceutical drugs and agrochemicals.

Asymmetric biocatalysis

The use of biocatalysis to obtain enantiopure compounds can be divided into two different methods:

  1. Kinetic resolution of a racemic mixture
  2. Biocatalyzed asymmetric synthesis

In kinetic resolution of a racemic mixture, the presence of a chiral object (the enzyme) converts one of the stereoisomers of the reactant into its product at a greater reaction rate than for the other reactant stereoisomer. The stereochemical mixture has now been transformed into a mixture of two different compounds, making them separable by normal methodology.

Scheme 1. Kinetic resolution General scheme for kinetic resolution.png
Scheme 1. Kinetic resolution

Biocatalyzed kinetic resolution is utilized extensively in the purification of racemic mixtures of synthetic amino acids. Many popular amino acid synthesis routes, such as the Strecker Synthesis, result in a mixture of R and S enantiomers. This mixture can be purified by (I) acylating the amine using an anhydride and then (II) selectively deacylating only the L enantiomer using hog kidney acylase. [6] These enzymes are typically extremely selective for one enantiomer leading to very large differences in rate, allowing for selective deacylation. [7] Finally the two products are now separable by classical techniques, such as chromatography.

Enzymatic Resolution.jpg

The maximum yield in such kinetic resolutions is 50%, since a yield of more than 50% means that some of wrong isomer also has reacted, giving a lower enantiomeric excess. Such reactions must therefore be terminated before equilibrium is reached. If it is possible to perform such resolutions under conditions where the two substrate- enantiomers are racemizing continuously, all substrate may in theory be converted into enantiopure product. This is called dynamic resolution.

In biocatalyzed asymmetric synthesis, a non-chiral unit becomes chiral in such a way that the different possible stereoisomers are formed in different quantities. The chirality is introduced into the substrate by influence of enzyme, which is chiral. Yeast is a biocatalyst for the enantioselective reduction of ketones.

Scheme 2. Yeast reduction Yeastreduction.gif
Scheme 2. Yeast reduction

The Baeyer–Villiger oxidation is another example of a biocatalytic reaction. In one study a specially designed mutant of Candida antarctica was found to be an effective catalyst for the Michael addition of acrolein with acetylacetone at 20 °C in absence of additional solvent. [8]

Another study demonstrates how racemic nicotine (mixture of S and R-enantiomers 1 in scheme 3) can be deracemized in a one-pot procedure involving a monoamine oxidase isolated from Aspergillus niger which is able to oxidize only the amine S-enantiomer to the imine 2 and involving an ammonia–borane reducing couple which can reduce the imine 2 back to the amine 1. [9] In this way the S-enantiomer will continuously be consumed by the enzyme while the R-enantiomer accumulates. It is even possible to stereoinvert pure S to pure R.

Scheme 3. Enantiomerically pure cyclic tertiary amines EnantiopuretertAmines.png
Scheme 3. Enantiomerically pure cyclic tertiary amines

Photoredox enabled biocatalysis

Recently, photoredox catalysis has been applied to biocatalysis, enabling unique, previously inaccessible transformations. Photoredox chemistry relies upon light to generate free radical intermediates. [10] These radical intermediates are achiral thus racemic mixtures of product are obtained when no external chiral environment is provided. Enzymes can provide this chiral environment within the active site and stabilize a particular conformation and favoring formation of one, enantiopure product. [11] Photoredox enabled biocatalysis reactions fall into two categories:

  1. Internal coenzyme/cofactor photocatalyst
  2. External photocatalyst

Certain common hydrogen atom transfer (HAT) cofactors (NADPH and Flavin) can operate as single electron transfer (SET) reagents. [11] [12] [13] Although these species are capable of HAT without irradiation, their redox potentials are enhance by nearly 2.0 V upon visible light irradiation. [14] When paired with their respective enzymes (typically ene-reductases) This phenomenon has been utilized by chemists to develop enantioselective reduction methodologies. For example medium sized lactams can be synthesized in the chiral environment of an ene-reductase through a reductive, baldwin favored, radical cyclization terminated by enantioselective HAT from NADPH. [15]

The second category of photoredox enabled biocatalytic reactions use an external photocatalyst (PC). Many types of PCs with a large range of redox potentials can be utilized, allowing for greater tunability of reactive compared to using a cofactor. Rose bengal, and external PC, was utilized in tandem with an oxidoreductase to enantioselectively deacylate medium sized alpha-acyl-ketones. [16]

Using an external PC has some downsides. For example, external PCs typically complicate reaction design because the PC may react with both the bound and unbound substrate. If a reaction occurs between the unbound substrate and the PC, enantioselectivity is lost and other side reactions may occur.

