EXAM #1: RBC & CANCER METABOLISM Flashcards
Do RBCs contain mitochondria and nuclei?
NO
Do RBCs have the ability to synthesize proteins?
NO
Can RBCs synthesize proteins to replace damaged molecules? Why or why not?
NO
RBCs do not contain nuclei; therefore, they cannot produce proteins.
What type of RBCs are trapped in the spleen? What causes to be phagocytosed by the spleen?
- Inelastic RBCs do not retain the flexibility needed to circulate through the spleen
- Consequently, splenic macrophages phagocytose these RBCs
Older RBCs have a cytoskeletin that degenerates and loses its elasticity making them inflexible.
What is extravascular hemolysis? What is the key biochemical marker for extravascular hemolysis? What is the key clinical marker for extravascular hemolysis?
Extravascular= outside of the circulation; splenic macrophages phagocytose of RBCs
- Biochemical= bilirubin/ jaundice
- Clinical= splenomegaly
In contrast to extravascular hemolysis, what is intravascular hemolysis? What is the key biochemical marker of intravascular hemolysis?
- Mechanical disruption of RBCs IN THE CIRCULATION
- Biochemical= HEMOGLOBIN from destroyed RBCs/ hemoglobinuria
What is the difference between spherocytic anemia and non-spherocytic anemia?
Spherocytic= defect in RBC cytoskeleton leaves the cell rounded w/ diminished volume and potential for lysis
- Leads to EXTRAVASCULAR HEMOLYSIS
Non-spherocytic= enzymatic/ non-cytoskeletal cause of anemia
- Leads to both INTRA AND EXTRA-VASCULAR HEMOLYSIS
What are the four major purposes of RBC metabolism?
1) Keeping iron reduced (Fe++ vs. Fe+++)
2) Maintaining K+/ Ca++ gradients
3) Keeping protein SH-groups reduced (vs. oxidized by ROS)
4) Maintaining cell shape
What is required to keep iron reduced?
NADH
NADH methoglobin reductase
What is required to maintain the K+/Ca++ gradient in RBCs?
ATP i.e. ATPases
What is required to keep protein SH-groups reduced in RBCs?
NADPH
What is required to maintain RBC cell shape?
ATP
What happens if RBC metabolism fails?
1) Fills with Ca++
2) Release K+
3) Lose bicocave shape
These cells will be taken up by the spleen b/c the spherical shaped cannot pass through resulting in extravascular hemolysis.
RBCs do NOT contain mitochondria; thus, what type of metabolism CANNOT happen?
1) Fatty acid oxidation
2) Aerobic metabolism
BOTH require mitochondria
What metabolic pathways CAN occur in RBCs?
1) Glyocolysis (anaerobic)
2) PPP
What are the regulated steps of glycolysis in RBCs? What regulates these two enzymes?
- Hexokinase
- Phosphofructokinase-1
In contrast to other cells, glucose is NOT the regulator of glycolysis in RBCs; rather pH is. A DECREASE in pH will STOP glycolysis in RBCs.*
When the RBC is full on ATP but needs NADH, how does the cell make NADH?
“Energy clutch” i.e. perform glycolysis without gain of ATP
Draw the pathway of ATP, NADH, and NADPH generation in RBCs.
See ppt.
What is the crucial step of the “energy clutch?”
1) 1,3 bisphosphoglycerate –>2,3 bisphosphoglycerate
2) 2,3 bisphosphoglycerate is dephosphorylated to 3-hosphoglycerate
3) 3-phosphoglycerate re-enters glycolysis WITHOUT net production of ATP
What metabolic pathway generates NADPH?
PPP
What happens to the “energy clutch” at low pH?
Recall, glycolysis STOPs at LOW pH; therefore,
2,3 BPG production STOPs at LOW pH
When pH is low and there is abundant lactate, what will RBCs do?
Oxidize/ consume lactate to obtain NADH for the defense of Hb
This returns the pH to normal.
What enzyme conversts 1,3 bisphosphoglycerate converted into 2,3 bisphosphoglycerate?
Diphosphoglyceromutase
What effect does 2,3 BPG have on Hb’s affinity for oxygen?
