1. From Proteins to Phenotype

2. Learning Objectives By the end of this class you should understand: Why an altered gene produces an altered phenotype The function and purpose of enzymes in the body Signs and symptoms of genetic metabolic disorders Results of defects in transport and structural proteins Genetic variation in smell, taste, and drug sensitivities

3. Protein Sequence DNA sequence produces amino acid sequence Altered DNA alters amino acid sequence Why does a different amino acid sequence change the phenotype?

4. Protein Structure Proteins depend on their shape to function Proteins serve many functions in the body  Enzymes  Transport proteins  Structural proteins  Signal molecules

5. Mutation Altered DNA is called mutation  More in chapter 11, will be on 3 rd exam Mutations produce random variations  Many variations are defective  Occasionally variations are superior  Our own structures have been refined by lucky mutations many times!

6. Enzyme Function

7. Enzyme Activity An enzyme is a protein that assists a chemical reaction  Is not consumed, only catalyzes reaction Binding site must precisely fit molecules in reactions Many enzymes work together

8. Alternative Visualization

9. Other Enzyme Info Enzyme names typically end in -ase Typically named for reactant, process or product  Alcohol dehydrogenase: breaks down alcohol  DNA Polymerase: Polymerizes DNA  Peptidyl Transferase: Transfers peptide in ribosome Sometimes contain cofactors and other binding sites  These let the body control the reaction rate

10. What Can Go Wrong? Phenylketonuria: an enzyme-related genetic disorder  “-uria” = something in urine The enzyme PAH breaks down excess phenylalanine to tyrosine  Phenylalanine Hydroxylase

11. PKU: An Enzyme Deficiency As always, we have two genes for PAH If one is defective, PAH can still be produced If both are defective, PAH is absent and PKU results

12. Metabolic Pathway

13. Treatment? Currently no technology exists to modify genes in developing humans  Check back in a couple decades! Primary risk is phenylalanine buildup, so treatment is a low- phenylalanine diet

14. PKU Testing PKU testing is mandatory for all newborns in all 50 states of the USA PKU screening is most common because PKU is relatively common and also dietary treatment is available Most critical until age 15 but now recommended for life

15. Galactosemia Another enzyme deficiency disorder  “-emia” = blood disorder Galactose is one of the three major body energy sugars Processed with galactose-1- phosphate uridyl transferase (GALT)

16. Where is John's GALT? Galactosemia is a disorder caused by two defective alleles for GALT  There is an allele of intermediate effectiveness, Duarte allele  G +, G D, and g are the three alleles When enzyme is absent, galactose builds up in blood and damages body Dietary treatment prevents death but mental retardation is common

17. Lactase Enzyme Another failure of metabolic enzyme is the enzyme lactase  Lactase cleaves the bond in lactose (milk sugar) allowing the two sugar rings to be absorbed  Failure to cleave the bond causes the lactose to enter the large intestine, where bacteria consume it and produce bacterial waste (gas & acid)

18. Variable Expression Some people cease to express lactase as they age  Originally humans only drank milk until their mom stopped making it! Some people continue to fully express lactase their entire life Some people cease to express it if they stop eating dairy for a long period of time

19. Transport Proteins Hemoglobin is a protein (globin) that holds four iron pigments (heme) to transport oxygen  Red blood cells hold large numbers of these proteins Hemoglobin is made of two alpha and two beta globins  Quaternary structure: four amino acid chains linked together

20. Hemoglobin structure

21. Hemoglobin Defects

22. Age-related Variable Expression

23. Sickle-Cell Anemia Mutation causes polymerization of hemoglobin molecules Form long fibers that bend shape of red blood cell Twisted and pointy RBCs can jam organs, causing health problems

24. Sickle-Cell Anemia Mutation affects single amino acid! Infant expression of different beta globin prevents illness, a particular anticancer drug seems to shift expression to infant globin

25. Signal Proteins: Taste Receptors Due to slight variations in the shapes of taste receptors, different people taste different things! A particular chemical called PTC is very bitter to some people but tasteless to others A similar chemical is in broccoli!

26. Variations in Smell Similar situation with smell  Some people can only smell the red flowers  Others can only smell the purple

27. Drug Metabolism Smell and taste may be cute, but drug metabolism is a matter of life and death! Having weaker alleles for plasma cholinesterase (an enzyme that breaks down cholines) makes a person very sensitive to succinylcholine  Life threatening!

28. Drug Metabolism Many drugs are designed to be metabolized by the body before they can become active  Failure of the body's enzymes to complete this conversion makes drugs less effective Drug-gene interaction is called pharmacogenetics  Eventually may lead to custom drugs!

29. Thousands of Enzymes! Virtually every chemical that is harmful to other organisms and not harmful to humans is metabolized by an enzyme in this manner  Pesticides!  Genetic variation in “cleaner enzymes” can mean some people are more sensitive to pesticides and antibiotics than others  Cancer and teratogen risk!

30. See you tomorrow!