Crystal structures of IspF from Plasmodium falciparum and Burkholderia cenocepacia: comparisons inform antimicrobial drug target assessment

Patrick E. F. O'Rourke; Justyna Kalinowska-Tłuścik; Paul K. Fyfe; Alice Dawson; William N. Hunter

doi:10.1186/1472-6807-14-1

Crystal structures of IspF from Plasmodium falciparum and Burkholderia cenocepacia: comparisons inform antimicrobial drug target assessment

Patrick E. F. O'Rourke, Justyna Kalinowska-Tłuścik, Paul K. Fyfe, Alice Dawson, William N. Hunter (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

Abstract

2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase (IspF) catalyzes the conversion of 4-diphosphocytidyl-2C-methyl-D-erythritol-2-phosphate to 2C-methyl-D-erythritol-2,4-cyclodiphosphate and cytidine monophosphate in production of isoprenoid-precursors via the methylerythritol phosphate biosynthetic pathway. IspF is found in the protozoan Plasmodium falciparum, a parasite that causes cerebral malaria, as well as in many Gram-negative bacteria such as Burkholderia cenocepacia. IspF represents a potential target for development of broad-spectrum antimicrobial drugs since it is proven or inferred as essential in these pathogens and absent from mammals. Structural studies of IspF from these two important yet distinct pathogens, and comparisons with orthologues have been carried out to generate reagents, to support and inform a structure-based approach to early stage drug discovery.

Original language	English
Article number	1
Number of pages	12
Journal	BMC Structural Biology
Volume	14
DOIs	https://doi.org/10.1186/1472-6807-14-1
Publication status	Published - 10 Jan 2014

Keywords

Amino Acid Sequence
Burkholderia cenocepacia
Catalytic Domain
Citric Acid
Crystallography, X-Ray
Erythritol
Models, Molecular
Phosphorus-Oxygen Lyases
Plasmodium falciparum
Protein Conformation
Protein Structure, Secondary
Recombinant Proteins
Sequence Alignment
Substrate Specificity
Sugar Phosphates
Zinc

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/1472-6807-14-1Licence: CC BY

A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. (Investigator) & Gilbert, I. (Investigator)
1/01/13 → 30/09/15
Project: Research
State-of-the-Art Facilities for Structural Biology at the University of Dundee
Hunter, B. (Investigator), Lilley, D. (Investigator), Owen-Hughes, T. (Investigator), Wyatt, P. (Investigator) & van Aalten, D. (Investigator)
1/03/12 → 28/02/17
Project: Research
Aref#d: 19401. Structure, specificity and mechanism of biosynthetic enzymes in trypanosomatids and inhibitor discovery of essential microbial functions (Programme Grant)
Hunter, B. (Investigator)
1/11/07 → 31/12/13
Project: Research

Cite this

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title = "Crystal structures of IspF from Plasmodium falciparum and Burkholderia cenocepacia: comparisons inform antimicrobial drug target assessment",

abstract = "2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase (IspF) catalyzes the conversion of 4-diphosphocytidyl-2C-methyl-D-erythritol-2-phosphate to 2C-methyl-D-erythritol-2,4-cyclodiphosphate and cytidine monophosphate in production of isoprenoid-precursors via the methylerythritol phosphate biosynthetic pathway. IspF is found in the protozoan Plasmodium falciparum, a parasite that causes cerebral malaria, as well as in many Gram-negative bacteria such as Burkholderia cenocepacia. IspF represents a potential target for development of broad-spectrum antimicrobial drugs since it is proven or inferred as essential in these pathogens and absent from mammals. Structural studies of IspF from these two important yet distinct pathogens, and comparisons with orthologues have been carried out to generate reagents, to support and inform a structure-based approach to early stage drug discovery.",

keywords = "Amino Acid Sequence, Burkholderia cenocepacia, Catalytic Domain, Citric Acid, Crystallography, X-Ray, Erythritol, Models, Molecular, Phosphorus-Oxygen Lyases, Plasmodium falciparum, Protein Conformation, Protein Structure, Secondary, Recombinant Proteins, Sequence Alignment, Substrate Specificity, Sugar Phosphates, Zinc",

author = "O'Rourke, {Patrick E. F.} and Justyna Kalinowska-T{\l}u{\'s}cik and Fyfe, {Paul K.} and Alice Dawson and Hunter, {William N.}",

year = "2014",

month = jan,

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doi = "10.1186/1472-6807-14-1",

language = "English",

volume = "14",

journal = "BMC Structural Biology",

issn = "1472-6807",

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T2 - comparisons inform antimicrobial drug target assessment

AU - O'Rourke, Patrick E. F.

AU - Kalinowska-Tłuścik, Justyna

AU - Fyfe, Paul K.

AU - Dawson, Alice

AU - Hunter, William N.

PY - 2014/1/10

Y1 - 2014/1/10

N2 - 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase (IspF) catalyzes the conversion of 4-diphosphocytidyl-2C-methyl-D-erythritol-2-phosphate to 2C-methyl-D-erythritol-2,4-cyclodiphosphate and cytidine monophosphate in production of isoprenoid-precursors via the methylerythritol phosphate biosynthetic pathway. IspF is found in the protozoan Plasmodium falciparum, a parasite that causes cerebral malaria, as well as in many Gram-negative bacteria such as Burkholderia cenocepacia. IspF represents a potential target for development of broad-spectrum antimicrobial drugs since it is proven or inferred as essential in these pathogens and absent from mammals. Structural studies of IspF from these two important yet distinct pathogens, and comparisons with orthologues have been carried out to generate reagents, to support and inform a structure-based approach to early stage drug discovery.

AB - 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase (IspF) catalyzes the conversion of 4-diphosphocytidyl-2C-methyl-D-erythritol-2-phosphate to 2C-methyl-D-erythritol-2,4-cyclodiphosphate and cytidine monophosphate in production of isoprenoid-precursors via the methylerythritol phosphate biosynthetic pathway. IspF is found in the protozoan Plasmodium falciparum, a parasite that causes cerebral malaria, as well as in many Gram-negative bacteria such as Burkholderia cenocepacia. IspF represents a potential target for development of broad-spectrum antimicrobial drugs since it is proven or inferred as essential in these pathogens and absent from mammals. Structural studies of IspF from these two important yet distinct pathogens, and comparisons with orthologues have been carried out to generate reagents, to support and inform a structure-based approach to early stage drug discovery.

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KW - Burkholderia cenocepacia

KW - Catalytic Domain

KW - Citric Acid

KW - Crystallography, X-Ray

KW - Erythritol

KW - Models, Molecular

KW - Phosphorus-Oxygen Lyases

KW - Plasmodium falciparum

KW - Protein Conformation

KW - Protein Structure, Secondary

KW - Recombinant Proteins

KW - Sequence Alignment

KW - Substrate Specificity

KW - Sugar Phosphates

KW - Zinc

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DO - 10.1186/1472-6807-14-1

M3 - Article

C2 - 24410837

SN - 1472-6807

VL - 14

JO - BMC Structural Biology

JF - BMC Structural Biology

M1 - 1

ER -

Crystal structures of IspF from Plasmodium falciparum and Burkholderia cenocepacia: comparisons inform antimicrobial drug target assessment

Abstract

Keywords

UN SDGs

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Projects

A Translational Engine for Biomedical Discoveries (Strategic Grant)

State-of-the-Art Facilities for Structural Biology at the University of Dundee

Aref#d: 19401. Structure, specificity and mechanism of biosynthetic enzymes in trypanosomatids and inhibitor discovery of essential microbial functions (Programme Grant)

Cite this