Chemistry of Respiration Flashcards
1
Q
4 Major Processes of Respiration
A
- Pulmonary Ventilation
- Diffusion of O2 and CO2 between alveoli and blood
- Transport of O2 and CO2 from different cell organism via blood
- Regulation of Ventilation
2
Q
Oxygen Movement
A
Atmosphere (159) → Alveoli (104) → Arterial Blood (100) → Cells (50)
3
Q
Carbon Dioxide Movement
A
Cells (60) → Venous Blood (46) → Alveoli (40) → Atmospheric Air (0.3)
4
Q
Transport forms of Oxygen
A
- Physically dissolves in Plasma
- Oxyhemoglobin
5
Q
Physically dissolved oxygen in the plasma (mL)
A
0.33 mL O2 / 100 mL of blood
6
Q
Oxyhemoglobin (mL)
A
1.34 mL of O2 / gm of Hb
7
Q
Structure of Hemoglobin
A
Tetrameric protein (four subunits)
8
Q
Conjugate Protein
A
Protein (Amino Acid Chain) + Non-Protein (Prosthetic Group) Combination
9
Q
Role of Prosthetic Group
A
Protein’s 3D structure
10
Q
Role of Prosthetic Group (Cytochrome)
A
Helps with electron transfer in the ETC
11
Q
Role of Prosthetic Group (Hemoglobin)
A
Deliver oxygen to peripheral tissues
12
Q
Main in fetuses
Composition: α₂γ₂
HbF (Fetal hemoglobin)
A
HbF (Fetal hemoglobin)
13
Q
Major hemoglobin in adults
Composition: α₂β₂
HbA (Adult Hemoglobin)
A
HbA (Adult Hemoglobin)
14
Q
Mutation in the beta chain causes sickling of RBCs.
A
HbS (Sickle cell hemoglobin)
15
Q
Minor form in adults
Composition: α₂δ₂
A
HbA2 (Minor adult hemoglobin)
16
Q
Formed when glucose binds to hemoglobin
Composition: α₂β₂ + glucose
A
HbA1c (Glycated Hemoglobin)
17
Q
Chains Produced in the Embryonic Stage (0-3 months of Gestation)
A
𝜀 (epsilon) and 𝜁 (zeta) chains.
18
Q
Forms early embryonic Hb in the Embryonic Stage (0-3 months of Gestation)
A
Gower hemoglobin
19
Q
Production decline in the Embryonic Stage after how many months
A
Decreases after 3 months
20
Q
Chains Produced in the Fetal Stage (3-9 months of Gestation)
A
𝛼 (alpha) and 𝛾 (gamma) chains.
21
Q
Forms Hb in the Fetal Stage (3-9 months of Gestation)
A
HbF (fetal hemoglobin, α₂𝛾₂).
22
Q
What happens in the Fetal stage (3-9 months of gestation)?
A
Increase in α-chain synthesis.
High 𝛾-chain production, which declines just before birth
23
Q
Main hemoglobin at birth
A
HbF (fetal hemoglobin, α₂𝛾₂).
24
Q
Changes of beta and delta chains at birth?
A
β (beta) chain increase,
δ (delta) chains low levels = forming HbA₂ (α₂δ₂).
25
What happens in the Postnatal period (after birth)?
Beta increases replacing Gamma →
HbA (α₂β₂) becomes dominant → Gamma diminishes → HbF decreases → low delta → forms HbA₂ (2-5% of adult Hb)
26
A cyclic molecule made of 4 pyrrole rings linked by methenyl bridges.
Porphyrin
27
Made up of Porphyrin
Heme (Prosthetic Group)
28
Variations of heme (I-IV) depends on
side chains attached to the pyrrole rings
29
Type of porphyrins that is physiologically important in humans.
Type III Porphyrins
30
Color of heme
Red
31
Located at the center of heme that is bounded to 4 nitrogens in a flat plane
Iron (Fe²⁺)
32
Two additional bonds of Iron
1. Side chain of a histidine (His)
2. Oxygen (O₂)
33
Made of polypeptide chains (subunits)
Globin (Protein part)
34
Helices in Alpha Chain
7 α-helices → 141 amino acids
35
Helices in Beta Chain
8 α-helices → 146 amino acids
36
Subunit Configuration of Globin
Each subunit → α-helical structure.
