1. Exam 3 Review I
1. Parkinson’s disease; dopamine biosynthesis, cofactors
2. Biochemistry of Epilepsy; neurotransmitters
3. Type 1 Diabetes; hypothesis
4. PKU; Phe->Tyr
5. Pernicious Anemia; B12

2. Production of Dopamine

3. Connections between low norepinephrine levels and dopamine levels

4. Connections between low norepinephrine levels and dopamine levels
Dopamine is a precursor to both Catecholamines, Norepinephrine and Epinephrine.
Dopamine + Dopamine Beta Hydroxylase & Vitamin C -> Norepinephrine
Norepinephrine + Phenylethanolamine N-Methyltransferase & S-Adenosyl Methionine with Cortisol -> Epinephrine
Dopamine
DBH
Vit. C
SAMe
Cortisol
Norepinephrine
PNMT
Epinephrine

5. Connections between low norepinephrine levels and dopamine levels
Why do we care about low levels of norepinephrine?
Dopamine
-Motor Control
-Lack of Dopamine => Loss of motor activity
Norepinephrine/Epinephrine
-Excitatory Neurotransmitters / Hormones
-Increase heart rate
-Increase fight or flight response
-Increase awareness and alertness

6. Neurotransmitters in Epilepsy
Serotonin
Acetylcholine
GABA

7. Formation of Serotonin
Synthesis from Tryptophan
Central Nervous System
Regulation of mood, appetite, sleep, and muscle contraction
Modulation used in antidepressants
Themedicalbiochemistrypage.org

8. Formation of GABA Synthesis from Glutamine Central Nervous System
Inhibitory Neurotransmitter
Cause Hyperpolarization
Themedicalbiochemistrypage.org

9. Population Affected
Type I Diabetes is most prevalent in Finland, Sardinia, Scandinavia, and Scotland
Extremely uncommon in Asian countries3
White Americans are 1.5 times more likely to have diabetes than black or Hispanic Americans
Males are at greater risk in regions of high incidence8
Increased incidence in winter months
Lack of vitamin D is a potential environmental trigger3
Risk increases as you move away from the equator

10. Hypothesis Type 1 Diabetes is an autoimmune disease:
1) A T1D susceptible gene is present
2) A mutated MHC protein is produced
3) An environmental trigger causes the MHC to function improperly
4) An autoimmune response destroys the beta cells of the pancreas
5) Insulin is no longer produced

11. Results of Insulin Deficiency8

12. Phenylalanine Essential Amino Acids
cannot be derived from anabolic processes in the body and must be consumed in the diet: F, L, I, V, M, T, W
a few of the AA, called essential amino acids, cannot be synthesized or converted in your body and have to be obtained from the food you eat.
We consume and access of phenylalanine in our diet which is converted by the enzyme PAH to tyrosine
Certain AA are conditionally essential, such as in PKU where the Phe catabolic pathway to Tyr is interrupted….Tyr becomes essential
Wikipedia.com

13. Phenylalanine-Biochemistry
Cofactor (BH4) aided catalysis
PAH
Biocyc.org
Essential amino acid Phe is converted to Tyr with the cofactor BH4, O2, and PAH

14. PKU-Impact and distribution
Region / Country Incidence of PKU
Asian Populations China 1 : 17,000
Japan 1 : 125,000
European Populations
Turkey 1 : 2,600
Yemenite Jews (in Israel) 1 : 5,300
Scotland 1 : 5,300
Czechoslovakia 1 : 7,000
Hungary 1 : 11,000
Denmark 1 : 12,000
France 1 : 13,500
Norway 1 : 14,500
United Kingdom 1 : 14,300
Italy 1 : 17,000
Canada 1 : 22,000
Finland 1 : 200,000
Arabic Populations Up to 1 : 6,000
Oceania Australia 1: 10,000
Unequal geographical distribution
Incidence of PKU is caucasians is 1 in 10,000 to 15,000
High incidence of PKU in Turkey due to high prevalence of consanguinity
Low incidence seen in Finland and Japan due to pronounced negative founder effect (loss of genetic variation as new population establishes) and genetic drift (may even causes alleles to disappear completely) in founding the Japanese Island population
Folling described 10 patients (some siblings) who excreted phenyl pyruvic acid and were mentally deficient
Early manifestation several weeks after birth
Signified by elevation of plasma phenylalanine and excretion of phenylpyruvic acid
Reduction of phenylalanine hydroxylase can be detected in the parents
Williams et al 2008 Adapted from Scriver and Kaufman 2001

15. Our 2 Biological Molecules
Intrinsic Factor
Vitamin B12
(Cobalamin)
20Research%20Group%20Website/Binding%20Proteins.htm

16. Vitamin B12 Continued… Vitamin B12 is a cofactor for:
Isomerases
Methyltransferases
Dehalogenases
Takes part in DNA synthesis, methylation and neuron function
Sources: Voet

17. Stomach Small Intestine Eat food with B12
Haptocorrins competativily bind with B12 in stomach at high pH
In the small intestine haptocorrins are degraded by pancreatic proteases
IF is active at lower pH of the intestine and binds B12
IF:B12 complex binds Cubulin receptor
The receptor protein complex is taken into the cell where B12 is released from IF
B12 then binds to Trans-Cbl-II and is released into circulation.
B12
Stomach HC
B12 HC HC
B12 HC HC
B12 HC
B12
B12
B12
B12
B12
B12 HC HC
B12 HC
B12 HC HC
B12 HC HC IF
Small Intestine
B12