PKU and Inheritance  
   
   1. There are 400+ mutations identified in the phenylalanine hydroxylase (PAH) gene.
       How significantly an individual is affected depends on the degree of PAH activity and blood
        phenylalanine concentrations.  Lower enzyme activity results in higher blood phenylalanine
        concentrations and a more severe clinical phenotype. Classic PKU, the most severe form of the disorder,
        occurs when phenylalanine hydroxylase activity is extremely reduced or absent. Less severe forms of this
        condition are called variant PKU and non-PKU hyperphenylalaninemia and carry a smaller risk of brain
        damage. People with very mild cases may not need to follow a low-phenylalanine diet.
        A deletion of a single base in the 55th codon of the PAH gene results in an allele that causes Classic PKU. 
        a. Why would this mutation be so deleterious?
        b. Explain how the allele exhibiting this mutation would specifically
             alter the structure/function of the protein the gene should code for.
   2. Explain the inheritance pattern of Classic PKU.
   3. a. On which chromosome is the PAH gene? 
        b. Identify where the PAH gene located on this chromosome, the size of the gene, and any
             other information you can  find re PAH gene regulation/expression.
   4. Describe the clinical implications (if any) for an individual possessing one copy of the mutated PAH
        allele identified in question 1. 
​   5. Watch this video...
        https://www.pku.com/about-pku/managing-pku#!
        People with PKU must avoid foods such as meat, fish, poultry, soy, dairy, nuts and legumes.
        a. Why?
        b. What can PKU individuals eat so that they can build structural/enzymatic proteins? 

                                                                     PKU and Ligands
     Neurochemical and behavioral studies have shown that animals fed diets with high amounts of the amino acid Phenylalanine show a decrease in brain serotonin levels and exhibit neurological symptoms similar to Parkinson's disease. These symptoms are due to a deficiency of a neurotransmitter called dopamine. This decrease in dopamine is thought to be caused by excess Phenylalanine reacting negatively with other amino acids in the brain, particularly Tyrosine and Tryptophan which are essential for neurotransmitter synthesis.  
     One type of membrane transport protein has a high affinity for Phenylalanine.  The
Phenylalanine competes with other amino acids, including Tyrosine and Tryptophan, for the use of the transport protein. Tyrosine and Tryptophan (among others) are necessary for the synthesis of neurotransmitters.
     Excess Phenylalanine may also interfere with the enzymes necessary for the production of neurotransmitters. Phenylalanine works as a competitive inhibitor of the enzymes Tyrosine hydroxylase and Tryptophan hydroxylase.   

1. What is a neurotransmitter and why would a decrease in neurotransmitter concentration be a problem?

2. a. What is the function of Tryptophan hydroxylase?
     b. What does it mean that Phenylalanine is a competitive inhibitor with this enzyme?

3. a. If Phenylalanine competes with Tyrosine for a membrane transport protein, what does this mean for the
         intracellular concentration of Tyrosine when Phenylalanine concentrations are high?
     b. Why?
     c.  How would this specifically affect neurotransmitter synthesis, ie, what is the specific role of Tyrosine
          in the production of neurotransmitters? 

​4. Reduced neurotransmitter concentration is known to play a role in several conditions.
    a. Besides Parkinson's Disease, describe one condition. Include onset, symptoms, cause and possible                       clinical treatments.  

​5. SSRIs are often prescribed to counteract low neurotransmitter levels. 
    a. For which condition(s) might SSRIs be prescribed?
    b. What are SSRIs?
    c. How do SSRIs work?

                                                      Phenylalanine, PKU and metabolism
​ 1. Children with PKU (phenylketonuria) may give off a musty body odor akin to mold or mildew. 
      Why?

 2. Additionally, children with PKU often exhibit light skin, hair and eye color. 
     Why?

 3. Phenylethylamine (PEA) is metabolized from phenylalanine. PEA is a hormone and also acts as a                        neurotransmitter. PEA supplements are sold because they are thought to serve as an antidepressive but            there is no empirical evidence to support this claim. Endogenous (naturally occurring) PEA increases                have been linked to the mood elevation that occurs after moderate exercise.  Researchers suggest this                increase causes the euphoric mood often called “runners’ high.” And because depressed people tend to              have low PEA levels, the researchers say there now is an explanation of why exercise has a natural                      antidepressant action. A research team studied 20 healthy young men by measuring their PEA levels after        one day of no exercise and after one day of moderate exercise. 18 of the men had increased PEA levels 24          hours after their exercise.
      My son skydives (for fun) with a professional group. He also flies his own plane to skydiving
      competitions. Again, for fun. Skydiving has been shown to induce a significant increase in urinary
      phenethylamine (PEA) concentrations.
      a. So please explain to me the mechanism by which PEA elevates mood so I can
         understand why my kid loves to jump out of perfectly good aeroplanes...

