When we eat, we consume many different essential biomolecules that our body needs to function correctly. These are things such as carbohydrates, lipids and proteins. Proteins are the most important biomolecule as they mediate every cell in the body and control the processes and functions that the cell may complete. Most importantly, proteins are the molecular method through which genetic information is displayed.
Proteins are naturally occurring polymers that are made from chains of amino acid groups. There are 20 different types of amino acids that the body needs to function perfectly; however, some are not essential. An essential amino acid is one that the body cannot synthesize itself, such as phenylalanine. Occasionally, there may be a genetic disorder that means a person doesn't have a particular enzyme to break down a protein. This means that their body cannot use these amino acids to function correctly further along the chemical pathways.
An example of this is Phenylketonuria (PKU). The defective gene that is responsible for reducing the activity of the enzyme phenylalanine hydroxylase is called PAH. This enzyme is responsible for converting phenylalanine into tyrosine. With this enzyme either missing or defective, the process cannot continue and there is an excessive build up of phenylalanine. This elevated level of phenylalanine is known as hyperphenylalaninemia.
Specifically for people that have PKU, there is a little used pathway that comes into play. This pathway allows phenylalanine to be transaminated with pyruvate to create phenylpyruvate. Phenylalanine and phenylpyruvate are then built up in the blood and in bodily tissues and then becomes excreted into the urine giving the disorder its name, Phenylketonuria. Phenylpyruvate can be either decarboxylated to phenylacetate, or it can be reduced to phenyllactate. Due to the fact that phenylpyruvate is excreted in the urine, once it has been decarboxylated into phenylacetate, it produces a particular smell in the urine which is used by doctors as part of the diagnosis of PKU.
Figure 1.
The alternative pathway for catabolism of phenylalanine in Phenylketonuria. This shows how phenylacetate and phenyllactate are produced, how they then build up in tissue, blood and urine and are then excreted.
The build up of phenylalanine and/or its metabolites in babies and young children will eventually lead to abnormal development of the brain and this in turn will then lead to intellectual disability. This is due to the fact of excess phenylalanine competing with other amino acids to cross the blood brain barrier, which then will result in a deficiency of other necessary metabolites.
Due to the fact that PKU is an inborn error of amino acid metabolism, if it is detected early enough, it can be relatively easy to manage. It isn't curable but can be controlled through special dietary requirements. As people with PKU cannot eat anything that contains protein, they can be prescribed special supplements that there will only be just enough phenylalanine and tyrosine to complete protein synthesis.
The tests that are used to detect PKU in babies and young children are relatively inexpensive and can lead to healthcare institutions saving millions in terms of healthcare costs later on in the sufferer's life.
Alternative methods of treatment are currently being tried and tested and one of these is by using the nutritional supplement BH4. BH4 is also known as tetrahydrobiopterin. Tetrahydrobiopterin is used in the catalisation of an O2 atom and becomes oxidised itself to form dihydrobiopterin. Scientists believe that if the BH4 can be given to someone with PKU, then their body will continue to function as normally as it can.
Figure 2.
This shows the role of tetrahydrobiopterin in the phenylalanine hydroxylase reaction.
Another method is by introducing a completely synthetic, genetically engineered version of the dysfunctional enzyme phenylalanine hydroxylase. This is still undergoing experimentation and is not a preferred method of treatment as of yet.
Another inborn error of amino acid metabolism is Alkaptonuria. This is when the defective gene is HGD and is used to control the enzyme is homogentisate dioxygenase. People who have Alkaptonuria, excrete large amounts of homogentisate in their urine. As soon as the homogentisate is oxygenated it turns black, meaning that it is one of the methods that can be used to detect someone who has Alkaptonuria.
Archibald Garrod discovered in 1922 that Alkaptonuria is an inherited trait, the first of all the inborn errors that were known. He managed to trace the cause of the problem down to a complete absence of the enzyme homogentisate dioxygenase, and became the first to make the connection between missing or defective enzymes and inborn errors of metabolism.
This metabolic disorder also includes a build up of dark pigment in tissues such as cartilage and skin which usually occurs in people 30 years old and more called Ochronosis. In early adulthood, the sufferer can also experience arthritis of the spine and large joints around the body. A few other problems that Alkaptonuria can cause include heart problems, prostate stones and kidney stones.
