Serum Albumin‐Catalyzed Trigger System by Using a Tandem Kemp Elimination/β‐Elimination Reaction

Boucher, Guillaume; Robin, Sylvain; Fargeas, Valérie; Dintinger, Thierry; Mathé-Allainmat, Monique; Lebreton, Jacques; Tellier, Charles

doi:10.1002/cbic.200400255

Cited by 17 publications

(9 citation statements)

References 23 publications

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“…Various protein scaffolds have been reported as Kemp eliminases, all operating by the traditional acid/base mechanism234567891011121314151617. In contrast, we have identified a Kemp eliminase that functions by a fundamentally different mechanism based on a redox process.…”

Section: Discussionmentioning

confidence: 77%

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A redox-mediated Kemp eliminase

Wang

Ilie

et al. 2017

Nat Commun

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The acid/base-catalysed Kemp elimination of 5-nitro-benzisoxazole forming 2-cyano-4-nitrophenol has long served as a design platform of enzymes with non-natural reactions, providing new mechanistic insights in protein science. Here we describe an alternative concept based on redox catalysis by P450-BM3, leading to the same Kemp product via a fundamentally different mechanism. QM/MM computations show that it involves coordination of the substrate's N-atom to haem-Fe(II) with electron transfer and concomitant N–O heterolysis liberating an intermediate having a nitrogen radical moiety Fe(III)–N· and a phenoxyl anion. Product formation occurs by bond rotation and H-transfer. Two rationally chosen point mutations cause a notable increase in activity. The results shed light on the prevailing mechanistic uncertainties in human P450-catalysed metabolism of the immunomodulatory drug leflunomide, which likewise undergoes redox-mediated Kemp elimination by P450-BM3. Other isoxazole-based pharmaceuticals are probably also metabolized by a redox mechanism. Our work provides a basis for designing future artificial enzymes.

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Section: Discussionmentioning

confidence: 77%

“…For more than two decades2, Kemp eliminases based on various protein scaffolds have provided valuable insights into understanding and mimicking enzymes23456789101112131415 (Fig. 1a).…”

mentioning

confidence: 99%

A redox-mediated Kemp eliminase

Wang

Ilie

et al. 2017

Nat Commun

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“…For example, the deprotection of the phenol moiety of estrone has been carried out by a tandem Kemp elimination-b-elimination reaction under basic conditions (Scheme 17). 64 This tandem reaction is efficiently catalyzed by BSA and HSA even at neutral pH. However, kinetic studies highlighted that the rate of the albumin-catalyzed reaction increased with pH.…”

Section: Kemp Eliminationmentioning

confidence: 99%

Albumin as a promiscuous biocatalyst in organic synthesis

Albanese

Gaggero

2015

RSC Adv.

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“…Considering the importance of 2-amino-4H-chromenes in both biological and chemical fields, the development of environmentally friendly catalysts and mild conditions to realize this important transformation is still desirable. A c c e p t e d M a n u s c r i p t 3 catalyze the tandem Kemp elimination/β-elimination reaction [22]. In 2007, Reetz and co-workers described that BSA could promote the Morita-Baylis-Hillman (MBH) reaction of 4-nitrobenzaldehyde with cyclohexenone affording the product with a certain degree of enatioselectivity [23].…”

Section: Introductionmentioning

confidence: 98%