37
Polypeptide Chains of Globin
Each dimer (αβ) → chains: hydrophobic interactions
38
Surface Structure of Globin
Polar amino acids
39
Interior Structure of Globin
Nonpolar amino acids
40
Heme Location
Crevice (heme pocket) → hydrophobic interior of hemoglobin.
41
Organization of Helical Segments
Globular subunits → distinct alpha helices (Helix A to Helix H)
42
Serve as connectors, forming random coil structures (not helical or pleated sheet structures).
Interhelical Segments (e.g., AB, CD, EF)
43
Located between Helix E and Helix F within the globin subunit.
Heme Pocket of Globin
44
Arrangement of globin in hemoglobin contribute to its function in gas transport
makes hemoglobin water-soluble but impermeable to water
45
Protein part of hemoglobin, crucial for structural integrity and oxygen interaction
Globin
46
2 Histidine Residues
Proximal Histidine Residue (F8)
Distal Histidine Residue (E7)
47
This histidine residue is directly involved in binding the heme group in both hemoglobin and myoglobin that plays a crucial role in oxygen binding by interacting with the heme group.
Proximal Histidine Residue (F8)
48
This histidine residue is positioned to stabilize the binding of oxygen to the heme group by interacting with the bound oxygen molecule
Distal Histidine Residue (E7)
49
Location of Proximal Histidine Residue (F8)
Alpha His 87, Beta His 92
50
Location of Distal Histidine Residue (E7)
Alpha His 58, Beta His 63
51
Helix Structure of Proximal Histidine Residue
Helix F, 8th residue
52
Helix Structure of Distal Histidine Residue
Helix E, 7th Residue
53
A basic amino acid with an imidazole group (imidazole ring) in its side chain, which plays a key role in oxygen binding and stabilization.
Histidine
54
First O₂ Binding of Deoxyhemoglobin
α-chain binds first, β-chain blocked by valine.
55
Rigid Bonds of Deoxyhemoglobin
α1-β1
α2-β2
17-19 H bonds
ionic bonds
56
Flexible Bonds of Deoxyhemoglobin
α1-β2
α2-β1
57
Bond from Deoxyhemoglobin that has a strong contact, restricts movement
Rigid Bonds
58
Bond from Deoxyhemoglobin that has a fewer contact, allows movement.
Flexible Bonds
59
Deoxyhemoglobin, no O₂, Fe²⁺ low-affinity
T-State (Tense/P4)
60
Oxyhemoglobin, O₂ bound, Fe²⁺ high-affinity
R-State (Relaxed/R4)
61
T-State Meaning
Taut, tense, deoxygenated Hb
62
R-State Meaning
Relaxed, oxygenated Hb.
63
Salt Bridges (T vs. R)
T-state → More salt bridges
R-state → Fewer salt bridges.
64
Oxygen Affinity (T vs. R)
T-state → Low O₂ affinity
R-state → High O₂ affinity.
65
Iron Position (T vs. R)
T-state → Fe above porphyrin plane (high spin)
R-state → Fe within plane (low spin).
66
2,3 BPG Presence (T vs. R)
Present in T-state
absent in R-state
67
Structural Stability (T-state)
More rigid & stable due to salt bridges.
68
Salt Bridge Bonds
Ionic bonds:
(+) nitrogen → low electron density
(–) oxygen → electron-rich
69
Ionic interaction between charged amino acids
Salt Bridge
70
Negative Residue
Aspartate (COO⁻).
71
Positive Residues
Histidine (NH⁺)
Arginine (NH₂⁺)
Lysine (NH₃⁺)
72
State that the salt bridges stabilizes
Tense State
73
Intrachain Salt Bridge
Asp 94 (COO⁻) binds His 146 (NH⁺) in β₂.
74
Interchain Salt Bridge
Arg 141 (COO⁻) of β₂ binds Lys 40 (NH₃⁺) of α₁.
75
State where O₂ binding breaks salt bridges
Relaxed state
76
T-State Iron Position
Fe²⁺ above plane → Low O₂ affinity.
77
Oxygen Binding Effect
O₂ binds Fe²⁺ → shifts position → distal histidine (E7) stabilizes.
78
R-State Iron Position
Fe²⁺ moves into porphyrin plane → High O₂ affinity.
