Hemoglobin is a red pigment in red blood cells that can bind with oxygen. This protein is responsible for binding oxygen in the lung and transporting the oxygen throughout the body to be used up in aerobic metabolic pathways. Hemoglobin is a protein made up of four polypeptide subunits, as seen in the picture above. Within each one of these subunits is a heme group. A heme group is an iron-containing ring structure that has the ability to bind to oxygen. Each hemoglobin protein can bind to four oxygen molecules - one oxygen molecule for each heme group.
What helps hemoglobin maintain its quaternary structure?
2) Van der Waals forces - These forces stabilize the close interactions between the hydrophobic residues.
4) Ionic bonds - These interactions occur between positively and negatively charged particles deep within the hemoglobin away from water.
The oxygen binding properties of hemoglobin exist because of the interaction between oxygen and the iron atom of the heme groups and hemoglobin's quaternary structure. However, the ability of hemoglobin to pick up or release oxygen also depends on the pO2, the partial pressure of the oxygen in its environment. When the partial pressure of the oxygen (pO2) is high, as it is in the capillaries around the lung, each molecule of hemoglobin can carry its maximum load of four oxygen molecules. As the blood circulates around the body, the blood experiences lower levels of partial pressure. At these low levels of pO2, the hemoglobin releases some of the oxygen it is carrying. See graph below.
This graph demonstrates the significant role that partial pressure of oxygen plays in hemoglobin's ability to bind and release oxygen. The graph above shows that the hemoglobin near the lungs is very close to its maximum value for carrying oxygen at a partial pressure of 100mm. When the partial pressure decreases to 40mm, the hemoglobin's oxygen concentration also decreases from close to 100% down to around 75%. Think about it: if a snakes falls in the hall right now we will all need a of oxygen to reach our muscles so that we can run. So our breathing rate increases, pO2 goes up and almost all the Hb molecules are saturated with O2. But when you walk back to your room lazily, the pO2 is low and you need less O2 so the Hb molecules carry fewer O2 molecules to our muscles.
Thus, CO2 is transported by CO2 binding to Hb (ie. 20% of CO2 is transported in the form of carbaminohemoglobin), via the carbonic anhydrase method (60%) and as CO2 dissolved in plasma (20%). Carbonic anhydrase is an enzyme that promotes conversion of CO2 + H2O to H2CO3 (carbonic acid). Most of the CO2 removed from the body, then, is carried to the lung in the form of carbonic acid. When the blood reaches the lungs, the CO2 transported in plasma is blown off in the expiratory gas, the CO2 transported to the lungs bound to hemoglobin is released and blown off in the expiratory gas, and the CO2 transported to the lungs in the form of carbonic acid is converted back to CO2 and blown off in the expiratory gas. See a picture developing here... no matter how the CO2 is transported to the lungs, it is all blown off in the expiratory gas.
2,3-BPG
In addition to hydrogen ions and carbon dioxide, a very important allosteric effector is 2,3-bisphosphoglycerate (2,3-BPG). It is a small, organic molecule that is synthesized in red blood cells from 1,3-BPG, an intermediate in glycolysis. This "costs" the red blood cell 1 ATP that it would have gained from converting 1,3-BPG to 3-phosphoglycerate, but 2,3-BPG has a major and critical effect on the affinity of hemoglobin for oxygen.
BPG affects oxygen binding affinity by binding in a small cavity at the center axis of deoxygenated hemoglobin. In oxygenated hemoglobin, this cavity is too small to effectively accommodate 2,3-BPG. When bound, 2,3-BPG stabilizes the deoxygenated conformation of hemoglobin, greatly diminishing the binding of oxygen and facilitating oxygen unloading to actively respiring tissues. At high altitude, when the proportion of oxygen in the atmosphere is lower and hence oxygen is harder to deliver to the tissues, the synthesis of 2,3-BPG is upregulated significantly. It takes about 24 hours for 2,3-BPG levels to rise, and over longer periods of time, the levels continue to increase. This is why athletes can train at high altitudes to temporarily increase their aeorbic capacity.
What's the difference between O2 binding and transport by Hemoglobin and Myoglobin?
Test Yourself
2) Which of the following reactions prevails in red blood cells traveling through pulmonary capillaries? (Hb = hemoglobin)
4) Which of the following is false concerning the hemoglobin molecule?
5) Which of the following is a characteristic of both hemoglobin and hemocyanin?
A) found within blood cells B) red in color C) contains the element iron as an oxygen-binding component D) transports oxygen E) occurs in mammals
6) A new organism is discovered in the forests of Costa Rica. Scientists there determine that the polypeptide sequence of hemoglobin from the new organism has 72 amino acid differences from humans, 65 differences from a gibbon, 49 differences from a rat, and 5 differences from a frog. These data suggest that the new organism
B) is more closely related to frogs than to humans.
C) may have evolved from gibbons but not rats.
D) is more closely related to humans than to rats.
E) may have evolved from rats but not from humans and gibbons.
7) The tertiary structure of a protein is the
A) bonding together of several polypeptide chains by weak bonds.
B) order in which amino acids are joined in a polypeptide chain.
