University of Otago, New Zealand

Chemistry

Te Tari Hua-Ruanuku

Casey Davies

contact photo
Casey Davies
Supervisor: Dr Guy N. L. Jameson
Tel: (03) 479 5248
Location: Science I, 101a
cdavies@chemistry.otago.ac.nz


Cysteine Metabolism


Cysteine is a non-essential amino acid is the intracellular precursor of inorganic sulfate which is formed by sequential oxidation of the sulfur atom largely via the cytosolic cysteine dioxygenase system. Additionally, due to its intrinsic reactivity, cysteine has many different roles in health and disease. Perturbation of the concentration of cysteine has been shown to occur in a variety of disease states. In fact cysteine is neurotoxic and therefore has to be tightly regulated. Its neurotoxic effects are believed to occur through blocking NMDA receptors.

The chemistry of cysteine and iron are closely intertwined in vivo. Iron is an essential cofactor in the first step of normal cysteine breakdown to cysteine sulfinate by the enzyme cysteine dioxygenase (CDO). Furthermore, iron and cysteine are both involved in the formation of neuromelanin, which is critically involved in the pathophysiology of the Parkinson’s disease. During Parkinson’s disease cysteine levels increase and so do levels of iron suggesting that this first enzymatic step in cysteine metabolism is compromised. Intriguingly the other enzymatic steps involved in the formation and breakdown of cysteine are PLP dependant and do not contain iron within their active sites. Activity of these enzymes may however be regulated or modulated by iron and/or cysteine.

The aim of this project is to develop a greater understanding of the kinetic factors that effect sulfur metabolism and how this influences concentrations of cysteine and iron and the activity of CDO, the key enzyme involved with these processes. 

Therefore three important and related questions need to be addressed:

  1. How is CDO activity affected by advanced metabolites of cysteine?
  2. How does iron concentration affect subsequent metabolic steps of cysteine? 
  3. Are the PLP enzymes kinetically regulated?