Diseases, Drugs, Targets so far

Question 1

Cystic Fibrosis: disease

Answer 1

Cystic fibrosis tranductance receptor: transmembrane protein channel allows chlorine and sodium across the membrane. Cystic fibrosis patients will have mucus build up in lungs which gets easily infected. Cystic fibrosis patients will have salty sweat. They’ll also have trouble with fat digestion and will need to eat a ton.

Question 2

CENP-E: target (G2 phase cell cycle motor protein)

Answer 2

CENP-E kinesin-like motor protein (motor proteins move stuff around the cell). It’s only present during G2, not during interphase. Most cells live their lives in interphase, only fast replicating cells are often in another stage of mitosis. All cells will get hit with drug that stops CENP-E but it will be proportionally more damaging in cell types that are more likely to be found proliferating while the drug’s concentration is enough to do damage.

Question 3

Imetelstat: drug (telomerase inhibitor)

Answer 3

Telomerase inhibitor stops telomerase from elongating telomeres, a common defect in cancer (the telomeres never get fully degraded). This would stop rapidly dividing cells because eventually their telomeres would run out and their DNA would start to degrade, leading to cell death.

Question 4

Diptheria: toxin

Answer 4

Mess with elongation factors, which means proteins aren’t synthesized. Leads to death

Question 5

Barbituates: toxins/drugs

Answer 5

Barbituates are lipid soluble sedatives. Mess with liver (cytochrome p450 in hepatocytes try to pull toxins out of filtrate), but at a high concentration the damage is insurmountable.

Question 6

Tetracycline: drug

Answer 6

Antibiotic, binds to bacterial 30S ribosomal unit, blocks access of A site on the ribosome

Question 7

Puromycin: drug

Answer 7

Antibiotic: Pretends to be a tRNA, accepts peptide chain from P site, terminates translation

Question 8

Chloramhenicol: drug

Answer 8

Antibiotic: binds to bacterial 50s subunit and inhibits peptidyl transferase (what transfers the peptide to the new A site tRNA aminoacyl

Question 9

Erythromycin: drug

Answer 9

Antibiotic: binds to bacterial 50s subunit and inhibits translocation (mRNA moving through ribosome)

Question 10

Streptomycin: drug

Answer 10

Antibiotic: binds to bacterial 30s subunit and prevents initiation, also causes misreading of mRNA which leads to premature termination

Question 11

Rifampin: drug

Answer 11

Rifampin inhibits DNA-dependent RNA polymerase.

Question 12

Thalassemia: disease

Answer 12

Often due to an alteration in RNA splicing, anemia (a guy from Georgia Tech presented on thalassemia). Often your skin is a bit off-colored. You have less oxygen carrying capacity in your red blood cells.

Question 13

Melanoma with large nucleoli means?

Answer 13

Cells making a lot of ribosomes

Question 14

Anderson’s Disease: disease

Answer 14

Chylomicron retention disease. COPII coating protein is essential for transfer of molecules from ER to golgi. Anderson’s disease has mutant coating protein, blocks transport in the ER. Affects small intestine (enterocytes)

Question 15

Cytochrome C deficiency: disease

Answer 15

Can’t generate energy through Kreb’s cycle, causes all sorts of trouble.

Question 16

Danon Disease: disease

Answer 16

Engorged structures in muscle fibers: mutations in vacuoles, lysosomes can’t destroy stuff for the vacuoles, so the vacuoles start to back up, get clogged.

Question 17

Pancreatitis: disease

Answer 17

Zymogens (secretory granules) are activated before they get to the duodenum and begin to break down the cells in the liver. That’s bad! Pancreatic acinar cells are making these zymogens. Zymogens are broken into active enzymes by hydrolysis.

