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PMID: 15078855 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Computational analysis of Plasmodium falciparum metabolism: organizing genomic information to facilitate drug discovery.

Genome research ·Vol. 14 ·No. 5 ·2004-05-00 ·Pages 917-24

Yeh I, Hanekamp T, Tsoka S, Karp PD, Altman RB

Abstract

Identification of novel targets for the development of more effective antimalarial drugs and vaccines is a primary goal of the Plasmodium genome project. However, deciding which gene products are ideal drug/vaccine targets remains a difficult task. Currently, a systematic disruption of every single gene in Plasmodium is technically challenging. Hence, we have developed a computational approach to prioritize potential targets. A pathway/genome database (PGDB) integrates pathway information with information about the complete genome of an organism. We have constructed PlasmoCyc, a PGDB for Plasmodium falciparum 3D7, using its annotated genomic sequence. In addition to the annotations provided in the genome database, we add 956 additional annotations to proteins annotated as "hypothetical" using the GeneQuiz annotation system. We apply a novel computational algorithm to PlasmoCyc to identify 216 "chokepoint enzymes." All three clinically validated drug targets are chokepoint enzymes. A total of 87.5% of proposed drug targets with biological evidence in the literature are chokepoint reactions. Therefore, identifying chokepoint enzymes represents one systematic way to identify potential metabolic drug targets.

MeSH Terms
Algorithms Animals Catalysis/drug effects Computational Biology/methods Databases, Genetic Enzyme Inhibitors/pharmacology Escherichia coli/enzymology,genetics,metabolism Escherichia coli Proteins/genetics,metabolism,physiology Genes, Bacterial/genetics,physiology Genes, Essential/drug effects,physiology Genes, Protozoan/genetics,physiology Genome, Protozoan Genomics/methods Humans Models, Chemical Plasmodium falciparum/drug effects,enzymology,genetics,metabolism Predictive Value of Tests Protozoan Proteins/antagonists & inhibitors,genetics,metabolism,physiology Software Substrate Specificity/genetics,physiology
Chemicals
Enzyme Inhibitors Escherichia coli Proteins Protozoan Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Yeh Iwei
Department of Genetics, Stanford University, Stanford, California 94305, USA.
Hanekamp Theodor
Tsoka Sophia
Karp Peter D
Altman Russ B
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Article Info
Journal
Genome research
Abbr.
Genome Res
ISSN
1088-9051
DOI
10.1101/gr.2050304
Published
2004-05-00
Epub
2004-00-12
Pages
917-24
Language
English
Region
United States
NLM ID
9518021
PMCID
PMC479120
Subset
IM
Grants
NHGRI NIH HHS · R01 HG002729 · United States
NIGMS NIH HHS · T32 GM007365 · United States
NIGMS NIH HHS · 5T32GM07365 · United States
NHGRI NIH HHS · R01-HG02729-01 · United States
External Links
PubMed source DOI: 10.1101/gr.2050304 PMC Full Text View journal details
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