How can an essential nutrient the amino acid phenylalanine-be toxic? The amino a

Question

How can an essential nutrient the amino acid phenylalanine-be toxic? The amino acid phenylalanine is present in many foods and commonly used in artificial sweeteners, but i is toxic to those born with a metabolic disorder called phenylketonuria (PKU). These people may have severe and permanent mental disability if they ingest high levels of phenylalanine. What type of metabolic defect causes this problem, and how might this knowledge lead to a cure? Part A Protein structure is often evaluated using enzymes like trypsin that cut the protein at specific amino acid residues exposed on the surface. The results from this type of experiment using PAH in the presence (+) or absence () of phenylalanine is shown below. Interpret the results in terms of the effect phenylalanine has on the structure of PAH. (+) (+) (+) Trypsin Phenylalanine size standard Da) 30

Explanation / Answer

Answer 1.

Phenylketonuria (PKU) is also an inherited disorder; it is inherited in autosomal recessive pattern as a result of a single gene i.e. mutation of PAH gene. It also shows pleiotropic effects.

Phe crosses the blood brain barrier with the help of Large Neutral Amino Acid (LNAA) transporters. In the brain, neutral amino acids like Phe and Tyr are required for protein and neurotransmitter synthesis.

Note that the PAH gene is responsible for conversion of the amino acid phenylalanine to tyrosine.

Now, if a person with the disease PKU ingests Phe, then the excess Phe will not be converted to Tyr. This is because the excess Phe saturates LNAA transporters; it disallows Phe to cross the blood-brain barrier. So the excess Phe accumulates in blood. This finally disallows synthesis of neurotransmitters; this results in mental disability. So, the essential amino acid Phe becomes toxic.

Part A

Option ‘b’ is correct.

PAH has different structure in presence and absence of Phe. In the first lane, ladder is there.

In the second lane, only PAH is there. There is no Phe and no trypsin. One band corresponding to PAH is shown.

In the third lane, trypsin is there. It cuts the PAH enzyme and shortens it. So, only one band is seen. This band is smaller than the band of the first lane.

In the fourth lane, trypsin, Phe and PAH, all three are there. PAH acts on Phe to form the third band that is present in between the two bands. The top most-band is of PAH, and the lowest band is that of PAH cut via trypsin. Note that the middle band is of changed structure of PAH in presence of Phe.

Part B

Option ‘b’ is correct.

The results support the hypothesis that Phe is the allosteric regulator of PAH enzyme. It changes its structure. Due to conformational change, the Phe is converted to Tyr.

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