C) unique three-dimensional shape of the fully folded polypeptide.
D) organization of a polypeptide chain into an α helix or β pleated sheet.
E) overall protein structure resulting from the aggregation of two or more polypeptide subunits.
8) The α helix and the β pleated sheet are both common polypeptide forms found in which level of protein structure?
A) primary
B) secondary
C) tertiary
D) quaternary
E) all of the above
In how many places does sickle cell hemoglobin differ from normal hemoglobin?
10. Sickle cell disease is beneficial to some individuals Why?
11. The affinity of Hemoglobin for Oxygen increases when:
b) protons concentration increases
c) the concentration of 2,3-BPG increases
d) an acidosis is established
e) the concentration of Carbon Dioxide increases
12. This substance, transported by Hemoglobin, promotes the relaxation of vascular walls, producing an important and potent vasodilator effect.
a) 2,3, BPG
b) Carbon monoxide
c) Carbon Dioxide
d) Nitric Oxide
e) Oxygen
13. Hemoglobin F is formed by:
a) 1 Hem group, two alpha peptide chains and two beta peptide chains
b) 1 Hem group, two alpha peptide chains and two gamma peptide chains
c) 2 Hem groups, two alpha peptide chains and two beta peptide chains
d) 2 Hem groups, two alpha peptide chains and two gamma peptide chains
e) 4 Hem groups, two alpha peptide chains and two beta peptide chains
f) 4 Hem groups, two alpha peptide chains and two gamma peptide chains
14. An important difference between Methemoglobin and hemoglobin is that:
a) Methemoglobin has four alpha chains
b) Methemoglobin has four beta chains.
c) Methemoglobin has two alpha chains and two gamma chains
d) Methemoglobin has iron in Ferric state instead of Ferrous state
e) Methemoglobin has cupper instead of iron.
15. Mountain climbers who are interested in reaching the summit of Mt Everest must do so in stages; spending extended periods of time at camps located at increasingly higher elevations along the trek. This helps to increase the oxygen carrying capacity of their blood by inducing the accumulation of the metabolite 2,3-bisphosphoglycerate in their blood. Explain how this accumulation leads to an increased oxygen carrying capacity.
16. Why is a horseshoe crab's blood blue, doesn't it contain hemoglobin?
17. Compare and contrast between Hb and Myb
18. Which of the following characteristics is NOT shared by both hemoglobin and myoglobin?
a) a multisubunit protein
b) binds O2 reversibly
c) A His residue is involved in O2 binding.
d) possesses a heme prosthetic group
e) Secondary structure is almost completely alpha-helix.
Figure 3.1 Collagen is a great example of building blocks. With just three amino acids that repeat, it forms long twisted strands (a triple helix). About one quarter of all of the protein in your body is collagen.
a) What parts of the body use collagen?
b) What is special about the places where I circled "H" and "OH"?
COLLAGEN
- It comprises of short stout elongated fibrils. Many collagen fibrils come together and form a collagen
and forma collagen fiber. - Collagen contributes to meat toughness.
- Diameter of collagen fibers is 1- 12 um.
- Rarely seen as branched.
- Collagen fibrils are formed of long tropocollagen molecules.
- Collagen is a glycoprotein containing galactose and glucose.
- Glycine is one - third of total amino acid content of collagen followed by hydroxyproline and proline
account for another one-third of amino acid content of collagen. Hydroxyproline is exclusive to collagen
and due to this reason to estimate collagen normally hydroxyproline is estimation is done. - Collagen has intermolecular cross linkages and due to these has high tensile strength of collagen
fibers. Younger the animal lesser are the cross links. - As the animal progresses in age the collagen cross-link concentration increases.
- Oxidative deamination initiates the cross linking through lysyl oxidase.
- Cross linking of collagen is a progressive process but it is not that it is in every muscle.
- There are about 14 types collagen. The type I, II, III comprise the bulk. Some these have been
discussed below–
Collagen type I
i)The fibers have diameter between 80 to 160nm.
ii)Found in bone, skin, tendon, muscles and walls of blood vessels.
Collagen type II
i)have a diameter <80nm>Collagen type III
i)Found in spleen, muscle, and aorta.
Collagen type IV
Found around different types of in the basement membranes and muscles.
Collagen type V
It is found in embryonic cell cultures and the basement membranes.
Collagen type VI
It is found in muscle and skin.
Tropocollagen - High molecular weight protein 300,000 daltons.
- Formed of three polypeptide strands forming triple helix.
- The binding cross links of the tropocollagen molecules are made between the helical shaft of one molecule
and the non-helical extension of the neighboring molecule.
ELASTIN - It is less abundant as compared to collagen.
- It is a rubbery protein.
- It is found in ligaments ( e.g. ligamentum nuchae ) , walls os arteries, organs and muscles,
- It has a high content of glycine.
- It contains 8 amino acids.
- The two amino acids specific to elastin are desmosine and isodesmosine. Desmosine forms cross links
and it binds 4 adjoining elastin chains by forming intermolecular linkage between their molecules due to
non polar amino acids and desmosine cross links.
