Neurodegenerative disorders, like Huntington’s and Alzheimer’s disease, are devastating. As you can imagine, witnessing the slow and progressive loss of a loved one’s mental and emotional states is an extremely painful and heartbreaking experience. Currently, there are no cures for neurodegenerative diseases, and the drugs that are available only alleviate symptoms, without slowing the progression of the disease.
For many years, neuroscientists have studied the link between neurodegeneration and the metabolism of an amino acid called tryptophan. Tryptophan is one of the 9 essential amino acids that the body cannot synthesize on its own, which means it must be obtained through one’s diet. Protein containing foods, such as chocolate, oats, milk, meat, fish, and turkey, contain high amounts of tryptophan. Remember that turkey feast you enjoyed on Thanksgiving last November and the subsequent “food coma” you experienced while watching football? The high levels of tryptophan in turkey are converted into the hormone, melatonin, which is really important in telling your brain that it’s time to sleep. Tryptophan can also be converted into many different types of small molecules in the brain. Interestingly, some of these metabolites are neurotoxic (i.e. causing neuron damage), while others are neuroprotective.
Scientists theorize that as we age, we produce more of the harmful metabolites, which may lead to neurodegeneration and neurodegenerative diseases. Years of research on tryptophan and neurodegeneration have supported this hypothesis. For example, the brains of patients with neurodegenerative diseases have higher levels of neurotoxic metabolites and lower levels of neuroprotective metabolites compared to non-diseased patients. Therefore, scientists and doctors have reasoned that correcting this imbalance may reduce brain degeneration.
In the tryptophan metabolism pathway, the enzyme called KMO is at a critical branching point between the production of harmful and beneficial metabolites. Many years of research have shown that blocking KMO activity can increase the production of neuroprotective metabolites. One compound that has been shown to block KMO is the drug UPF648. When researchers gave this drug to fruit flies that were genetically engineered to have Huntington’s disease, they showed fewer symptoms. This provided some evidence that blocking the “bad” tryptophan metabolism pathway could be an important target for therapeutic drugs.
If that drug could increase the neuroprotective potential for many acute and chronic neurological disorders, they why not cure all people with neurodegenerative diseases by giving them the KMO inhibitor? Unfortunately, it is not that simple. The trouble is that KMO inhibitors do not cross the blood-brain barrier (BBB). Essentially, the blood-brain barrier prevents many types of drugs from passing from the blood into the brain. Anita will describe the BBB in more detail on Wednesday. If the drugs can’t reach the brain, then they can’t help treat neurodegenerative diseases. That means that scientists have to invent new molecules that not only block KMO but also pass the blood-brain barrier! Not an easy task, I assure you!
To overcome this obstacle to KMO-targeted drug discovery, researchers at the Manchester Institute of Biotechnology worked for five years to establish discover how UPF648 interacts with KMO. The researchers used a technique called crystallography to obtain structural information about the molecules in their active state and where UPF648 interacts with KMO. Their results, published in Nature, detail the molecular configuration of the enzyme-inhibitor structure. This is really important because it provides information about how UPF648 blocks KMO activity. With this knowledge, new drugs can be produced that block KMO and are able to cross the blood-brain barrier. Hopefully, we will have drug therapies that target neurodegenerative diseases soon!
Amaral M., Levy C., Heyes D.J., Lafite P., Outeiro T.F., Giorgini F., Leys D. & Scrutton N.S. (2013). Structural basis of kynurenine 3-monooxygenase inhibition, Nature, 496 (7445) 382-385. DOI:10.1038/nature12039