Current research interests
- The kynurenine pathway of tryptophan metabolism
Although the amino acid tryptophan is often considered primarily for its role as the precursor of 5-hydroxy-tryptamine (5-HT; serotonin), it is also oxidised to kynurenine which can then be transaminated to kynurenic acid or further oxidised to quinolinic acid (see figure 1 for a summary of the pathway and Figure 2 for a more complete version). The biochemistry of tryptophan metabolism was studied widely in the period up to 1970 because of the medical importance of the product nicotinamide (niacin; vitamin B3). The concept that the other metabolites along the pathway from tryptophan to nicotinamide had independent, highly specific effects in the brain was initiated by our discovery that quinolinic acid was able to activate, selectively, NMDA-sensitive receptors for glutamate, producing excitation of neurons in the cerebral cortex when applied by microiontophoresis to individual cells [Stone & Perkins, 1981]. It was then discovered that kynurenic acid was an antagonist at glutamate receptor [Perkins & Stone, 1982]. Within a few years both compounds became routine experimental tools for studying glutamate-mediated neurotransmission, and the field of kynurenine pathway research has now expanded dramatically into all fields of biology.
Up to the present time, Professor Stone’s research group has continued to study basic aspects of the kynurenine pathway as well as links with medical conditions. This and related work in other laboratories has implicated the kynurenines in a range of brain disorders including stroke, Huntington's disease, schizophrenia, Alzheimer's disease, cognitive problems after major surgery, cerebral malaria and trypanosomiasis. His present primary interest concerns the role of the kynurenine pathway in brain development and the relationship between effects of the kynurenines on the nervous system and the immune system.
1. Figure 1. Main components of the kynurenine pathway
- The Role of Serine Proteases in cell interactions and Cancer
Professor Stone is currently also continuing to explore the role of serine proteases in the biology of the central nervous system, developing recent work on the potential transduction processes underlying the long-term depression (LTD) of synaptic activity and modulation of neuronal excitability which they produce in the hippocampus.
Understanding the mechanisms of these effects led to the discovery that the serine proteases chymotrypsin and subtilisin suppress the expression of tumour suppressors proteins such as DCC (Deleted in Colorectal Cancer), neogenin and unc-5. (Forrest CM et al., 2016; Stone & Darlington, 2017). Chymotrypsin is produced by the gut as a digestive enzyme but it is also absorbed in the bloodstream, giving it access to all organs and tissues.
Subtilisin is a bacterial enzyme (secreted by Bacillus subtilis and other species) which is widely present in the environment, especially the soil. It is also added to meat and other food products to make them more tender and tasty. The bacteria are used in probiotics given to farm animals to increase their rate of growth and muscle mass. This raises the possibility of subtilisin entering the human food chain, gaining access to most organs and tissues and possibly contributing to the potential link between environment, diet, obesity and cancer.