Introduction

So last Friday we had such an awesome time on the STEMNG server with one of the steemstem co-founders in person of @JustTryMe90. In the course of our regular discussions and normal chit-chatting, the term PKU popped up. PKU stands for phenylketonuria and it is a consequence of an enzyme deficiency. I was particularly surprised that most people were not aware of this disorder so I have made it a point to do something we love to do on steemstem – enlighten. So yeah, let’s have fun.

What Really is the Big Deal About Phenylketonuria (PKU) ?

Metabolism is essential for life and survival. If we did not break down or synthesize molecules we would be fucked. Metabolism is not voodoo so there are guys who make this process possible. They are called enzymes. But you can choose to call them anything anyway. You remember when I told you they were the workaholics of the biological system. I wasn’t kidding. Their importance in the biological system cannot be undermined. So when they are absent or deficient, it ends up manifesting as disease conditions.
This is basically the case with PKU. It all starts with the catabolism (break down) of the amino acid – phenylalanine gone wrong. Under normal metabolic conditions, phenylalanine, like glucose, is harmless. The problem is when it accumulates. Phenylalanine is acted on by the enzyme – phenylalanine hydroxylase to yield Tyrosine. It is a hydroxylation reaction where an hydroxyl group is added to carbon-4 of phenylalanine with a co-enzyme, tetrahydrobiopterin, playing a huge role here. In phenylketonuria, this enzyme is missing. So phenyl ketonuria accumulates. I wish this was all what happened.
You remember I just mentioned that tetrahydrobiopterin plays a huge role in the conversion of phenylalanine to tyrosine. Well, the aforementioned coenzyme is converted to dihydrobiopterin simultaneously with phenylalanine being converted to tyrosine. The enzyme responsible here is dihydrobiopterin reductase. So what do you think would happen if this enzyme was also absent ? PKU of course.

Why is PKU such a cause for concern ?

PKU results in the accumulation of phenylalanine in blood and tissues due to the lack of the enzyme – Phenylalanine hydroxylase. The body tries to catabolize it anyway by exploiting a much less used pathway. This pathway converts phenylalanine to phenylpyruvate and this phenylpyruvate accumulates with phenylalanine too, further making PKU dangerous. The phenylpyruvate can be converted to phenyllactate via a decarboxylation reaction. This phenyllactate is known to accumulate in urine yielding the characteristic odor noticed in the urine of patients with PKU. The shitty part about this condition is that it affects the brain. PKU could occur due to the deficiency of phenylalanine hydroxylase or dihydrobiopterin reductase. The accumulation of phenylalanine in the brain per se is dangerous because phenylalanine seems to compete with other amino acids while crossing the blood-brain barrier resulting in the deficiency of amino acids required for normal neuronal processes. This could present as mental retardation. In the PKU that results due to the deficiency of the enzyme dihydrobiopterin reductase, neurological symptoms present more as this enzyme generates tetrahydrobiopterin which is needed for the production of the neurotransmitters; noradrenaline and serotonin.

Your Urine Could Turn Black Literally ! Why ?

So during the course of our normal chit chat or discussions, I mistakenly mentioned darkening of urine as one of the symptoms of PKU. But well, I was wrong. Urine only darkens (due to a disorder of amino acid metabolism) in a condition known as Alkaptonuria. It also occurs as a result of a deficiency of an enzyme along the phenylalanine catabolic pathway. The enzyme in this case is homogentisate dioxygenase. It catalyzes the conversion of homogentisic acid to maleylacetoacetate. This condition is not detrimental to health anyway. The urine just turns black on standing for some time. This is because homogentisic acid undergoes oxidation by polyphenol oxidase yielding benzoquinone acetate. Benzoquinone acetate undergoes polymerization to yield alkaptone bodies which are seen as black pigments in urine. They can also be deposited in bone and cartilages and can be implicated in arthritis. So yeah we have that figured out.

How are these conditions diagnosed and managed ?

For diagnosis, PKU used to be and is still by the characteristic odor of urine especially in new born babies but more advanced techniques like Tandem mass spectroscopy, Guthrie test and ferric chloride test are used. Alkaptonuria diagnosis starts off with leaving urine to stand for some time and observing if it turns black. It is quick to turn black due to adequate exposure to oxygen and sunlight. Ferric chloride test and benedict’s test are also used routinely.
Management of these conditions requires that you keep phenylalanine consumption to the barest minimum. That would mean avoiding foods like soybeans, egg whites, shrimp, chicken breast, spirulina, watercress, fish, nuts, crayfish, lobster, tuna, turkey, legumes or….. better still avoiding everything edible lol. Phenylketonuria that results due to the deficiency of the enzyme homogentisate dioxygenase requires L-3,4-dihydroxyphenylalanine (Ldopa) and 5-hydroxytryptophan be supplied in diet as these are precursors of noradrenaline and serotonin which are required for normal neurological functions. So on this note, I rest my case ! Till next time.

References

^{(1) Principles of Biochemistry by Albert Leningher. p. 680.
(2) Textbook of Biochemistry For Medical Students, 6th Edition. pp. 207-209.
(3) https://en.wikipedia.org/wiki/Phenylketonuria
(4) https://www.mayoclinic.org/diseases-conditions/phenylketonuria/symptoms-causes/syc-20376302
(5) https://en.wikipedia.org/wiki/Alkaptonuria
(6) https://www.healthline.com/health/alkaptonuria}