2,3 BPG DECREASES Hb’s affinity for oxygen
What happens to 2,3 BPG at low pH?
Synthesis is INHIBITED
What is the effect less 2,3 BPG production acidic conditions?
Increased Hb/RBC oxygen affinity/saturation
Thus, acidosis INCREASES the oxygen saturation of the blood. However, the BOHR EFFECT DECREASES oxygen saturation in acidic conditions. This gives the RBC a higher oxygen affinity in the lungs b/c of the effects of 2,3 BPG and a lower oxygen affinity in the tissue b/c of the Bohr effect, which facilitates oxygen unloading to hypoxic tissues.
What is the”gate-keeper” enzyme of the PPP?
Glucose-6 phosphate dehydrogenase
What activates Glucose 6-phosphate dehydrogenase?
Low NADPH
What is the role of NADPH in RBCs?
- Antioxidant
This is also the reduction equivalent needed for biosynthesis.
What are the products of the PPP? What happens to the products of the PPP?
Fructose 6-phosphate and Glyceraldehyde 3-phosphate (PPP starts with glucose 6-phosphate)
The products are re-introduced to glycolysis
What is the function of Glutathione in RBCs?
Glutathione (GSH) protects RBCs from ROS.
Specifically, there are two kinds of ROS that RBCs need to be protected from:
1) ROS extract electrons from sulfhydryl groups, which leads to the formation of disulfide bridges (preventing function)–>GSH gives electrons back
2) Provides electrons to convert hydrogen peroxide to water
Note that superoxide radical is converted to hydrogen peroxide by superoxide dismutase. GSH then converts hydrogen peroxide into water.
Draw the role of glutathione peroxidase and glutathione reductase in antioxidant defense.
See ppt.
Where do the electrons come from the GSH transfers to either sulfhydrl groups or hydrogen peroxide in combating ROS?
NADPH
What are the two typical causes of nonspherocytic anemia?
- G6PD
- Pyruvate kinase deficiency
What is G6PD deficiency?
- Most common cause of non-spherocytic hemolytic anemia
- X-linked recessive deficiency in Glucose 6-Phosphate Dehydrogenase, the “gate-keeper” of the PPP
- Without G6PD, NADPH cannot be produced to combat ROS damage in times of stress, leading to hemolysis
What are the common triggers of hemolytic crises in G6PD?
- Infection
- Hydrogen peroxide producing drugs
- Fava beans
What are the symptoms of G6PD?
- Splenomegaly
- Jaundice
- Kernictuerus= bilirubin-induced brain dysfunction
What is the most common enzymopathy seen as a glycolysis defect?
Pyruvate kinase deficiency
Enzyme that converts phosphoenolpyruvate to pyruvate
What causes hemolysis in Pyruvate Kinase Deficiency?
B/c RBCs cannot produce pyruvate, they also cannot make ATP to maintain ion gradients, which leads to premature degeneration
How does Pyruvate Kinase Deficiency differ from G6PD deficiency?
G6PD= induced by specific triggers
Pyruvate Kinase= lacks ROS induced crises
- Gallstones
There other symptoms are largely the same*
What is the importance of the “grey top tube” in enzymopathies?
asdf
What metabolic pathway provides energy for cancer cells?
Like RBCs, anaerobic glycolysis
Why are tumor cells acidic?
Produce a large amount of lacate from the breakdown of glucose under anaerobic conditions
What factor allows tumor cells to operate under a hypoxic environment?
Expression of “hypoixa-inducible factor” HIF-1a that supports anaerobic metabolism
This is a transcription factor the supports anaerobic metabolism.
Describe the normal cytoskeletal structure of a RBC.
- Spectrin= filamentous scaffold
- Ankyrin= peripheral membrane protein
- Band 3= integral membrane protein
- Glycophorin= integral membrane protein
What is Hereditary Spherocytosis?
RBC cytoskeletal defects that caused by mutations in RBC cytoskeletal proteins e.g.
1) Ankrin
2) Spectrin
3) Band 3
4) Glycophorin
What is the most common cause of Hereditary Spherocytosis?
Autosomal dominant Ankyrin mutation