The gene that is responsible for this genetic deformity is homogentisate 1,2-deoxygenase. This gene is responsible for controlling the enzyme homogentisate oxidase which is used to break down phenylalanine and tyrosine into maleylacetoacetate. As phenylalanine and tyrosine a broken down, the produce a substance called homogentisic acid which then builds up in the body. With large excess amounts of homogentisic acid, it accumulates in connective tissue which is the reason that cartilage and skin darken. Over a longer period of time, the excessive build up causes the aforementioned arthritis in the affected joints. Finally, homogentisic acid is excreted with urine, which when it becomes oxygenated, turns dark, almost black in colour.
Once again, as with PKU, this condition is currently being controlled by the sufferer having either a low protein diet or no intake at all and using supplemental medication to help the phenylalanine and tyrosine pathways continue as normally as possible.
Figure 3.
This shows the pathway from phenylalanine to acetoacetyl-CoA. The healthy route and where if there is a defective or missing enzyme, where it is and the condition that this will cause.
Finally, a third inborn error of amino acid metabolism is Tyrosinemia. There are three types of this condition depending upon the stage of the pathway that an enzyme is missing, Type I, Type II and Type III. Each has its own characteristics and symptoms that make them identifiable but are all caused along the same pathway, just in different places due to which enzyme is dysfunctional.
Type I Tyrosinemia is the most severe of this disorder and is caused by the defective gene FAH. This gene is responsible for controlling the enzyme fumarylacetoacetase which breaks fumarylacetoacetate into fumarate and acetoacetate succinyl-CoA. (See Figure 3.) Among some of the symptoms of this condition are jaundice, a cabbage like odour and an increased tendency to bleed. More severe problems that can occur are liver and kidney failure, problems related to the nervous system and the sufferer is at an increased risk of contracting liver cancer. The problems to do with the liver are due to the fact that the processes all happen there and when tyrosine hasn't been broken down completely to form acetoacetyl-CoA, these toxic levels build up in the organs and tissues and begin to cause damage to these areas.
Type II Tyrosinemia is caused by the defective gene TAT. This gene is responsible for controlling the enzyme tyrosine aminotransferase. This enzyme is responsible for breaking down α-ketoglutarate into glutamate and p-Hydroxyphenylpyruvate. (See Figure 3.) This enzymatic deficiency mainly affects the eyes and skin and roughly 50% of people that suffer from it develop some form of intellectual disability. This is once again due to the high levels of tyrosine in the blood and tissues which once built up begin to cause damage to the brain.
Type III Tyrosinemia is caused by the defective gene HPD which is responsible for controlling the enzyme p-Hydroxyphenylpyruvate dioxygenase. This enzyme is responsible for breaking down p-Hydroxyphenylpyruvate into homogentisate. (See Figure 3.) This is the second most severe type of Tyrosinemia with symptoms of intellectual disability, seizures and loss of balance and coordination. This is once again similar to the previous two Tyrosinemia types due to the fact that there is a build up of tyrosine in the blood and tissues causing these problems.
All three types of Tyrosinemia can be controlled by having a low protein diet from as soon as it is diagnosed for the rest of the sufferer's life, where only just enough phenylalanine and tyrosine are provided. This ensures that there will not be an excessive build up of either causing problems later on in the patients life. Due to the severity of damage that Tyrosinemia causes to the liver, in some extreme cases, the patient may need to undergo surgery for a liver transplant. However, if this condition goes undiagnosed for an extended period of time, approximately a year, then unfortunately the patient will become deceased. This is due to the extent of the damage to the liver and the brain, meaning that their body can no longer function.
Overall, inborn errors of amino acid metabolism, if detected at a young enough age (babies and infants) can be easy to diagnose and control. This can be achieved by having a low protein or zero protein diet and by avoided foods with artificial sweeteners such as phenylalanine and aspartame as these contain amino acids that could be potentially lethal to someone that has a genetic disorder that doesn't allow for these to be broken down.
Doctors and nurses now understand the importance of detecting these conditions early and therefore, tests for them tend to be carried out within 6 months of a baby being born in the UK and the US. If an inborn error is diagnosed, then it makes handling the condition easier and is more cost effective for hospitals. This is because the long term cost of medical care for someone that has controlled the disorder is a lot less due to the fact that there are not as many problems in later life for that person. For someone that has an inborn error of metabolism that is left undiagnosed however, the costs involved to look after them once some of the damage has been done is an incredible amount more. This includes things from organ transplants to care homes if the patient has suffered from intellectual disability as an effect of leaving their condition untreated.