Question 18

NARP syndrome: disease

Answer 18

Neuropathy, ataxia, retinal pigmentosa. Genetic mutation in mitochondria

Question 19

Hepatitis B: disease

Answer 19

Viral infection that attacks the liver, causes jaundiced skin tone, nausea, extreme fatigue. Disrupts hepatocyte function

Question 20

Fatty liver disease: disease

Answer 20

Accumulation of fat in the liver (could be caused by hepatitis B). Symptoms: loss of weight, weakness, nausea, confusion, feeling tired

Question 21

Bacterial Meningitis: disease

Answer 21

Bacterial infection of the brain: severe headache, stiff neck

Question 22

Pompe Disease: disease

Answer 22

Build up of complex sugars (glycogen) in the body’s cells. Build up in muscles limits their ability to function normally. Symptoms: progressive muscle weakness, falls, difficulty chewing, gait abnormalities

Question 23

Niemann Pick Type C disease: disease

Answer 23

Can’t metabolize cholesterol and other lipids, so cholesterol builds up in the liver and spleen, and in the brain. Inability to move eyes up and down, enlarged liver, enlarged spleen, jaundice.

Question 24

What is hemolytic anemia?

Answer 24

A deficiency in RBCs where they have reduced pyruvate kinase activity. Pyruvate kinase turns PEP into pyruvate, and is one of the 2 steps in glycolysis that produces ATP directly. Since RBCs do not have mitochondria, they are dependent on glycolysis for their energy needs. With this step hindered, glycolysis is now energy neutral instead of energy producing. So RBCs die really quickly, the patient has decreased oxygen transporters, and ultimately gets anemia.

Question 25

What is type 1 diabetes?

Answer 25

Pancreatic beta cells, which produce insulin, are destroyed by the immune system. Without insulin the body loses its ability to fluctuate metabolic activity in response to meals. Beyond being unable to break down glucose, cells involved with high levels of activity (muscle cells) are limited in their ability to pull glucose from the body. GLUT 4, the glucose transport muscle cells use, can be positively regulated by insulin to accept more glucose

Question 26

What is leigh disease?

Answer 26

Leigh disease is a metabolic disease where the patient’s pyruvate dehydrogenase complex enzyme is hindered. This means the body cannot readily take pyruvate and turn it into acetyl CoA for use in the TCA cycle. Instead, pyruvate is shunted into lactate. Lactate is acidic, so this can harm the body. In addition, lacking access to the TCA cycle means the body is constantly deficient of energy. Common symptoms include acidosis (tissue damage), muscle weakness, damage to the brain stem and other “lower order” parts of the brain (cerebellum, basal ganglia)

Question 27

What would happen if oxidative phosphorylation was inhibited? What are some toxins that hinder oxidative phosphorylation?

Answer 27

The body would lose access to ATP, and a lot of key reactions wouldn’t be able to take place. Muscle/motor impairment, decreased cell viability, tissue death. Rotenone (fish poison) and amytal (barbiturate sedative) block NADH –> NAD+ oxidation, which cuts out tons of energy from the body.
Antimycin A blocks electron flow through cytochrome b-c1 (complex 3) (an electron transport component), which means we lose all but complex 1’s H+ output.
Cyanide, azide, and carbon monoxide block electron flow through cytochrome C oxidase (complex 4), losing 4H+.
Oligomycin stops ATP synthase from working. This is probably the worst, because there’s absolutely no way to get around ATP synthase. No ATP synthase = no energy.
DNP stops proton gradient

Question 28

What would happen if ATP synthesis was “uncoupled” from electron transport (no longer able to use electron transport)

Answer 28

ATP synthase would only be able to use the natural H+ gradient between the intermembrane space (higher initially) and the inner membrane matrix (lower initially). DNP is a known herbicide that acts as a hydrogen ion transport facilitator across the membrane. So it takes the H+ along the concentration gradient, except no ATP is produced. Electron transport chain can work great, but DNP counteracts and ATP synthase doesn’t get any H+ to work with.

Question 29

What are key aspects of mitochondrial diseases?

