MCM_Final_TBL12

Question 1

Globular proteins

Answer 1

1. spherical (hydrophilic surface with hydrophobic core)
2. soluable in H20
3. sensitive to pH and heat

Question 2

Function of Globular Proteins

Answer 2

1. storage of ions and molecules
   
   • myoglobin & ferrin
2. transport of ions and molecules
   
   • hemoblogin & serationin transporter
3. defense against pathogens
   
   • antibodies & cytokines
4. muscle** **contraction
   
   • actin & myosin
5. catalysis
   
   • chymotripsin & lysozyme

Question 3

Globin Gene Families

Answer 3

• gene family = set of similar genes, formed by duplication of a single original gene & typically with similar biochemical functions.
  
  • non-identical primary sequences
  • can be clustered or dispersed
• (ex) hemoglobin
  
  • ​heterotetrameric protein made of two subunits from two clustered gene families
    
    • 2x unit of ​α-globin = on Chrm. 16
    • 2x unit of β-globin; located on Chrm. 11

Question 4

Globulin Gene Switching

Answer 4

• produces a variety of different hemoglobin tetramers throughout development

Question 5

Primary Hb Species (2)

Answer 5

1. HbF
   
   • during fetal development
     
     • 2 Adult α2-subunits
     • 2 Fetal β-subunits
2. HbA
   
   1. major form shortly after birth through adulthood
   2. 2 Adult α2-subunits
   3. 2 Adult β-subunits

Question 6

Myoglobin vs Hemoglobin

Answer 6

• hemoglobin = heterotetramer
• myglobin = monomer (abundent in muscle)
  
  • designed to store O2

Fe2+-protoporphyrin IX (9) prosthetic grounp

• binds O2 to BOTH proteins

Question 7

Oxygen Binding in MYOGLOBIN

Answer 7

• α- helical SECONDARY & TERTIARY structure
• single heme group = binds 1 O2 molecule
• O2 binds to ferrous iron on heme group
• in the absence of allosteric interactions, the O2 binding curve is hyperbolic

Question 8

Allosteric Regulator (Effector)

Answer 8

allosteric regulation of hemoglobin depends on many allosteric effectors

• molecule that binds to a protein and induces a conformational change that alters:

1. affinity for a substrate (i.e O2) (“K effect”)
2. the Vmax of enzyme (“V effect”)
3. OR both (“V/K effect”)

Question 9

H+ & CO2 are …

Answer 9

NEGATIVE allosteric effectors of O2 binding in HB

• ↓ O2 affinity for hemoglobin = shifts curve TO RIGHT
• ↑ efficiency for O2 unloading in tissues
  
  • facillitates the H+ & CO2 transport from tissues → lungs

Question 10

Myoglobin vs Hemoglobin Curve Comparison

Answer 10

Note: O2 Binding to Myoglobin-Hemoglobin Curves = Substrate- Enzyme Velocity Curves

• Due to monomeric structure, myglobin has hyperbolic curve
• Due to complex, tetrametic structure, hemoblogin has SIGMOIDAL COOPERATIVE binding curve

Question 11

P50

Answer 11

• partial pressure of oxygen yielding 50% saturation
• “partial pressure of oxygen when hemoglobin is 50 % saturated with oxygen”

Question 12

Hyperbolic vs Cooperative Binding

Answer 12

Myoglobin

• ↓ P50 = ↑ O2 affinity…. leads to hyperbolic binding of myoglobin
• when O2 is ↓ (i.e during exercise), myoglobin will release O2 to maintain activity for long time

Hemoglobin

• cooperative binding of Hb = efficiency in Loading O2 in Lungs & unloading in tissues

Question 13

Hb’s Squential Cooperative O2 Binding

Answer 13

• binding O2 in one subunit induces a conformational change that is _partially_ transmitted to _adjcacent_ subunits
  
  • ​↑ O2 affininty in adjacent subunits

Question 14

Conformational Change Trigger

Answer 14

• trigger = orientation of Fe2+ in protoporphyrin ring
• iron’s movement is transmitted to the Hb subunit via histidine axial ligand
• in deoxyHb, the Fe2+ and porphyrin ring are not* perfectly *aligned
• in oxyHB, the ring becomes straighter pulling in the proximal histadine axial ligand

