Change search
ReferencesLink to record
Permanent link

Direct link
The Competing Mechanisms of Phosphate Monoester Dianion Hydrolysis
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Oxford, Chem Res Lab, 12 Mansfield Rd, Oxford OX1 3TA, England.;Univ Oxford, Phys & Theoret Chem Lab, S Parks Rd, Oxford OX1 3QZ, England..
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
Univ Sheffield, Dept Chem, Sheffield S3 7HF, S Yorkshire, England..
Show others and affiliations
2016 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 33, 10664-10673 p.Article in journal (Refereed) Published
Abstract [en]

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 plc 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 pK(a) 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 pK(a)s 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.

Place, publisher, year, edition, pages
2016. Vol. 138, no 33, 10664-10673 p.
National Category
Structural Biology Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-307885DOI: 10.1021/jacs.6b06277ISI: 000382181900044PubMedID: 27471914OAI: oai:DiVA.org:uu-307885DiVA: diva2:1048829
Funder
EU, European Research Council, 306474The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), 2012-2097Swedish National Infrastructure for Computing (SNIC), SNIC 2015/16-12 2016/1-293
Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2016-11-22Bibliographically approved

Open Access in DiVA

fulltext(1123 kB)22 downloads
File information
File name FULLTEXT01.pdfFile size 1123 kBChecksum SHA-512
a1bad08bdbfc8453d9861e7c807dd76f895bd2f5a93d7601e2c943b08476ce88fd55911d9f9abd551616c1183df4b32f22c97702316644a66990605b040e54c2
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Åqvist, JohanKamerlin, Shina C. Lynn
By organisation
Structure and Molecular BiologyScience for Life Laboratory, SciLifeLabDepartment of Cell and Molecular BiologyComputational Biology and Bioinformatics
In the same journal
Journal of the American Chemical Society
Structural BiologyOrganic Chemistry

Search outside of DiVA

GoogleGoogle Scholar
Total: 22 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 28 hits
ReferencesLink to record
Permanent link

Direct link