79
R-State Effect
Conformational change → Increases hemoglobin’s O₂ affinity
80
T → R Transition
Allosteric change, no amino acid sequence change.
81
Key Modifications of T → R Transition
Salt bridges break
Subunits rearrange
Flexibility increases.
82
Oxygen Binding Effect (T → R)
Fe²⁺ moves into heme plane → Proximal histidine shifts.
83
Structural Shift (T → R)
Globin chains pulled → Conformational change to R-state.
84
Rotation & Shift
α₂β₂ dimer rotates 15° relative to α₁β₁.
85
Axis of Rotation
Eccentric, α₂β₂ moves toward axis.
86
Fixed vs. Moving Parts
α₁β₁ fixed
α₂β₂ rotates & shifts.
87
Cooperative Binding
More O₂ → Hemoglobin binds better to additional O₂.
88
Salt Bridge Breakdown
Salt bridges weaken and disappear as O₂ binds.
89
Stronger α₁β₁ Interactions
Held by hydrophobic forces, weaker α₂β₂ interactions
90
Oxygen Capacity
Hb binds 4 O₂ molecules, one per iron in heme.
91
Allosteric Effects
O₂ binding weakens subunit interactions, increases O₂ affinity.
92
Size Comparison (M vs H)
Myoglobin: Small, monomeric
Hemoglobin: Larger, tetrameric.
93
Oxygen Affinity (M vs H)
Myoglobin: Higher affinity for O₂
Hemoglobin: Lower affinity for O₂.
94
P50 Comparison (M vs H)
Myoglobin: Lower P50 (1 mmHg)
Hemoglobin: Higher P50 (26 mmHg).
95
Oxygen Binding Curve (M vs H)
Myoglobin: Hyperbolic
Hemoglobin: Sigmoidal (S-shaped).
96
High affinity for oxygen storage in muscles, binds tightly to O₂.
Myoglobin
97
Lower affinity for oxygen transport in blood, cooperative binding, oxygen release in tissues.
Hemoglobin
98
Myoglobin Structure
Monomeric heme protein (single polypeptide chain).
99
Hemoglobin Structure
Tetrameric protein (four polypeptide chains).
100
Both myoglobin and hemoglobin contain proximal and distal residues interacting with heme
Histidine Residues
101
As one oxygen binds to hemoglobin, it increases the affinity for the next oxygen, making oxygen binding progressively easier.
Cooperative Binding
102
Hemoglobin affinity for O₂ when no oxygen is bound.
Low Affinity (Deoxygenated State)
103
Each subsequent O₂ binding increases the affinity for the next oxygen.
Increased Affinity
104
Binding Order (Oxygen)
1st oxygen: Slow
2nd to 3rd: Faster
3rd to 4th: Fastest.
105
Oxygen Release
Once one O₂ is released, hemoglobin releases 2-3 more due to decreased affinity.
106
The more O₂ bound, the higher the affinity for additional O₂.
Increased Affinity
107
Retention of O₂
Some hemoglobin retains at least one O₂ even after releasing others
108
Describes how hemoglobin saturation changes with varying PO₂ levels.
Oxygen Hemoglobin Dissociation Curve
109
Hemoglobin is almost fully saturated; rapid loading/unloading occurs in the steep curve region.
Unloading at 70 mmHg PO₂
110
Oxygen Delivery
25% of oxygen is delivered to tissues
75% remains in venous blood.
111
Increases O₂ release, lowers hemoglobin’s O₂ affinity, favors T-state.
Rightward Shift (Decreased Affinity for O₂)
112
Factors Causing Rightward Shift
↑CO₂
↑pCO₂
↑H⁺
↑temperature
↑2,3-BPG
More O₂ released.
↓pH
↓O₂ affinity (T state)
113
Enhances O₂ binding, favors R-state, hemoglobin holds onto oxygen.
Leftward Shift (Increased Affinity for O₂)
114
Factors Causing Leftward Shift
↓CO₂
↓H⁺
↓temperature
↓2,3-BPG
Hemoglobin holds onto O₂.
↑pH
↑O₂ affinity (R state)
115
Right or Left: T-State vs. R-State
Rightwards shift: T-state (tense) releases O₂ easily
Leftwards shift: R-state (relaxed) binds O₂ tightly.