Question 15

R vs T States of Hb

Answer 15

• T = Tense state
  
  • ↑ interactions = ↑ stability
  • ↓ O2 affinity
• R = Relaxed state
  
  • ↓ interactions = ↑ flexibility
  • ↑ O2 affinity
• O2 binding triggers a T → R conformational change by breaking ion pairs between the α1-β2 interface

Question 16

Fetal Hemoglobin (HbF)

Answer 16

• HbF has ↑ O2 affinity than HbAdults
  
  • = LEFTWARD shift in the oxygen binding curve
• why?
• HbF needs to work with the O2 lvls the placental interface

Question 17

Allosteric Effectors: Oxygen

Answer 17

• POSITIVE allosteric effector for its own binding
  
  • basis for subunit cooperativity
• BUT ALSO NEGATIVE allosteric effector for CO2 & H+ binding
  
  • why? that ↑ efficiency of H+ & CO2 unloading in lungs

AKA the Bohr Effect = *reciprocal relationship* between O2 & CO2/H+ binding

Question 18

Curve Shift Trends

Answer 18

Question 19

HbA2

Answer 19

• synthesized in the adult,
• although at low levels compared with HbA

Question 20

Globin Gene Organization

Answer 20

• α-gene cluster on chromosome 16 contains two genes for the α-globin chains
• single gene for the β-globin chain is located on chromosome 1
  
  1. ​​ζ gene, is expressed early in embryonic
  2. two γ genes (Gγ and Aγ that are expressed in HbF)
  3. δ gene found in the minor adult hemoglobin HbA2.

Question 21

Hemoglobinopathies

Answer 21

group of genetic disorders caused by production of a structurally abnormal hemoglobin molecule OR synthesis of insufficient quantities

Question 22

qualitative hemoglobinopathy

Answer 22

• altered A A sequence i.e sickle cell

Question 23

quantitative hemoglobinopathy

Answer 23

• thalassemias
• decreased production of normal hemoglobin

Question 24

Sickle Cell Anemia (Hemoglobin S disease)

Answer 24

1. (a point mutation) in the gene for β-globin:
   
   • replacement of the charged glutamate → nonpolar valine
2. ccurs primarily in the African American population
3. autosomal-recessive disorder
4. infant does not begin showing symptoms of the disease until sufficient HbF has been replaced by HbS
5. hyperbilirubinemia

Question 25

Hemoglobin C disease

Answer 25

* lysine → glutamate * relatively mild, chronic hemolytic anemia. * do not suffer from infarctive crises, and no specific therapy is required.

Question 26

Methemoglobinemias (HbM)

Answer 26

* **Oxidation** of the **heme** **iron** from **Fe2+** → **Fe3+** = **methemoglobin**, which **cannot bind O2.** * characterized by “**chocolate cyanosis**” (a **blue** coloration of the **skin** **and mucous** membranes and **brown-colored bloo**d) as a _result_ of the **dark-colored methemoglobin.** * **Treatment is with methylene blue**, which is oxidized as **Fe3+ is reduced.**

Question 27

Thalassemias

Answer 27

## Footnote the synthesis of **either the α- or the β-globin chain is defective**, and **hemoglobin** concentration is **reduced**.

Question 28

β- Thalassemias

Answer 28

* result of **point mutations** * α-globin chain synthesis is normal but dissolves bc no B-globin to connect with * **Increase** in α2δ2 (**HbA2**) and **α2γ2** (**HbF**) also occurs. * * β-thalassemia **minor**= if they have only **one defective β-globin** * β-thalassemia **major** (**Cooley** **anemia**) if **both** genes are **defective**. * ineffective erythropoiesis * require **regular transfusions of blood.**

Question 29

**α- Thalassemias**

Answer 29

typically because of **deletional** mutations ## Footnote **four** **copies** of the α-globin gene (two on each chromosome **16**), **“silent”** carrier of α-thalassemia, because no physical manifestations