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Ozlem Demir Quantum Theory
Project VOICE: (352)
392-7184 EMAIL: demir_at_qtp.ufl.edu |
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Who am I? Özlem
started PhD studies at University of Florida in Gainesville in 2002
after completing B.S and M.S. studies at Bilkent University in Turkey.
Her research topic for M.S. study was investigating the N/pi and
N/sigma interactions of the amide linkage with its N-substituents
under the supervision of Assoc. Prof. Andrzej S. Cieplak. Özlem
is now working on the mechanism of Trypanosoma cruzi trans-sialidase
(TcTS). Trypanosoma cruzi is a parasite that causes Chagas' disease
with a report of 50,000 deaths a year in Central and South America.
No drug is available for the disease. The parasite uses trans-sialidase
enzyme as a perfect tool to evade from the immune system of the
host body and is capable of invading any kind of cell. Until the
X-ray crystal structure of the enzyme is obtained by Frasch group
in 2002, not much was known about the mechanism of the enzyme despite
the experimental efforts for decades. In the crystal structure there
was not a proper residue found around the reaction site that can
act as a nucleophile. In 2003 the mysterious nucleophile is identified
to be a Tyr residue which has never been found with such a function.
Horenstein group got first evidence for the formation of a covalent
intermediate between the ligand and the enzyme in 2000 and the X-ray
crystal structure of the intermediate with a fluorinated ligand
is obtained by Withers group in 2004. One of the striking properties
of TcTS is that it catalyzes sialyl transfer reaction very efficiently
compared to Trypanosoma rangeli sialidase (TrSA) which is very similar
in structure but can only catalyze hydrolysis. Additionally, the
inhibitors of TrSA do not work for TcTS. The reasons for the difference
of the two enzymes and the detailed mechanism of trans-sialidase
are of great interest. The theoretical approach is using hybrid
methods (QM/MM, ONIOM) to get a better insight about these issues.
Molecular dynamics simulations of free and liganded enzymes are
being performed additionally to compare local interactions and dynamic
effects. Our long term goal is to identify the transition state
structures and design specific inhibitors. The fact that this enzyme
is not found in eukaryotic cells makes it a bright candidate for
inhibitor design. An effective inhibitor will be able to stop the
parasite right at the beginning of the infection and prevent the
disease to a large extent.
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Contact kim@qtp.ufl.edu for more information.