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Substrate Distortion to a Boat Conformation at Subsite −1 Is Critical in the Mechanism of Family 18 Chitinases

Brameld, Ken A. and Goddard, William A., III (1998) Substrate Distortion to a Boat Conformation at Subsite −1 Is Critical in the Mechanism of Family 18 Chitinases. Journal of the American Chemical Society, 120 (15). pp. 3571-3580. ISSN 0002-7863. https://resolver.caltech.edu/CaltechAUTHORS:20180517-143013980

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Abstract

Using molecular dynamics simulations, we examined the plausible conformations for a hexaNAG substrate bound to the active site of Chitinase A. We find that (i) the hydrolysis mechanism of Chitinase A (a family 18 chitinase from Serratia marcescens) involves substrate distortion, (ii) the first step of acid-catalyzed hydrolysis (protonation of the linking anomeric oxygen between GlcNAc residues −1 and +1) requires a boat conformation for the GlcNAc residue at binding subsite −1; (iii) ab initio quantum mechanical calculations (HF/6-31G**) predict that protonation of a GlcNAc in a boat conformation leads to spontaneous anomeric bond cleavage to yield an oxazoline ion intermediate. We also studied several conformations of two possible hydrolysis intermediates:  the oxocarbenium ion and the oxazoline ion. Only the oxazoline ion orients in the enzyme active site so as to allow stereoselective attack by water. This leads to retention of configuration in the anomeric product as observed experimentally. It is possible that all family 18 chitinases share a common mechanism. Hence, we suspect that distortion of the substrate into a boat form at subsite −1 is required for any glycosyl hydrolase which has only one acidic residue in the active site. The design of an inhibitor for these systems based on the boat distorted sugar conformation is discussed.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/ja972282hDOIArticle
ORCID:
AuthorORCID
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 1998 American Chemical Society. Received July 9, 1997. Revised Manuscript Received January 21, 1998. Publication Date (Web): April 4, 1998. We are grateful to Professor Barbara Imperiali for many helpful discussions. This research was initiated with funding by DOE-BCTR (DE-FG36-93CH105 81, David Boron) and completed under NSF-CHE 95-22179. The facilities of the MSC are also supported by grants from NSF (CHE 95-22179 and ASC 92-100368), Chevron Petroleum Technology Co., Saudi Aramco, Asahi Chemical, Owens-Corning, Exxon, Chevron Chemical Company, Chevron Research and Technology Co., Avery-Dennison, Hercules, BP Chemical, and Beckman Institute.
Funders:
Funding AgencyGrant Number
Department of Energy (DOE)DE-FG36-93CH105 81
NSFCHE 95-22179
NSFASC 92-100368
Chevron Petroleum Technology Co.UNSPECIFIED
Saudi AramcoUNSPECIFIED
Asahi ChemicalUNSPECIFIED
Owens-CorningUNSPECIFIED
ExxonUNSPECIFIED
Chevron Chemical Co.UNSPECIFIED
Chevron Research and Technology Co.UNSPECIFIED
Avery-DennisonUNSPECIFIED
HerculesUNSPECIFIED
BP ChemicalUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Issue or Number:15
Record Number:CaltechAUTHORS:20180517-143013980
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180517-143013980
Official Citation:Substrate Distortion to a Boat Conformation at Subsite −1 Is Critical in the Mechanism of Family 18 Chitinases. Ken A. Brameld and and William A. Goddard III. Journal of the American Chemical Society 1998 120 (15), 3571-3580. DOI: 10.1021/ja972282h
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:86441
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 May 2018 17:04
Last Modified:03 Oct 2019 19:43

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