Answer 29

The mitochondria is the source of basically everything to do with energy production in the cell. If you inhibit some enzyme in the TCA cycle you lose energy. If you inhibit some part of the electron transport chain you lose energy. If you inhibit ATP synthase you can’t produce any energy (lethal). In all of these, nervous system damage and muscle weakness are common. Mitochondrial diseases can only be inherited from the mother, because the mitochondrial genome comes straight from her. It may be a small mutation for her but would be amplified in her offspring. Mitochondria produce their own ribosomes, tRNA, complex 1,3 & 4, and atp synthase.

Question 30

What would happen if acyl triglyceride lipase was defunct?

Answer 30

Acyl triglyceride lipase is used to degrade triacylglycerides into glycerol and three fatty acids through addition of water. Without ATGL function you’re not able to expose fatty acids. You can’t degrade triacylglycerides for energy, so you’ll be deficient in energy. You’ll also have huge reservoirs of fat.
A genetic condition that causes this is called Chanon-Dorfman Syndrome. It leads to muscle weakness, an enlarged liver, and overheating (a lot of energy wasted as heat instead of ATP?)

Question 31

What is diabetic ketoacidosis?

Answer 31

In type 1 diabetes you’re unable to make insulin. What happens? Your body can’t digest glucose, so you’re low on energy. Glucose is a key reactant for the formation of oxaloacetate. Without OAA you’re unable to go through TCA or create aspartate for the Urea cycle, or unable to help with fatty acid synthesis (OAA is used to transport acetyl CoA out of the mitochondria for use by the body). The energy deficit induces the production of ketone bodies as energy storage units. Ketone bodies are acidic, so having high concentrations of ketone bodies in the body leads to tissue damage and enzyme dysfunction. Most notable in the nervous system.

Question 32

What does fatty acid synthesis look like in tumor cells?

Answer 32

Fatty acids are common precursors for signaling molecules. Tumor cells need a lot of signaling molecules to interact with the environment and acquire more resources from the ECM. Fatty acid synthesis is boosted in cancer. Acetyl CoA carboxylase and beta-ketoacyl ACP synthase enzymes are both overactive. Acetyl CoA carboxylase facilitates the committed step in fatty acid synthesis (malonyl coa from acetyl coa). Beta-ketoacyl ACP synthase catalyzes the elongation of fatty acids (malonyl coa attacks acetyl coa, acetyl coa is added to malonyl coa). Tumor therapies that target these enzymes can lead to apoptosis (cancer cells are often overdependent on their mutations)

Question 33

What would happen if you weren’t able to adequately create/store glycogen?

Answer 33

Without glycogen you’d have decreased energy storage capacity, but more importantly (since glycogen doesn’t account for much of our total energy needs/storage) you lose rapid energy sources (glycogen breakdown is much faster than fatty acid breakdown or ketone body use).

What if you can make glycogen but can’t use it? You’d have huge buildup of glycogen in the liver and the muscles. If you couldn’t move the glycogen to the muscles your liver would get stuffed. Tired, hyperglycemia (because you can’t do stuff with the glucose so it just sits in the blood). This is called Von Gerke disease. It’s a defect in glucose 6 phosphatase, which is used to turn g6p (from gluconeogenesis and glycogen breakdown) into glucose.
You also have glycogen storage disease type III (defect in branching enzyme) means you aren’t able to breakdown glycogen as quickly, so you’re often tired.

Question 34

How does alcohol ingestion mess with metabolism?

Answer 34

Alcohol digestion requires NAD+ (reduces it to NADH). This changed ratio (NADH/NAD+) decreases fatty acid oxidation (fatty acid oxidation wants to generate energy, but alcohol digestion creates NADH so you don’t need to breakdown fatty acids). It also uses up NADPH, which is needed for fatty acid synthesis and amino acid synthesis. Fatty acids accumulate in the liver. Acetyl CoA is shifted towards ketone body production (because NADH presence inactivates pyruvate dehydrogenase complex for TCA). This causes ketoacidosis. High levels of NADH also push equilibrium of pyruvate –> lactate towards lactate (to regenerate NAD+). This causes lactic acidosis (also bad, can cause gout)

Question 35

What is the main way that alcohol influences metabolic pathways?