       PEA is also present in cocoa beans and chocolate. PEA concentrations increase during the roasting of
       cocoa beans. It had been suggested that people could increase their PEA levels by eating chocolate.                     Again, not a lot of  empirical evidence to support this claim. Chocolate has also been linked to romance             and love because of the mood boosting effects theoretically experienced after eating chocolate.                             Unfortunately, the rapid metabolism of phenylethylamine (PEA) by an enzyme called MAO-B  
       (monoamine oxidase B) which metabolizes PEA to phenylacetic acid,  stops ingested PEA from reaching           the brain.
       b. What then would a monoamine oxidase inhibitor do? Explain your rational. 
 
4. In the absence of PAH (phenylalanine hydroxylase...refer to an earlier question set for info re PAH) excess
     phenylalanine is converted to phenylpyruvate instead of tyrosine. It is the accumulation of 
     phenylpyruvate that can lead to mental retardation in PKU infants.
     Why?

​5. Phenethylamine (PEA) "substitutes" are molecules made from phenethylamine by substituting/replacing         hydrogen atoms on the phenethylamine structure. Several "substituted" phenethylamines are                               psychoactive drugs such as amphetamines and methylamphetamines (known as crystal meth) as well as
     appetite suppressants and nasal decongestants. In the crime drama Breaking Bad, phenylacetic acid is
     featured twice as a precursor to methamphetamine. And dopamine is just PEA with a hydroxyl group                 attached to two positions on the molecule. What seems like simple modifications to certain molecules
     result in dramatically different functions in how the brain processes these altered molecules.  
     What is the mechanism by which methylamphetamines alter brain  function?
  
6. Attention-deficit / hyperactivity disorder (ADHD) is a condition that affects about 10% of children/4% of           adults in the US. ADHD is diagnosed via a patient’s history and symptoms including inattention,
     excessive talking, poor response to stress, fidgeting and disorganization. Since the criteria for diagnosis
     are subjective, ADHD is often misdiagnosed/underdiagnosed. I have ADHD and I suspect other family             members do as well. Since the therapeutics used to treat ADHD alter biomarker levels, clinical researchers
     are trying to find a biomarker for ADHD that would help in the diagnosis of this disorder.
      How might this condition (and the presence of potential biomarkers) relate to PKU?

Please be mindful of the threat of plagiarism. Plagiarism occurs when anyone uses another person's words without giving t hem credit. DO NOT cut and paste any part of your answers and DO NOT simply reword a source you found on the internet. DTCC screens for plagiarism. If you are found to have used a source's words without citing them, you are guilty of plagiarism and will be referred to the division Dean for disciplinary action.
​Please research these questions and then write your own answers to them, incorporating the information you learned.  

                                                                    PKU and phenyalanine
​                             Many diet sodas contain an artificial sweetener called aspartame. 
                   Aspartame consists of two amino acids—aspartic acid and phenylalanine. 

1. a. Which R group is exhibited by aspartic acid?
    b. What characteristics would this R group confer to this amino acid?
    c. Due to these characteristics, how would you expect this amino acid to interact with other amino acids
         in a polypeptide?

2. a. Which R group is exhibited by phenylalanine?
     b. What characteristics would this R group confer to this amino acid?
     c. Due to these characteristics, how would you expect this amino acid to interact with other
         amino acids in a polypeptide chain?

3. Individuals with a condition called PKU (phenylketonuria) don't produce sufficient amounts of
    phenylalanine hydroxylase (PAH). 
    a. What type of molecule is phenylalanine hydroxylase?
    b. What products are produced by this molecule's actions.
    c. What is the formula for the reaction facilitated by this molecule?
    d. Does this molecule function in an anabolic or catabolic reaction?

#5 : due Monday, 12/5 

This series of questions is designed to integrate many of the topics we will explore in our course this semester. Please answer the questions and submit your typed, hard copy answers when you arrive in lab on the date they are due.
​Late submissions can not be accepted. 

#3 : due Monday, 10/24 

 and what is the "chemistry" of love...?

 "new drug  in the 70s...)

these questions were modified 10/27

#1 : due Monday, 9/12

#4 : due Monday, 11/14 

                                                                 PKU and evolution

Review this page on population genetics:

​

 then...
    Since PKU occurs when an individual inherits two recessive alleles (= homozygous recessive)
    and as of 2020 there were 16,500 people living with PKU in the United States 
    when the population of the US was 330 million:               
   
​    a. calculate the frequency of the PKU recessive allele in the US population.
    b. calculate  the frequency of the "normal" dominant allele (correctly coding for PAH) in
         the US population.
​    c. calculate the frequency of heterozygotes in the US population.
   
d. given that there were approx. 3.6 million infants born last year in the US, and 1 in 10,000                     newborns were diagnosed with PKU last year in the US, do the Hardy Weinberg numbers                  suggest this gene is or is not experiencing microevolution? 
         Which of the five HW influences do you think would lead to the possible microevolution of this
         gene in the US population? Explain your reasoning.

                                                Please show and explain all of your work...

Semester Question Series

#2 : due Monday, 9/26