116
4 Major Factors of a Rightward Shift
1. Increased carbon dioxide tension
2. Increased hydrogen ion or acidity
3. Increased temperature
4. Increased erythrocyte concentration of 2,3-BPG
117
Bohr Effect & Rightward Shift
↑CO₂
↑H₂CO₃
↑H⁺
↓pH
O₂ unloading in tissues.
118
Mechanism of Bohr Effect
His-146 protonated → Salt bridges form → Stabilizes T-state → O₂ released.
119
CO₂ & pH in Tissues
High CO₂ → Carbonic anhydrase → H₂CO₃ → H⁺ + HCO₃⁻ → ↓pH → O₂ release.
120
CO₂ & pH in Lungs
Low CO₂ → ↑pH → Hemoglobin shifts to R-state → O₂ binding increases.
121
Key Concept: Bohr Effect
More CO₂ = More H⁺ = ↓pH = O₂ release
Less CO₂ = Less H⁺ = ↑pH = O₂ binding.
122
Factors affecting changes in the Hemoglobin Molecule
1. pH of the Environment (Bohr Effect)
2. pO2 (Partial Pressure of Oxygen)
3. pCO2 (Partial Pressure of Carbon Dioxide)
4. 2,3-BPG (2,3-biphosphoglycerate)
123
Factor 1: Bohr Effect & pH (environment)
↓pH (acidic) → ↓O₂ affinity → O₂ release
↑pH (alkaline) → ↑O₂ affinity → O₂ binding.
124
Factor 2: pO₂ & Oxygen Binding
High pO₂ (lungs) → O₂ binding
Low pO₂ (tissues) → O₂ release.
125
Factor 3: pCO₂ & Oxygen Release
High pCO₂ (tissues) → Bohr Effect → ↓pH → O₂ release
Low pCO₂ (lungs) → ↑pH → O₂ binding.
126
Factor 4: 2,3-BPG & O₂ Affinity
↑2,3-BPG → ↓O₂ affinity → O₂ release
↓2,3-BPG → ↑O₂ affinity → O₂ binding.
127
Bohr Effect
↓pH (↑H⁺) → ↓O₂ affinity → O₂ unloading
↑pH (↓H⁺) → ↑O₂ affinity → O₂ binding.
128
Peripheral Tissues (O₂ Unloading)
CO₂ + H₂O → H₂CO₃ → HCO₃⁻ + H⁺ → ↓pH → Protonation of His-146 → Salt bridges stabilize T state → O₂ release.
129
Lungs (O₂ Loading)
High O₂ → Hb binds O₂ → R state shift → Salt bridges break → H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ exhaled
130
T State (Deoxyhemoglobin)
High H⁺ affinity → His-146 protonation → Salt bridge formation → O₂ unloading.
131
R State (Oxyhemoglobin)
Low H⁺ affinity → Salt bridge rupture → Increased flexibility → O₂ binding
132
CO₂ Transport in Tissues
CO₂ binds Hb (carbamation) → T state stabilization → O₂ release.
133
CO₂ Transport in Lungs
Carbonic anhydrase: H₂CO₃ → CO₂ + H₂O → CO₂ exhaled → R state shift → O₂ uptake.
134
Forms of CO₂ Transport
60–70% HCO₃⁻
20% carbaminohemoglobin
5–10% dissolved CO₂.
135
20% of CO₂ binds to Hb’s N-terminal amino groups → Enhances O₂ unloading.
Carbaminohemoglobin (Hb∙CO₂)
136
5–10% CO₂ dissolves in plasma (2.96 mL CO₂/100 mL blood).
Dissolved CO₂
137
Major Route; 60–70% CO₂ → CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻.
Bicarbonate (HCO₃⁻)
138
Peripheral Tissues (CO₂ Loading)
↑CO₂ → HCO₃⁻ formation & CarbaminoHb formation → O₂ unloading.
139
Lungs (CO₂ Elimination)
HCO₃⁻ + H⁺ → H₂CO₃ → CO₂ + H₂O → CO₂ exhaled (via carbonic anhydrase).