Answer 35

Alcohol digestion ramps up presence of NADH. Any pathway that uses or is regulated by NAD+ or NADH will be affected.

Question 36

What is homocystinuria?

Answer 36

Homocystinuria means you have less cysteine than you should. Caused by a defect in cystathionine synthase (takes homocysteine + serine –> cystathionine). You’re not able to clear homocysteine and methionine (steps in production of cysteine. methionine turns into homocysteine. homocysteine reacts with serine to become cystathionine. cystathionine gives off an ammonia group to become cysteine), so the concentrations of homocysteine and methionine are abnormally high. Homocysteine is toxic to the body. Leads to intellectual disability, eye trouble, thrombi (blood clots).

Question 37

What is hyperhomocysteinemia?

Answer 37

Having too much homocysteine (caused by multiple mutations in the homocysteine –> methionine pathway. could be defective FH4, lack of vitamin B12, or defective cystathionine synthase (other direction, turning homocysteine into cystathionine)) leads to cardiovascular and central nervous system damage/disease. Fatal to fetus. Pregnant women take folate supplements to make sure this isn’t an issue.

Question 38

What are some genetic disorders that affect phenylalanine degradation? What are their mechanisms and symptoms?

Answer 38

Tyrosine, Acetoacetate, and fumarate are all byproducts of phenylalanine degradation. Disruption in this pathway can decrease the body’s ability to make any of these products.
Tyrosinemia 1 is caused by a defect in furarylacetoacetate hydrolase which is one of the enzymes taking you from homogentisate to acetoacetate and fumarate. This leads to liver failure, death, and “cabbage-smelling’ breath.
Tyrosinemia 2 is a defect in tyrosine aminotransferase (takes you from tyrosine to p-hydroxyphenylpyruvate). Leads to eye, skin, and brain troubles.
Alkaptonuria - defect in homogentisate oxidase. Homogentisate accumulates, causes joint pain and dark pee.
Phenylketonuria - defect in phenylalanine hydroxylase. Phenylalanine concentrations are too high. Tyrosine is an important precursor, and can’t be made since phenylalanine hydroxylase is the first step in the process. This leads to severe mental disability unless put on a low phenylalanine diet with tyrosine supplements. Brain damage could be caused by lack of dopamine (formed out of tyrosine)

Question 39

What is maple syrup urine disorder?

Answer 39

Branched chain dehydrogenase enzyme (for breakdown of valine, isoleucine, and leucine) is defunct. alpha-ketoacids are formed but can’t be broken down. Urine smells like maple syrup. If you don’t have a low valine/isoleucine/leucine diet you’ll have serious mental and physical disability.

Question 40

What is albinism?

Answer 40

A lack of melanin (formed from tyrosine) due to defunct tyrosinase enzyme. Your skin is white, your eyes are red because the blood vessels are visible. The eye is super sensitive to light because nothing is blocking the rays.

Question 41

What is hyperammonemia?

Answer 41

Having too much ammonia in your system (which is toxic). Some disorders that cause hypoerammonemia can be countered by supplementing the diet with urea cycle intermediates. Others (defects in early steps of the urea cycle) can't be fixed, but only managed by finding alternative ways to get rid of ammonia. Arginosuccinase is the enzyme that takes you from arginosuccinate to arginine (lose fumarate). If this enzyme is defunct you can add arginine and limit other protein intake. Arginine loses its nitrogens as urea, is used up as ornithine to bind to free ammonia groups, and then is discarded as arginosuccinate. 
Ornithine transcarbamoylase (takes you from ornithine + carbamoyl phosphate --> citrulline) deficiency prevents ammonia from entering the urea cycle.
Carbamoyl phosphate synthetase (takes you from co2 + nh4 --> carbamoyl phosphate) deficiency prevents ammonia from entering urea cycle as well. These have to be solved by finding other ways to get rid of ammonia. One way is to use benzoate and phenylacetate (these remove glycine and glutamine from the system. glycine and glutamine have nh4 groups so removing them decreases nh4+ concentration in the body.