The Competing Mechanisms of Phosphate Monoester Dianion Hydrolysis
Duarte, Fernanda ; Barrozo, Alexandre ; Åqvist, Johan ; Williams, Nicholas H and Kamerlin, Shina C L LU
(2016)
In Journal of the American Chemical Society
138(33).
p.73-10664
- Abstract
Despite the numerous experimental and theoretical studies on phosphate monoester hydrolysis, significant questions remain concerning the mechanistic details of these biologically critical reactions. In the present work we construct a linear free energy relationship for phosphate monoester hydrolysis to explore the effect of modulating leaving group pKa on the competition between solvent- and substrate-assisted pathways for the hydrolysis of these compounds. Through detailed comparative electronic-structure studies of methyl phosphate and a series of substituted aryl phosphate monoesters, we demonstrate that the preferred mechanism is dependent on the nature of the leaving group. For good leaving groups, a strong preference is observed... (More)
Despite the numerous experimental and theoretical studies on phosphate monoester hydrolysis, significant questions remain concerning the mechanistic details of these biologically critical reactions. In the present work we construct a linear free energy relationship for phosphate monoester hydrolysis to explore the effect of modulating leaving group pKa on the competition between solvent- and substrate-assisted pathways for the hydrolysis of these compounds. Through detailed comparative electronic-structure studies of methyl phosphate and a series of substituted aryl phosphate monoesters, we demonstrate that the preferred mechanism is dependent on the nature of the leaving group. For good leaving groups, a strong preference is observed for a more dissociative solvent-assisted pathway. However, the energy difference between the two pathways gradually reduces as the leaving group pKa increases and creates mechanistic ambiguity for reactions involving relatively poor alkoxy leaving groups. Our calculations show that the transition-state structures vary smoothly across the range of pKas studied and that the pathways remain discrete mechanistic alternatives. Therefore, while not impossible, a biological catalyst would have to surmount a significantly higher activation barrier to facilitate a substrate-assisted pathway than for the solvent-assisted pathway when phosphate is bonded to good leaving groups. For poor leaving groups, this intrinsic preference disappears.
(Less)
- author
- Duarte, Fernanda
; Barrozo, Alexandre
; Åqvist, Johan
; Williams, Nicholas H
and Kamerlin, Shina C L
LU
- publishing date
- 2016-08-24
- type
- Contribution to journal
- publication status
- published
- in
- Journal of the American Chemical Society
- volume
- 138
- issue
- 33
- pages
- 10 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:84983598220
- pmid:27471914
- ISSN
- 1520-5126
- DOI
- 10.1021/jacs.6b06277
- language
- English
- LU publication?
- no
- id
- c4a1272e-2ce7-45a1-a9b1-89caeb42ea97
- date added to LUP
- 2025-01-11 21:29:36
- date last changed
- 2025-05-18 18:07:17
@article{c4a1272e-2ce7-45a1-a9b1-89caeb42ea97,
abstract = {{<p>Despite the numerous experimental and theoretical studies on phosphate monoester hydrolysis, significant questions remain concerning the mechanistic details of these biologically critical reactions. In the present work we construct a linear free energy relationship for phosphate monoester hydrolysis to explore the effect of modulating leaving group pKa on the competition between solvent- and substrate-assisted pathways for the hydrolysis of these compounds. Through detailed comparative electronic-structure studies of methyl phosphate and a series of substituted aryl phosphate monoesters, we demonstrate that the preferred mechanism is dependent on the nature of the leaving group. For good leaving groups, a strong preference is observed for a more dissociative solvent-assisted pathway. However, the energy difference between the two pathways gradually reduces as the leaving group pKa increases and creates mechanistic ambiguity for reactions involving relatively poor alkoxy leaving groups. Our calculations show that the transition-state structures vary smoothly across the range of pKas studied and that the pathways remain discrete mechanistic alternatives. Therefore, while not impossible, a biological catalyst would have to surmount a significantly higher activation barrier to facilitate a substrate-assisted pathway than for the solvent-assisted pathway when phosphate is bonded to good leaving groups. For poor leaving groups, this intrinsic preference disappears.</p>}},
author = {{Duarte, Fernanda and Barrozo, Alexandre and Åqvist, Johan and Williams, Nicholas H and Kamerlin, Shina C L}},
issn = {{1520-5126}},
language = {{eng}},
month = {{08}},
number = {{33}},
pages = {{73--10664}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of the American Chemical Society}},
title = {{The Competing Mechanisms of Phosphate Monoester Dianion Hydrolysis}},
url = {{http://dx.doi.org/10.1021/jacs.6b06277}},
doi = {{10.1021/jacs.6b06277}},
volume = {{138}},
year = {{2016}},
}