TDO and the Kynurenine Pathway: Evaluating Their Importance to Neuroscience

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TDO and the Kynurenine Pathway Evaluating Their
Importance to Neuroscience

• By
• Channing Twyner

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Tryptophan Metabolism
Nature Reviews Drug Discovery 2002
Acetyl-CoA
NAD
ACMSD
ACMS
QUIN
HAD
3-hydroxyanthranilic acid
formylkynurenine
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TDO Catalyzes the Insertion Both Oxygens
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Hypothesis

• Does TDO only catalyze dioxygenation reactions
  when L-Tryptophan is the substrate?
• We believe that TDO can dioxygenate other
  substrates.

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Methods

• Uv-vis spectra
• Detects Chromophores
• Conjugated Pi System

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Optical Spectrum
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New Spectra!

TDO Enzyme
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WT
Y130F
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Conclusions

• There are two new substrate analogues for TDO!
• The TDO active site may have flexibility or may
  be large enough to accommodate OH group at the 5
  position.
• This knowledge of new but less active substrates
  may be useful in further studies that utilize the
  trapping of intermediates as well as studies that
  investigate the position of the substrate in TDO.
• The amino group and the carboxylate group
  attached to the alpha carbon in L-Trp may not be
  necessary for partial activity, which may lead to
  the development of TDO partial agonist

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Acknowledgements

• Dr. Aimin Lu
• Rong Fu
• Teng Feng Li
• Rachel
• Dr. Ian Paul, neuroscience administrators, other
  mentors, and other CPN affiliates