Hemoglobin Synthesis and Catabolism Flashcards
composition of hemoglobin
*2 alpha chains
*2 beta chains
*4 heme molecules:
-protoporphyrin IX attach to ferrous iron (Fe2+)
note - 1 heme group per chain; each heme combines reversibly with one molecule of oxygen
globin chains - overview
*2 pairs of polypeptide chains (4 total)
*each chain has ~140 amino acids
*alterations in the amino acid sequences results in different globin chains
hemoglobin formation - overview
- genes for globin chains get transcribed into mRNA
- mRNA gets translated to a globin polypeptide chain and released into cytoplasm from the ribosomes
- each globin chain binds with a heme molecule
- heterodimers are formed between an alpha chain and a non-alpha chain
- 2 heterodimers combine to form tetramers -> hemoglobin
Hb affinity for oxygen at low pO2
at LOW oxygen tension, Hb has a LOW affinity for oxygen (more likely to release its oxygen to the tissues)
Hb affinity for oxygen at high pO2
at HIGH oxygen tension, Hb has a HIGH affinity for oxygen (less likely to release bound O2)
how does low pH affect hemoglobin’s affinity for oxygen
low pH (acidic environment) shifts the curve to the RIGHT [allosteric INHIBITION of binding oxygen by H+; DECREASED affinity for O2; Hb RELEASES the O2]
how does 2,3 BPG affect hemoglobin’s affinity for oxygen
increased 2,3 BPG shifts the curve to the RIGHT [DECREASED affinity for O2; Hb RELEASES the O2]
how does fever impact the hemoglobin curve
shifts curve to the RIGHT [DECREASED affinity for O2; Hb RELEASES the O2]
how does acidosis impact the hemoglobin curve
shifts curve to the RIGHT [DECREASED affinity for O2; Hb RELEASES the O2]
hemoglobin F - overview
*composed of 2 alpha chains and 2 gamma chains (α2γ2)
*has INCREASED OXYGEN AFFINITY (lelft shift) compared to Hb A [how fetus extracts oxygen from maternal circulation]
*Hb F doesn’t release oxygen as easily as Hb A so fetus needs more Hb to adequately oxygenate tissues (hence, why newborns have higher Hb values)
RBC metabolism - overview
*known as Embden-Meyerhof pathway or anaerobic glycolytic pathway:
- glucose enters RBC through facilitated membrane transport system
- glucose gets metabolized to lactic acid via glycolysis: uses 2 ATP and generates 4 ATP for NET GAIN OF 2 ATP
- GENERATES 2,3-BPG
- methemoglobin (Fe3+) is reduced to hemoglobin (Fe2+)
- via the hexose monophosphate shunt, G6PD PROTECTS RBCs FROM OXIDATIVE DAMAGE
how does G6PD deficiency lead to hemolytic anemia
no G6PD -> decreased NADPH -> oxidative damage to Hb -> denatured proteins -> increased cell death aka HEMOLYSIS
examples of intracorpuscular defects as causes of hemolysis
*problems with hemoglobin, cell membrane, or Embden-Meyerhof Pathway:
- red cell membrane disorders:
-hereditary spherocytosis
-hereditary elliptocytosis - red cell enzyme disorders:
-G6PD deficiency
-pyruvate kinase deficiency - hemoglobin disorders:
-unstable hemoglobins
-methemoglobinemia
-thalassemia
-sickle cell disease
examples of extracorpuscular defects as causes of hemolysis
*antibodies to RBC membrane components
*sludging, entrapment, and destruction of RBCs in an enlarged spleen
*trauma due to high velocity jets (poorly functioning prosthetic valves, fibrin strands in DIC, etc)
*exposure to chemicals
*infectious destruction of RBCs
intravascular hemolysis
*destruction of RBCs WITHIN the vascular space
examples:
-shear stress due to defective mechanical heart valves
-lysis from bacterial toxins
-direct trauma
-osmotic lysis due to hypotonic solutions
-complement-induced lysis
extravascular hemolysis
*destruction of RBCs OUTSIDE of the vascular space (in the liver, spleen, etc)
example:
-RBCs destroyed in tissues by monocytes and macrophages, primarily in liver and spleen
**iron gets recycled; bilirubin gets produced from heme rings and excreted in urine and stool (BILIRUBIN IN URINE/STOOL INDICATES EXTRAVASCULAR HEMOLYSIS)
impact of intravascular hemolysis on: haptoglobin levels, hemoglobinuria, and hemosiderinuria - detailed
- formerly intracellular Hb is now in plasma following intravascular hemolysis
- free Hb binds to haptoglobin, and the complex is removed by the liver, leading to LOW LEVELS OF HAPTOGLOBIN
- some Hb is broken down into alpha-beta dimers
-these are small enough to be filtered by the glomerulus, leading to hemoglobinuria - some dimers are taken up by renal tubular cells, broken down, and the iron is stored as hemosiderin, which can leak into the urine and cause hemosiderinuria
relationship between hemolysis and haptoglobin levels - simple
hemolysis usually causes LOW HAPTOGLOBIN LEVELS (because the the free Hb binds to haptoglobin in the plasma)
is bilirubin in the urine/stool indicative of intravascular or extravascular hemolysis
EXTRAvascular hemolysis
Coomb’s test
*helps to identify the presence of antibodies (immunoglobulins) or complement on the surface of RBCs
what test is used to determine if a patient has an autoimmune hemolytic anemia
Direct Coomb’s Test [agglutination is a positive test, meaning patient has an autoimmune hemolytic anemia]
factors that increase oxygen release (RIGHT shift of the oxygen-hemoglobin dissociation curve)
*decrease in pH (increase in H+ concentration)
*increase in PCO2
*increase in temperature
*increase in 2,3 BPG
what is a rightward shift of the oxygen-hemoglobin dissociation curve?
*R shift means less oxygen is bound to hemoglobin at a given PO2 (MORE is RELEASED to the tissues)
*more hemoglobin is in the “T” or “taut” formation, favoring oxygen release from RBCs
note - increased RELEASE of oxygen means decreased AFFINITY for oxygen
factors that decrease oxygen release (LEFT shift of the oxygen-hemoglobin dissociation curve)
*increase in pH (decrease in H+ concentration)
*decrease in PCO2
*decrease in temperature
*decrease in 2,3 BPH
what is a leftward shift of the oxygen-hemoglobin dissociation curve?
*L shift means that hemoglobin binds to oxygen at a lower PO2 than normal
*more hemoglobin is in the “R” or “relaxed” formation, favoring oxygen binding to RBCs
note - decreased RELEASE of oxygen (or increased binding of oxygen) means INCREASED AFFINITY for oxygen