140
CO affinity for Hb: 220× > O₂ (strong, irreversible)
Effect: Competitive inhibitor of O₂ → blocks O₂ binding
Toxicity: Rapid binding → tissue hypoxia
Carboxyhemoglobin (Hb·CO)
141
Consequences on CO binding → Locks Hb in R-state (high O₂ affinity)
O₂ dissociation curve shifts left (hyperbolic, like myoglobin)
Hb holds O₂ → reduced tissue delivery
142
CO blocks O₂ release → cells starved of O₂
Hypoxia
143
CO binds cytochrome oxidase → halts ATP production
ETC Inhibition
144
worsens hypoxia causes dysfunction of what part of the cell
Mitochondrial dysfunction
145
100% O₂ at high pressure:
Competes with CO for Hb binding
Forces dissolved O₂ into plasma → bypasses Hb
Goal: Reduce Hb·CO, restore tissue O₂ delivery
Hyperbaric O₂ Therapy
146
Most abundant organic phosphate in RBCs; Binds to T-form hemoglobin, stabilizing it → Promotes O₂ unloading.
2,3-Biphosphoglycerate (BPG)
147
Formed from 1,3-BPG by what bifunctional enzyme
BPG mutase (2,3-BPG synthase/2-phosphatase)
148
Synthesis Trigger for 2,3-BPG
↓ pH (acidosis) → ↑ 2,3-BPG synthesis → More O₂ unloading.
149
Molecular Binding for 2,3-BPG
Negatively charged, binds electrostatically to β-chain (N-terminal Val, Lysine EF6, Histidine H21).
150
2,3 BPG stabilizes the T-form by forming 3 salt bridges with:
1. N-terminal Val (NA1)
2. Lysine EF6
3. Histidine H21
151
2,3-BPG & High Altitude
↑ 2,3-BPG at high altitude → More O₂ delivery to tissues (↑ RBC production and ↑ hemoglobin concentration) → Prevents hypoxia symptoms.
152
HbF & 2,3-BPG
HbF binds 2,3-BPG weakly (γ-chains lack positively charged His into Ser) → weak binding of 2,3-BPG to HbF → Higher O₂ affinity → fetal oxygen transfer → maternal anemia
153
Chronic Hypoxia & 2,3-BPG
COPD, anemia → ↑ 2,3-BPG → Enhances O₂ unloading in tissues (metabolic needs)
154
O₂ binding to Hb displaces CO₂
Opposite of Bohr effect
Haldane Effect
155
Key Mechanism of Haldane Effect
O₂ binds Hb → releases H⁺ → shifts carbonic anhydrase reaction → towards formation of CO₂ → expired.
156
Comparison: Bohr vs Haldane
Bohr Effect: CO₂/H⁺ promote O₂ unloading.
Haldane Effect: O₂ binding promotes CO₂ release.
157
Physiological Role of Haldane
Enhances CO₂ removal in lungs during oxygenation.
158
Location: Medulla
Detects: ↑ pCO₂ → ↓ CSF pH (acidic)
Response: Stimulates respiratory centers
Central Chemoreceptors
159
Location: Carotid & aortic bodies
Detects: ↓ O₂ (indirectly from ↑ pCO₂)
Response: Stimulates breathing
Peripheral Chemoreceptors
160
Medulla sends signals →
Phrenic nerve → diaphragm contracts
Costal nerves → intercostal muscles contract
Result: ↑ Ventilation (increased breathing)
Respiratory Response
161
↑ Ventilation → ↓ pCO₂ (exhaled) → ↑ CSF pH
Restores acid-base balance
CO₂ & pH Correction
162
Key Feedback Loop of CSF pH Regulation via Ventilation
↑ pCO₂ → ↓ pH → ↑ Ventilation → ↓ pCO₂ → Normal pH
163
Process of HbA1c Formation
Non-enzymatic glycosylation of HbA (slow reaction)
164
Binding Site of HbA1c Formation
Glucose attaches to N-terminal valine (β-globin chains)
165
HbA1c Formation depends on
Plasma glucose concentration
166
Most abundant form
HbA1c
167
Clinical Use of HbA1c
Diagnosis & Monitoring: Diabetes mellitus → Reflects long-term blood glucose levels (~3 months)
168
Key Feature of HbA1c
Marker for Diabetes Control:
Higher HbA1c = Poorer glycemic control
Lower HbA1c = Better glucose management
