Studies on the stereospecificity of the clavaminic acid synthase catalysed hydroxylation reaction

Baldwin, Jack E.; Merritt, Kirsten D.; Schofield, Christopher J.; Elson, Stephen W.; Baggaley, Keith H.

doi:10.1039/c39930001301

Cited by 23 publications

(41 citation statements)

References 11 publications

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Section: Resultssupporting

confidence: 76%

“…The binding mode of DGPC as identified by QM/MM calculations is consistent with the stereospecificity of the hydrogen atom abstraction, as manifested in the labelling experiments with deuterated substrate analogues. [41] Thus, the distance between the C3-bound pro-R hydrogen of DGPC and the oxo ligand is reasonably short, that is, 2.03 ,w hich facilitates the reaction, whereas the pro-S hydrogen atom points away from the ferryl species. For the CAS:DHC complex, the analogous distance for the C3-bound hydrogen atom is 2.34 ,w hich is also in agreement with the labellings tudies and suggestst he desaturation reactiono fD HC starts with C3ÀHb ond cleavage.…”

Section: Initial Hatf or The Native Substratesmentioning

confidence: 99%

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Enzyme Multifunctionality by Control of Substrate Positioning Within the Catalytic Cycle—A QM/MM Study of Clavaminic Acid Synthase

Wojdyla

Borowski

2020

Chemistry A European J

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Clavaminic acid synthase from Streptomyces clavuligerus is an FeII/2‐oxoglutarate‐dependent dioxygenase, crucial for the biosynthesis of the β‐lactamase inhibitor clavulanic acid. It catalyses three consecutive oxidative reactions, that is, hydroxylation, cyclisation and desaturation, in a single binding cavity. As follows from the results of this QM/MM study, CAS versatility and selectivity depends on the binding cavity, which interplays differently with the substrate for each reaction. The enzyme–substrate interactions affect the substrate's ability to re‐position during the reaction, either constraining it in its primary position, which impedes processes other than oxygen rebound, or allowing change, which facilitates desaturation. This differential effect originates from two aspartate residues, which strongly interact with the guanidine group of the hydroxylation substrate and stabilise the orientation of the molecule. These residues interact less effectively with the smaller amine group of the desaturation substrate(s), aiding their re‐positioning and the subsequent formation of a double bond.

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Section: Resultssupporting

confidence: 76%

Section: Initial Hatf or The Native Substratesmentioning

confidence: 99%

Enzyme Multifunctionality by Control of Substrate Positioning Within the Catalytic Cycle—A QM/MM Study of Clavaminic Acid Synthase

Wojdyla

Borowski

2020

Chemistry A European J

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“…This mechanism is supported by recent MCD results on PKU mutants which oxi- Bacterial resistance to penicillin antibiotics is largely because of the hydrolytic activity of the ␤-lactamases. CS2 catalyzes the key biosynthetic ring closure step in the formation of clavulanic acid, a potent ␤-lactamase inhibitor (19). CS2 catalyzes three different reactions (Table 1) The binding of each of the three substrates to the resting Fe II -CS2 site produces no change in the ligand field spectrum (Fig.…”

mentioning

confidence: 99%

Non-heme iron enzymes: Contrasts to heme catalysis

Solomon

Decker

Lehnert

2003

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

222

187

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Non-heme iron enzymes catalyze a wide range of O2 reactions, paralleling those of heme systems. Non-heme iron active sites are, however, much more difficult to study because they do not exhibit the intense spectral features characteristic of the porphyrin ligand. A spectroscopic methodology was developed that provides significant mechanistic insight into the reactivity of non-heme ferrous active sites. These studies reveal a general mechanistic strategy used by these enzymes and differences in substrate and cofactor interactions dependent on their requirement for activation by iron. Contributions to O2 activation have been elucidated for non-heme relative to heme ligand sets, and major differences in reactivity are defined with respect to the heterolytic and homolytic cleavage of OOO bonds.

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“…Fully protected didehydro-arginine derivatives 8e – h therefore did not undergo the aza-Michael addition anymore, even in the presence of highly reactive activating agents. However, both compounds 8e – h and their respective azide precursors might be useful synthetic intermediates for the preparation of isotope-labelled ornithine or arginine derivatives (also see Baldwin et al 1993a, b). Overall, the obtained results demonstrate that a biomimetic 1,4-addition of a guanidine moiety to a didehydro amino acid unit is synthetically feasible, but that a fine-tuning of the reactivity is essential.…”

Section: Resultsmentioning

confidence: 99%

A biomimetic domino reaction for the concise synthesis of capreomycidine and epicapreomycidine

2012

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The non-proteinogenic amino acids capreomycidine and epicapreomycidine are constituents of antibiotically active natural products, but the synthesis of these unusual cyclic guanidine derivatives is challenging. The biosynthesis of capreomycidine has therefore been employed as a guideline to develop a concise biomimetic synthesis of both epimeric amino acids. The resulting domino-guanidinylation-aza-Michael-addition reaction provides the most convenient access to these amino acids in racemic form. Attempts to dissect the domino reaction into two separate transformations for a stereocontrolled version of this synthetic approach have also been made. The synthesized didehydro-arginine derivatives with urethane-protected guanidine moieties did not undergo the aza-Michael-addition anymore. These results may have wider implications for the 1,4-addition of guanidines to α,β-unsaturated carbonyl compounds, particularly to didehydro amino acids.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-012-1309-8) contains supplementary material, which is available to authorized users.

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Studies on the stereospecificity of the clavaminic acid synthase catalysed hydroxylation reaction

Cited by 23 publications

References 11 publications

Enzyme Multifunctionality by Control of Substrate Positioning Within the Catalytic Cycle—A QM/MM Study of Clavaminic Acid Synthase

Enzyme Multifunctionality by Control of Substrate Positioning Within the Catalytic Cycle—A QM/MM Study of Clavaminic Acid Synthase

Non-heme iron enzymes: Contrasts to heme catalysis

A biomimetic domino reaction for the concise synthesis of capreomycidine and epicapreomycidine

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