Work

Adherence to Bürgi–Dunitz stereochemical principles requires significant structural rearrangements in Schiff-base formation: insights from transaldolase complexes

Year: 2014

Type: article

Abstract: The Bürgi-Dunitz angle (αBD) describes the trajectory of approach of a nucleophile to an electrophile. The adoption of a stereoelectronically favorable αBD can necessitate significant reactive-group repositioning over the course of bond formation. In the context of enzyme catalysis, interactions with the protein constrain substrate rotation, which could necessitate structural transformations during bond formation. To probe this theoretical framework vis-à-vis biocatalysis, Schiff-base formation was analysed in Francisella tularensis transaldolase (TAL). Crystal structures of wild-type and Lys→Met mutant TAL in covalent and noncovalent complexes with fructose 6-phosphate and sedoheptulose 7-phosphate clarify the mechanism of catalysis and reveal that substrate keto moieties undergo significant conformational changes during Schiff-base formation. Structural changes compelled by the trajectory considerations discussed here bear relevance to bond formation in a variety of constrained enzymic/engineered systems and can inform the design of covalent therapeutics.

Source: Acta Crystallographica Section D Biological Crystallography

DOI: 10.1107/s1399004713030666

Authors: Samuel H. Light, George Minasov, Mark-Eugene Duban, Wayne F. Anderson

Institution: Northwestern University

Language: English

Topic: Chemical Reaction Mechanisms

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: hybrid

Estimated APC paid: $4,740

Funder: National Institute of Allergy and Infectious Diseases