Anti-Metallocene Antibodies: A New Approach to Enantioselective Catalysis of the Diels-Alder Reaction

Yli‐Kauhaluoma, Jari; Ashley, Jon; Lo, Chih-Hung L.; Tucker, Lee; Wolfe, Mary M.; Janda, Kim D.

doi:10.1021/ja00132a001

Cited by 111 publications

(52 citation statements)

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“…It is 30-to 300-fold more active than catalytic antibodies that promote the same [4+2] cycloaddition (9,11), and it outperforms the best artificial enzymes for other Diels-Alder reactions, including antibody catalysts (7)(8)(9)(10)(11)(12), ribozymes (13)(14)(15)(16), and artificial metalloenzymes (17,18) (Fig. 5D and Table S3).…”

Section: Discussionmentioning

confidence: 99%

“…A range of biocatalysts for both normal and inverse electron-demand Diels-Alder reactions has been elicited in response to immunogenic transition-state analogs (7)(8)(9)(10)(11)(12). Analogous nucleic acid-based catalysts have been isolated from large random libraries with powerful in vitro selection techniques (13)(14)(15)(16).…”

mentioning

confidence: 99%

“…1). Judging from its catalytic proficiency, [k cat /(K diene ·K dienophile )]/k uncat , which reflects the enzyme's ability to lower the activation barrier for reaction (22), the starting design is a poorer catalyst than analogous catalytic antibodies (9,11). However, its low initial activity was increased substantially by targeted mutagenesis of active site residues (21) and installation of a lid element through further computational refinement (23).…”

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confidence: 99%

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Impact of scaffold rigidity on the design and evolution of an artificial Diels-Alderase

Preiswerk

Beck

Schulz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

101

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By combining targeted mutagenesis, computational refinement, and directed evolution, a modestly active, computationally designed DielsAlderase was converted into the most proficient biocatalyst for [4+2] cycloadditions known. The high stereoselectivity and minimal product inhibition of the evolved enzyme enabled preparative scale synthesis of a single product diastereomer. X-ray crystallography of the enzyme-product complex shows that the molecular changes introduced over the course of optimization, including addition of a lid structure, gradually reshaped the pocket for more effective substrate preorganization and transition state stabilization. The good overall agreement between the experimental structure and the original design model with respect to the orientations of both the bound product and the catalytic side chains contrasts with other computationally designed enzymes. Because design accuracy appears to correlate with scaffold rigidity, improved control over backbone conformation will likely be the key to future efforts to design more efficient enzymes for diverse chemical reactions.biocatalysis | computational enzyme design | Diels-Alder reaction | laboratory evolution | enzyme mechanism

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Impact of scaffold rigidity on the design and evolution of an artificial Diels-Alderase

Preiswerk

Beck

Schulz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

101

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“…While naturally occurring protein enzymes capable of catalyzing the Diels-Alder reaction have been elusive, the immune system has proven a rich source for unique and interesting Diels-Alderase catalytic antibodies [32][33][34][35][36]. A number of clever approaches have been used to elicit antibodies capable of accelerating various carbocyclic Diels-Alder reactions.…”

Section: Protein Diels-alderases: Catalytic Antibodiesmentioning

confidence: 99%

The Diels-Alder reaction and biopolymer catalysis

Tarasow¹,

Eaton²

1999

CMLS, Cell. Mol. Life Sci.

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The Diels-Alder reaction provides a general site. The RNA Diels-Alderase activity was also shown to be absolutely dependent on the nature of the base and facile entry for the synthesis of six-membered modification and the presence of cupric ion. Together, cyclic structures. Consequently, it has been used extenthese results suggest that this RNA Diels-Alderase sively by organic chemists for the construction of complex compounds with pharmaceutical potential. Nature achieves a portion of its rate acceleration through also appears to have utilized this reaction in the Lewis acid catalysis, a different mechanistic mode than biosynthesis of several secondary metabolites. Given similar protein Diels-Alderases. The notion that RNA its utility, various catalysts have been discovered for can accelerate reactions through Lewis acid catalysis suggests that modified RNA may serve as a tunable the reaction ranging from simple Lewis acidic transition metals to complex catalytic antibodies. More re-catalytic platform for the creation of structurally diverse compounds using a variety of powerful chemical cently, modified RNA has also been shown to be an effective Diels-Alderase with a highly specific active transformations.

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“…None of the antibody Diels-Alderases require transition metals. [55][56][57][58][59] An inescapable conclusion is that modified RNAs are able to access mechanistic pathways yet to be discovered for their protein counterparts. Evaluating the merits of the two platforms more rigorously will require additional structural and mechanistic investigation of catalysts from both platforms for the same reactions.…”

Section: Comparison Of Selected Nucleic Acid and Protein Catalystsmentioning

confidence: 99%

Dressed for success: Realizing the catalytic potential of RNA

Tarasow¹,

Eaton²

1998

Biopolymers

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Anti-Metallocene Antibodies: A New Approach to Enantioselective Catalysis of the Diels-Alder Reaction

Cited by 111 publications

References 0 publications

Impact of scaffold rigidity on the design and evolution of an artificial Diels-Alderase

Impact of scaffold rigidity on the design and evolution of an artificial Diels-Alderase

The Diels-Alder reaction and biopolymer catalysis

Dressed for success: Realizing the catalytic potential of RNA

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