Further reading

See also

Related Research Articles

<span class="mw-page-title-main">Enantiomer</span> Stereoisomers that are nonsuperposable mirror images of each other

In chemistry, an enantiomer – also called optical isomer, antipode, or optical antipode – is one of two stereoisomers that are nonsuperposable onto their own mirror image. Enantiomers are much like one's right and left hands; without mirroring one of them, hands cannot be superposed onto each other. No amount of reorientation in three spatial dimensions will allow the four unique groups on the chiral carbon to line up exactly. The number of stereoisomers a molecule has can be determined by the number of chiral carbons it has.

<span class="mw-page-title-main">Chirality (chemistry)</span> Geometric property of some molecules and ions

In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality. The terms are derived from Ancient Greek χείρ (cheir) 'hand'; which is the canonical example of an object with this property.

In organic chemistry, a group transfer reaction is a class of the pericyclic reaction where one or more groups of atoms is transferred from one molecule to another. Group transfer reactions can sometimes be difficult to identify when separate reactant molecules combine into a single product molecule. Unlike other pericyclic reaction classes, group transfer reactions do not have a specific conversion of pi bonds into sigma bonds or vice versa, and tend to be less frequently encountered. Like all pericyclic reactions, group transfer reactions must obey the Woodward–Hoffmann rules. Group transfer reactions can be divided into two distinct subcategories: the ene reaction and the diimide reduction. Group transfer reactions have diverse applications in various fields, including protein adenylation, biocatalytic and chemoenzymatic approaches for chemical synthesis, and strengthening skim natural rubber latex.

<span class="mw-page-title-main">Enantioselective synthesis</span> Chemical reaction(s) which favor one chiral isomer over another

Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction in which one or more new elements of chirality are formed in a substrate molecule and which produces the stereoisomeric products in unequal amounts."

In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non-stereospecific creation of a new stereocenter or during a non-stereospecific transformation of a pre-existing one. The selectivity arises from differences in steric and electronic effects in the mechanistic pathways leading to the different products. Stereoselectivity can vary in degree but it can never be total since the activation energy difference between the two pathways is finite: both products are at least possible and merely differ in amount. However, in favorable cases, the minor stereoisomer may not be detectable by the analytic methods used.

The chiral pool is a "collection of abundant enantiopure building blocks provided by nature" used in synthesis. In other words, a chiral pool would be a large quantity of common organic enantiomers. Contributors to the chiral pool are amino acids, sugars, and terpenes. Their use improves the efficiency of total synthesis. Not only does the chiral pool contribute a premade carbon skeleton, their chirality is usually preserved in the remainder of the reaction sequence.

<span class="mw-page-title-main">Henry reaction</span>

The Henry reaction is a classic carbon–carbon bond formation reaction in organic chemistry. Discovered in 1895 by the Belgian chemist Louis Henry (1834–1913), it is the combination of a nitroalkane and an aldehyde or ketone in the presence of a base to form β-nitro alcohols. This type of reaction is also referred to as a nitroaldol reaction. It is nearly analogous to the aldol reaction that had been discovered 23 years prior that couples two carbonyl compounds to form β-hydroxy carbonyl compounds known as "aldols". The Henry reaction is a useful technique in the area of organic chemistry due to the synthetic utility of its corresponding products, as they can be easily converted to other useful synthetic intermediates. These conversions include subsequent dehydration to yield nitroalkenes, oxidation of the secondary alcohol to yield α-nitro ketones, or reduction of the nitro group to yield β-amino alcohols.

Reductive amination is a form of amination that involves the conversion of a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. It is a common method to make amines and is widely used in green chemistry since it can be done catalytically in one-pot under mild conditions. In biochemistry, dehydrogenase enzymes use reductive amination to produce the amino acid, glutamate. Additionally, there is ongoing research on alternative synthesis mechanisms with various metal catalysts which allow the reaction to be less energy taxing, and require milder reaction conditions. Investigation into biocatalysts, such as imine reductases, have allowed for higher selectivity in the reduction of chiral amines which is an important factor in pharmaceutical synthesis.

