An ACE in the hand
Unravelling the biochemistry of nutrition
By understanding what's happening with rare human disorders we sometimes generate knowledge that's fundamental to how our bodies function. In so doing we can directly assist the handful of people suffering from that rare condition, and indirectly advance the broader field of human biochemistry. Such a situation exists with Hartnup disorder. It's a rare genetic condition that manifests itself mainly in children, and has symptoms of skin rash and neurological problems. What causes it is an impairment with the absorption of amino acids in the intestine. Researchers at ANU are studying this impairment and have recently made some significant advances in understanding the uptake of amino acids in the intestine and kidneys.
"Protein forms up to 20 per cent of our nutrition," says Professor Stefan Bröer, the biochemist leading the team doing the research at the ANU School of Biology. "Before it can be used by the human body, protein is split into its subunits called amino acids. The amino acids are then removed from the intestine by specialised cells which are endowed with a large number of molecular transporters that move nutrients from the intestine and into the cells.
"A few years ago we identified a new subfamily of these amino acid transporters that is responsible for the uptake of neutral amino acids in these tissues. Together with colleagues from ANU and Sydney University, we subsequently could demonstrate that Hartnup disorder is caused by mutations in one of these amino acid transporters so we're hopeful that our research will generate insights that will help with the treatment of this disease while, at the same time, advancing the whole area of amino acid uptake and kidney function. The kidney is also involved because these amino acid transporters also play an important role in the kidney in reabsorbing metabolites that the body needs to retain."
But the transporters are only half the story and Professor Bröer's team has recently demonstrated that for the transporter to be fully functional it needs another protein named ACE2 working with it. Scientists have suspected that the ACE2 protein plays a role in regulating blood pressure but this is the first time it's been implicated in digestion and the uptake of amino acids.
"The ACE proteins are involved in generating a hormone which regulates blood pressures," explains Professor Bröer. "ACE inhibitors are widely prescribed drugs that reduce the risk of heart failure and protect against the long-term effects of diabetes.
"Two versions of the protein are known: ACE1 and ACE2. ACE 1 is a very well known target for blood pressure regulation, and many people take drugs to lower their blood pressure by inhibiting this particular enzyme.
"More recently they discovered a second protein, ACE2; and it was found just by looking at the human genome. While it's known to be related to ACE1, no-one really knew what role ACE2 played though it was expected that it has something to do with blood pressure regulation.
"What my lab found was from a quite different direction. We looked at nutrient uptake in the intestine. We are interested in protein digestion, how it gets split into amino acids, and how these amino acids get taken up in the intestine.
"And what we've discovered is that the ACE2 protein plays an important role in both of these areas. It helps split proteins into constituent amino acids and it's an important partner to the amino acid transporters that allow those amino acids to then be taken up into the cells."
Professor Bröer's research has several implications. It provides a more detailed understanding of what drives Hartnup disorder, it suggests we need to be very careful if we consider using ACE2 as a target for blood pressure drugs because ACE2 plays an important role in nutritional uptake, and it suggests that there might be other approaches available for treating high blood pressure.
"One thing we're looking into is the link between amino acids and blood pressure," explains Professor Bröer. "New research on metabolites found in urine is suggesting that certain amino acids in the urine correlate with higher blood pressure. This ties in neatly with our studies on the connections with ACE2, amino acid transporters and blood pressure. In the long term it might result in a different way to treat blood pressure. Normally, when you talk about blood pressure you work on salt intake but maybe there are other approaches that focus on proteins."
For now, the researchers are working to better understand the interactions between amino acid transporters and the ACE2 protein. Professor Bröer's lab has recently acquired a breeding population of ‘knock-out' mice that have had the gene for one of the amino-acid transporters removed (or knocked out). These mice, then, are perfect models to study Hartnup disorder as they lack the same functionality as humans with Hartnup disorder.
"The results of these studies will go beyond just assisting people with Hartnup disorder as it will help develop our basic understanding of intestinal and kidney function," says Professor Bröer. "These findings could have important implications for the way we treat common disorders such as diabetes and celiac disorder.
"I suppose my over arching interest is on how the human body works. When I'm teaching, this is the basic point I try to get over to my students - that we're trying to unravel is how the human system operate - the basic system that allows us to live and grow.
"The fascinating thing about this system is that as you focus down on the role played by individual proteins, you often discover they play multiple interacting roles. This is exactly what we've found as we've looked at the role of the ACE2 protein."