Journal
NATURE CHEMICAL BIOLOGY
Volume 7, Issue 9, Pages 631-638Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.628
Keywords
-
Categories
Funding
- Bill and Melinda Gates Foundation
- Samsung Fellowship
- Biotechnology and Biological Sciences Research Council
- Royal Society
- Engineering and Physical Sciences Research Council
- BBSRC [BB/E001696/1, BB/E004350/1] Funding Source: UKRI
- EPSRC [EP/I500200/1, EP/G026688/1, EP/E000614/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/C510824/1, EGA17763, B20376, BB/E004350/1, BB/E001696/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/G026688/1, EP/I500200/1, EP/D023343/1, GR/T26542/01, EP/D023335/1, EP/E000614/1] Funding Source: researchfish
Ask authors/readers for more resources
A previously determined crystal structure of the ternary complex of trehalose-6-phosphate synthase identified a putative transition state-like arrangement based on validoxylamine A 6'-O-phosphate and uridine diphosphate in the active site. Here linear free energy relationships confirm that these inhibitors are synergistic transition state mimics, supporting front-face nucleophilic attack involving hydrogen bonding between leaving group and nucleophile. Kinetic isotope effects indicate a highly dissociative oxocarbenium ion-like transition state. Leaving group O-18 effects identified isotopically sensitive bond cleavages and support the existence of a hydrogen bond between the nucleophile and departing group. Bronsted analysis of nucleophiles and Taft analysis highlight participation of the nucleophile in the transition state, also consistent with a front-face mechanism. Together, these comprehensive, quantitative data substantiate this unusual enzymatic reaction mechanism. Its discovery should prompt useful reassessment of many biocatalysts and their substrates and inhibitors.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available