Homochirality is a uniformity of chirality, or handedness. Objects are chiral when they cannot be superposed on their mirror images. For example, the left and right hands of a human are approximately mirror images of each other but are not their own mirror images, so they are chiral. In biology, 19 of the 20 natural amino acids are homochiral, being L-chiral (left-handed), while sugars are D-chiral (right-handed). Homochirality can also refer to enantiopure substances in which all the constituents are the same enantiomer, but some sources discourage this use of the term.

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The article concerns the total synthesis of galanthamine, a drug used for the treatment of mild to moderate Alzheimer's disease.

In organic chemistry, kinetic resolution is a means of differentiating two enantiomers in a racemic mixture. In kinetic resolution, two enantiomers react with different reaction rates in a chemical reaction with a chiral catalyst or reagent, resulting in an enantioenriched sample of the less reactive enantiomer. As opposed to chiral resolution, kinetic resolution does not rely on different physical properties of diastereomeric products, but rather on the different chemical properties of the racemic starting materials. The enantiomeric excess (ee) of the unreacted starting material continually rises as more product is formed, reaching 100% just before full completion of the reaction. Kinetic resolution relies upon differences in reactivity between enantiomers or enantiomeric complexes.

Asymmetric hydrogenation is a chemical reaction that adds two atoms of hydrogen to a target (substrate) molecule with three-dimensional spatial selectivity. Critically, this selectivity does not come from the target molecule itself, but from other reagents or catalysts present in the reaction. This allows spatial information to transfer from one molecule to the target, forming the product as a single enantiomer. The chiral information is most commonly contained in a catalyst and, in this case, the information in a single molecule of catalyst may be transferred to many substrate molecules, amplifying the amount of chiral information present. Similar processes occur in nature, where a chiral molecule like an enzyme can catalyse the introduction of a chiral centre to give a product as a single enantiomer, such as amino acids, that a cell needs to function. By imitating this process, chemists can generate many novel synthetic molecules that interact with biological systems in specific ways, leading to new pharmaceutical agents and agrochemicals. The importance of asymmetric hydrogenation in both academia and industry contributed to two of its pioneers — William Standish Knowles and Ryōji Noyori — being collectively awarded one half of the 2001 Nobel Prize in Chemistry.

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An enantiopure drug is a pharmaceutical that is available in one specific enantiomeric form. Most biological molecules are present in only one of many chiral forms, so different enantiomers of a chiral drug molecule bind differently to target receptors. Chirality can be observed when the geometric properties of an object is not superimposable with its mirror image. Two forms of a molecule are formed from a chiral carbon, these two forms are called enantiomers. One enantiomer of a drug may have a desired beneficial effect while the other may cause serious and undesired side effects, or sometimes even beneficial but entirely different effects. The desired enantiomer is known as an eutomer while the undesired enantiomer is known as the distomer. When equal amounts of both enantiomers are found in a mixture, the mixture is known as a racemic mixture. If a mixture for a drug does not have a 1:1 ratio of its enantiomers it is a candidate for an enantiopure drug. Advances in industrial chemical processes have made it economical for pharmaceutical manufacturers to take drugs that were originally marketed as a racemic mixture and market the individual enantiomers, either by specifically manufacturing the desired enantiomer or by resolving a racemic mixture. On a case-by-case basis, the U.S. Food and Drug Administration (FDA) has allowed single enantiomers of certain drugs to be marketed under a different name than the racemic mixture. Also case-by-case, the United States Patent Office has granted patents for single enantiomers of certain drugs. The regulatory review for marketing approval and for patenting is independent, and differs country by country.

<span class="mw-page-title-main">Synergistic catalysis</span>

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<span class="mw-page-title-main">Photoredox catalysis</span>

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Donna Blackmond is an American chemical engineer and the John C. Martin Endowed Chair in Chemistry at Scripps Research in La Jolla, CA. Her research focuses on prebiotic chemistry, the origin of biological homochirality, and kinetics and mechanisms of asymmetric catalytic reactions. Notable works include the development of Reaction Progress Kinetic Analysis (RPKA), analysis of non-linear effects of catalyst enantiopurity, biological homochirality and amino acid behavior.

