Tryptophan is the least abundant of the 20 standard amino acids and a member of the essential acid group – we can’t synthesise it from other compounds so have to take it in through our diet.
It has three roles in the body: it is incorporated into proteins, a small amount is used as a precursor for serotonin and melatonin, and it is metabolised into kynurenine, which is used for a number of purposes including the production of niacin, the control of blood pressure and in reproduction.
The kynurenine pathway is of great interest as it plays a major role in immunomodulation and central nervous system disorders. The pathway is triggered by two enzymes: tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). TDO is highly expressed in the liver and works to control levels of tryptophan in the bloodstream, and if inhibited can increase levels of serotonin.
IDO, on the other hand, is expressed in the intestines, the placenta and in endothelial cells. While it is not clear what it does in the intestines, in the placenta it works to suppress the immune system of the mother so she is able to tolerate the presence of the alien life form known as the fetus. In endothelial cells, IDO is switched on by the cytokine interferon gamma and is highly active in inflammation.
Dr Helen Ball began studying IDO and the kynurenine pathway to try to understand their implications in cerebral malaria. “We know that the disease is dependent on cytokines such as interferon gamma and lymphotoxin alpha, so that started our interest in the kynurenine pathway,” Ball says. “Interferon gamma obviously has many effects but one of them is as the major inducer of this pathway.”
Last year, Ball and her colleagues at the University of Sydney had a bit of a breakthrough. Working on a mouse model of cerebral malaria, they found a huge induction of IDO activity, but there was an imbalance in the levels of two downstream metabolites of the kynurenine pathway, the neuro-toxic quinolinic acid and the neuro-protective kynurenic acid. These metabolites can interact with an N-methyl-D-aspartate (NMDA) class of receptors through opposing actions.
“We thought this might contribute to pathology because it would contribute to the seizures you see in cerebral malaria,” Ball says. “We did a lot of work looking at the activity of IDO in the brain and measuring these metabolites.
“Then we got the idea of creating a knockout mouse model, but were rather disappointed as the phenotype was not at all different. There have also been some other results – for example, when people used an inhibitor of IDO in pregnancy it can result in the loss of pregnancy, and these IDO knockout mice breed normally. So there were indications that there were perhaps some redundancies there.”
Ball suspected there was something else playing a part so began to look for possible homologues of IDO. She came across what is now called IDO2, sitting right next to the IDO1 gene on chromosome 8. “It was really quite a surprise because it was sitting there next to the IDO1 gene all along and no one had noticed it in the past 20 years,” she says. “It seemed like there had been a gene duplication and you get these two IDO isoforms.”
She explained her work to the AH&MR Congress in Brisbane yesterday.
