The rational of catalytic activity of herpes simplex virus thymidine kinase - A combined biochemical and quantum chemical study

Autoren

Marialore Sulpizi
Pierre Schelling
Gerd Folkers
Paolo Carloni
Leonardo Scapozza

DOI

10.1074/jbc.m010223200

ISSN

0021-9258

Ausgabe der Veröffentlichung

24

Zeitschrift

Journal of Biological Chemistry

Sprache

en

Paginierung

21692 - 21697

Datum der Veröffentlichung

2001

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1074/jbc.m010223200

Datum der Datenerfassung

2022

Titel

The Rational of Catalytic Activity of Herpes Simplex Virus Thymidine Kinase

Ausgabe der Zeitschrift

276

Data source: Crossref

Abstract

Most antiherpes therapies exploit the large substrate acceptance of herpes simplex virus type 1 thymidine kinase (TK(HSV1)) relative to the human isoenzyme. The enzyme selectively phosphorylates nucleoside analogs that can either inhibit viral DNA polymerase or cause toxic effects when incorporated into viral DNA. To relate structural properties of TK(HSV1) ligands to their chemical reactivity we have carried out ab initio quantum chemistry calculations within the density functional theory framework in combination with biochemical studies. Calculations have focused on a set of ligands carrying a representative set of the large spectrum of sugar-mimicking moieties and for which structural information of the TK(HSV1)-ligand complex is available. The k(cat) values of these ligands have been measured under the same experimental conditions using an UV spectrophotometric assay. The calculations point to the crucial role of electric dipole moment of ligands and its interaction with the negatively charged residue Glu(225). A striking correlation is found between the energetics associated with this interaction and the k(cat) values measured under homogeneous conditions. This finding uncovers a fundamental aspect of the mechanism governing substrate diversity and catalytic turnover and thus represents a significant step toward the rational design of novel and powerful prodrugs for antiviral and TK(HSV1)-linked suicide gene therapies.

Addresses

Scuola Internazionale Superiore di Studi Aranzati, International School for Advanced Studies, via Beirut 2-4, 34013 Trieste, Italy.

Autoren

M Sulpizi
P Schelling
G Folkers
P Carloni
L Scapozza

DOI

10.1074/jbc.m010223200

eISSN

1083-351X

Externe Identifier

PubMed Identifier: 11262392

Open access

false

ISSN

0021-9258

Ausgabe der Veröffentlichung

24

Zeitschrift

The Journal of biological chemistry

Schlüsselwörter

Humans
Herpesvirus 1, Human
Isoenzymes
Thymidine Kinase
Recombinant Fusion Proteins
Enzyme Inhibitors
Antiviral Agents
Ligands
Crystallography, X-Ray
Binding Sites
Protein Conformation
Substrate Specificity
Kinetics
Catalysis
Quantum Theory
Models, Molecular
Software

Sprache

eng

Medium

Print-Electronic

Online publication date

2001

Paginierung

21692 - 21697

Datum der Veröffentlichung

2001

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2001

Titel

The rational of catalytic activity of herpes simplex virus thymidine kinase. a combined biochemical and quantum chemical study.

Sub types

Comparative Study
Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

276

Data source: Europe PubMed Central

Abstract

Most antiherpes therapies exploit the large substrate acceptance of herpes simplex virus type 1 thymidine kinase (TK(HSV1)) relative to the human isoenzyme. The enzyme selectively phosphorylates nucleoside analogs that can either inhibit viral DNA polymerase or cause toxic effects when incorporated into viral DNA. To relate structural properties of TK(HSV1) ligands to their chemical reactivity we have carried out ab initio quantum chemistry calculations within the density functional theory framework in combination with biochemical studies. Calculations have focused on a set of ligands carrying a representative set of the large spectrum of sugar-mimicking moieties and for which structural information of the TK(HSV1)-ligand complex is available. The k(cat) values of these ligands have been measured under the same experimental conditions using an UV spectrophotometric assay. The calculations point to the crucial role of electric dipole moment of ligands and its interaction with the negatively charged residue Glu(225). A striking correlation is found between the energetics associated with this interaction and the k(cat) values measured under homogeneous conditions. This finding uncovers a fundamental aspect of the mechanism governing substrate diversity and catalytic turnover and thus represents a significant step toward the rational design of novel and powerful prodrugs for antiviral and TK(HSV1)-linked suicide gene therapies.

Autoren

M Sulpizi
P Schelling
G Folkers
P Carloni
L Scapozza

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/11262392

DOI

10.1074/jbc.M010223200

ISSN

0021-9258

Ausgabe der Veröffentlichung

24

Zeitschrift

J Biol Chem

Schlüsselwörter

Antiviral Agents
Binding Sites
Catalysis
Crystallography, X-Ray
Enzyme Inhibitors
Herpesvirus 1, Human
Humans
Isoenzymes
Kinetics
Ligands
Models, Molecular
Protein Conformation
Quantum Theory
Recombinant Fusion Proteins
Software
Substrate Specificity
Thymidine Kinase

Sprache

eng

Country

United States

Paginierung

21692 - 21697

PII

S0021-9258(20)78746-6

Datum der Veröffentlichung

2001

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2001

Titel

The rational of catalytic activity of herpes simplex virus thymidine kinase. a combined biochemical and quantum chemical study.

Sub types

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

276

Data source: PubMed

The rational of catalytic activity of herpes simplex virus thymidine kinase - A combined biochemical and quantum chemical study

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