Tehshik Peter Yoon is a Canadian-born chemist who studies the new reaction methods for organic synthesis with the use of catalysis. Yoon currently is a professor at the University of Wisconsin–Madison in the chemistry department. For his contributions to science, he has received numerous awards including the Beckman Young Investigator Award and National Science Foundation CAREER Award.

In homogeneous catalysis, C2-symmetric ligands refer to ligands that lack mirror symmetry but have C2 symmetry. Such ligands are usually bidentate and are valuable in catalysis. The C2 symmetry of ligands limits the number of possible reaction pathways and thereby increases enantioselectivity, relative to asymmetrical analogues. C2-symmetric ligands are a subset of chiral ligands. Chiral ligands, including C2-symmetric ligands, combine with metals or other groups to form chiral catalysts. These catalysts engage in enantioselective chemical synthesis, in which chirality in the catalyst yields chirality in the reaction product.

Nicholas John Turner, is a British chemist and a Professor in the Department of Chemistry at The University of Manchester. His research in general is based on biochemistry and organic chemistry, specifically on biotechnology, cell biology, biocatalysis and organic synthesis.

References

  1. ↑ Anthonsen, Thorlief (2000). "Reactions Catalyzed by Enzymes". In Adlercreutz, Patrick; Straathof, Adrie J. J. (eds.). Applied Biocatalysis (2nd ed.). Taylor & Francis. pp. 18–59. ISBN   978-9058230249.
  2. ↑ Faber, Kurt (2011). Biotransformations in Organic Chemistry (6th ed.). Springer. ISBN   9783642173936.[ page needed ]
  3. ↑ Jayasinghe, Leonard Y.; Smallridge, Andrew J.; Trewhella, Maurie A. (1993). "The yeast mediated reduction of ethyl acetoacetate in petroleum ether". Tetrahedron Letters. 34 (24): 3949–3950. doi:10.1016/S0040-4039(00)79272-0.
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  10. ↑ Prier, Christopher K.; Rankic, Danica A.; MacMillan, David W. C. (2013-07-10). "Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis". Chemical Reviews. 113 (7): 5322–5363. doi:10.1021/cr300503r. ISSN   0009-2665. PMC   4028850 . PMID   23509883.
  11. 1 2 Nakano, Yuji; Biegasiewicz, Kyle F; Hyster, Todd K (April 2019). "Biocatalytic hydrogen atom transfer: an invigorating approach to free-radical reactions". Current Opinion in Chemical Biology. 49: 16–24. doi:10.1016/j.cbpa.2018.09.001. PMC   6437003 . PMID   30269010.
  12. ↑ Sandoval, Braddock A.; Meichan, Andrew J.; Hyster, Todd K. (2017-08-23). "Enantioselective Hydrogen Atom Transfer: Discovery of Catalytic Promiscuity in Flavin-Dependent 'Ene'-Reductases". Journal of the American Chemical Society. 139 (33): 11313–11316. doi:10.1021/jacs.7b05468. ISSN   0002-7863. PMID   28780870.
  13. ↑ Li, Zhining; Wang, Zexu; Meng, Ge; Lu, Hong; Huang, Zedu; Chen, Fener (April 2018). "Identification of an Ene Reductase from Yeast Kluyveromyces Marxianus and Application in the Asymmetric Synthesis of ( R )-Profen Esters". Asian Journal of Organic Chemistry. 7 (4): 763–769. doi:10.1002/ajoc.201800059.
  14. ↑ Emmanuel, Megan A.; Greenberg, Norman R.; Oblinsky, Daniel G.; Hyster, Todd K. (December 14, 2016). "Accessing non-natural reactivity by irradiating nicotinamide-dependent enzymes with light". Nature. 540 (7633): 414–417. Bibcode:2016Natur.540..414E. doi:10.1038/nature20569. ISSN   1476-4687. PMID   27974767. S2CID   205252473.
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  17. ↑ Kim, Jinhyun; Lee, Sahng Ha; Tieves, Florian; Paul, Caroline E.; Hollmann, Frank; Park, Chan Beum (5 July 2019). "Nicotinamide adenine dinucleotide as a photocatalyst". Science Advances. 5 (7): eaax0501. Bibcode:2019SciA....5..501K. doi:10.1126/sciadv.aax0501. PMC   6641943 . PMID   31334353.
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