TRYPANOCYC
A Metabolic Pathway Database for
Trypanosoma brucei
BRIDGET CHUKUALIM
INTERNATIONAL TRYPANOTOLERANCE
CENTER
THE GAMBIA
FEB 2011
Map of Africa showing demographics of Sleeping sickness disease
Tb gambiense – chronic
form of disease
Tb rhodesiense – acute
form
ttp://www.who.int/mediacentre/factsheets/
Why TrypanoCyc
  To understanding better the biochemistry of the
Trypanosoma brucei parasite
  To computationally query the database to identify
new drug targets
Pathway Tools Software
Summary of Trypanosoma brucei data set version 9.0.1.1.1
TrypanoCyc – a metabolic pathway database for Trypanosoma species
(http://biocyc.org/TRYPANO/ and htttp://pathways.genedb.org)
TrypanoCyc – a metabolic pathway database for Trypanosoma species
Trypanothion
e
TrypanoCyc – a metabolic pathway database for Trypanosoma species
Biopterin
TrypanoCyc – a metabolic pathway database for Trypanosoma species
Manual Curation
  Manual curation involved:
  Removal of redundant pathways
  Addition of metabolic pathways unique to Trypanosoma
brucei
  An initial run of Pathway hole filler algorithim identified
possible gene products within the Trypanosoma brucei
metabolic network for the 221 pathway holes – gene product
yet to be identified in Trypanosoma brucei
 
Manual identification of gene products (based on literature
review) and corresponding annotation which has also been
submitted to the Genedb database
Case Study – Choke Point Enzymes
  Choke point enzymes are believed to be essential to
the parasite and are therefore potential drug targets
( Yeh et al, 2004)
  These enzymes catalyse unique reactions within the
Trypanosoma brucei metabolic network
  Further refinement of the chokepoint analyses
excluded choke point reactions that also occur in
Humans, because antimicrobials targeting them
might harm a patient too
Results
  A chokepoint analysis was done to identify unique
reactions in Trypanosoma brucei metabolic network
  A total of 168 drug targets have been identified –
  100% of clinically validated drug targets against
nagana
  Available
drugs include: Trypamidium, Novidium, Berenil
  94% of Clinically validated drug targets against
Sleeping sickness disease
  Available
drugs include: Pentamidine, Suramin, Melarsoprol,
Eflornithine
Chokepoint enzymes in overview map of
TrypanoCyc
Pathway Glyph report
Lists of identified drug targets in Manuscript
  Table 1: - Current known drug targets for sleeping
sickness disease/nagana and references including
status in chokepoint analysis
  Table 2 – A list of 168 chokepoint enzymes/
identified drug targets
Future work
  It is interesting that TrypanoCyc which was created
with the Trypanosoma brucei brucei genome,
causative agent of nagana disease, has identified
100% of clinically validated drug targets against
nagana disease and 94% of clinically validated drug
targets against the African sleeping sickness disease
  The drug targets identified in the Trypanosoma
brucei network will be modeled/prioritized
according to druggability and this will be related
drugs targeted at homologues in other species
Acknowledgements
  Dr Matt Berriman and members of the Pathogen Sequencing Unit at the
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Wellcome Trust Sanger Institute
The UNDP/World bank/WHO Special Programme for Research and Training
in Tropical Diseases (TDR) for providing financial support to set up the
database. ·
The Royal Society, UK for providing financial support to further curate, analyse
the data and to make it web accessible.
Peter Karp, members of the Bioinformatics Research group at SRI
International, USA and Nick Peters for the technical support of the software
throughout the period.
Professor Alan Fairlamb, School of Life Sciences, University of Dundee,
Scotland and Professor Fred Opperdoes, University of Louvain, Belgium for
their support with Literature and scientific reviews of experimentally elucidated
pathways in the metabolism of the Trypanosoma brucei parasite. ·
The management of the International Trypanotolerance Centre in Banjul, The
Gambia for their support during this period.
My present Supervisor, Dr Mark Carrington for ongoing support
References
  Karp PD, P.S., Romero P, The Pathway Tools software.
Bioinformatics, 2002. 18(Suppl 1): p. S225-32
  World Health Organisation: Human African
trypanosomiasis (sleeping sickness).
http://www.who.int/mediacentre/factsheets/
  Yeh I, H.T., Tsoka S, Karp PD, Altman RB, Computational
analysis of Plasmodium falciparum metabolism:
organizing genomic information to facilitate drug
discovery. . Genome Res, 2004. 14(5): p. 917-24.
http://pathways.genedb.org/TRYPANO
http://biocyc.org/TRYPANO
Thank You