(I think as a pharmacist you have to understand what skin moisturizers do and the biochemistry behind this. You will be manufacturing some of these yourself)
The skin is our principle organ of beauty, touch, pleasure, and sensuality. Your skin is the largest organ of the body, accounting for 12% to 16% body weight covers 12 to 20 square feet. With age the amount of subcutaneous (under-the-skin) fat is reduced resulting in a looser look to the skin.
The approximate chemical composition of the skin is:
Water 70.0%
Protein 25.5%
Lipids 2.0%
Trace Minerals 0.5%
Other 2.0%
The skin's barrier has a difficult dual function. First it must protect the body against invasion from microorganisms and against losing fluid and drying out. However, this barrier must still be open and permeable enough to allow an exchange of warmth, air and fluids. It also must act as the sensory organ for our delicate sense of touch. The skin regulates the body temperature by evaporating water. The skin replaces itself about every 27 days and continuously produces a horny protective cover of hardened proteins (keratinization) while shedding the outermost layer of dead cells (exfoliation).
Skin Firmness, Elasticity, and Moisture-holding.
Collagen and elastin are the skin proteins responsible for elasticity, tone and texture. Glycosoaminoglycans (GAG's or mucopolysaccharides) and proteoglycans hold water in the skin (these are very similar to mucus proteins) and are the true skin moisturizers. In contrast, cosmetic moisturizers cover the skin with a water impermeable barrier such as petrolatum or a heavy oil. This artificially slows the loss of moisture from the skin and gives the skin a temporary appearance of plumpness and fullness.
Major Skin Molecules - Collagen, Elastin, GAG’s and Proteoglycans
Collagen forms the structural network of our skin and is the most abundant protein in the body. It is primarily composed of glycine, proline and hydroxyproline. It is one of the strongest proteins in nature and gives skin its strength and durability. As we age, it is believed that collagen begins to deteriorate and causes the skin to become thinner and eventually sag. Elastin is similar to collagen but is a more stretchable protein that maintains the skin's elasticity. It provides the matrix that holds individual skin cells in place. Elastin also contains two unique amino acids, desmosine and isodesmonsine. The two proteins together permit the skin to stretch, then regain its original shape. With age, the skin's elastin breaks down and causes wrinkles. GAGs contain special sugars such as glucosamine hydrochloride, N-acetyl glucosamine, and glucosamine sulfate that have high water-holding properties. These are built into larger water-holding chains of sugars such as hyaluronic acid, keratin sulfate, heparin, heparin sulfate, dermatin sulfate, and chondroitin sulfate.
Proteoglycans are larger molecules with many attached GAG’s. Proteoglycans are linear GAGs made up of repeating disaccharide units composed of sugars (glucuronic or iduronic acid) and hexosamines (glucosamine or galactosamine) that are bound to a protein core. The abundance of hydroxyl, carboxyl and sulfate groups makes the GAGs intensely hydrophilic (water-loving) molecules able to form porous, hydrated gels. Hydrated GAG's cushion and provide mechanical support to tissues.
Test youself
1. Which of these is not a globular protein?
a. The skin protein collagen
b. The hormone insulin
c. The enzyme amylase
d. The oxygen carrier haemoglobin
2. The collagen defect present in scurvy is
a) decreased protein stability due to decreased hydroxylation of pro and lys residues.
b) conversion of the collagen helix from a right- to a left-handed triple supercoil.
c) decreased protein stability due to increased glycosylation.
d) increased formation of Schiff base crosslinks.
e) substitution of gly for pro and lys residues in the collagen sequence.
3. Substitution of Gly in the primary sequence of collagen with almost any other amino acid results in defective collagen assembly because
a) the contact points of the triple helix are so close that only the Gly side chain fits well into the space available.
b) collagen is glycosylated on Gly residues.
c) Gly forms critical hydrogen bonds with neighboring glycines.
d) Gly is crosslinked to allysine residues in the mature protein.
e) intrachain hydrogen bonding is dependent on the presence of gly residues.
4. You discover a fibroblast cell line that produces defective collagen. The collagen that this cell line synthesizes does not forms a triple helix and no collagen is secreted. Which of the following might explain this mutation?
a) The collagen has an Gly->Arg mutation.
b) A defect is present in prolyl or lysyl hydroxylase
c) A defect in lysyl oxidase.
d) A defect in vitamin C uptake.
5. Which of the following amiono acids is most important in stabilizing the structure of the collagen triple helix?
b) proline
c) hydroxyproline
d) lysine
e) cysteine
6. Which of the following events will not cause a disorder related to impaired collagen synthesis?
a) deficiency in vitamin C
b) deficiency in vitamin D
c) deficiency in procollagen-N-propeptidase
d) deficiency in lysyl oxidase
e) deficiency in prolyl hydroxylase
7. The following statements concerning collagen are correct EXCEPT:
a) Type IV collagen is a component of basement membrane.
b) Type I collagen is a component of microfibrils.
c) Type III collagen is present in reticular fibrils.
d) Type I collagen fibrils are characterized by a 67 nm periodicity.
e) Procollagen peptides do not form part of collagen fibrils.
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