MSAP Biochemistry of Respiratory System Flashcards
How are proteins formed
Many amino acids may polymerize together to form proteins; may form peptide chain
Peptide bond
carbonyl linked to nitrogen (limited bond roation between N and carbonyl atom)
Planar arrangement with C-N bonds
R-groups in trans configuration
Repetitive peptide bonds creat polypeptides:
O on carbonyl is Hydrogen bond donor; always carries slightly negative charge
H on N carries slightly positive charge and is a hydrogen bond acceptor
Secondary Structure of Protein
Alpha Helix: Stabilized by hydrogen bonding (involves the atoms that participate in the peptide bond; repetitive hydrogen bonding; amino acid side chains stick out to the side of the helix
Beta Sheet: Stabilized by hydrogen bonding; amino acid side chains stick out above and below the plane of the sheet
Tertiary Structure of Protein
Secondary Structures that fold in on themselves
Quaternary Structure of Protein
More than one polypeptide that associate together to carry out some function
Globular vs. Fibrous Proteins
Fibrous Protein: tightly wound triple helix of proteins (not alpha helix)
ex. Collagen (not a globular protein)
Globular Proteins: water soluble and are approximately a spherical shape
Characteristics of Globular Proteins
Polar aa side chains on surface (good H2O solubility)
Non-polar aa side chains in interior (Hydrophobic)
Variety of secondary structure type (combo of beta sheet, alpha helix, and turns)
Some kind of biological/metabolic function (Catalytic , Regulatory, Transport)
What is a prosthetic group?
non-protein-component found on some proteins (heme for Hb)
Allosteric regulation
“other” site regulation
Strong forces of molecular attraction
covalent bond
the polar covalent bond
Weak forces of molecular attraction
ion-dipole, H-bond, dipole/dipole, attractive force, the London force (aka Van der Waals), the hydrophobic effect
What is the prophyrin ring assembled from?
Assembled from: 1) Amino acids (contain nitrogen), 2) TCA cycle intermediates
What is heme?
Prophyrin ring with the ferrous ion in the center
Globular heme proteins contain heme as prosthetic group
Almost all cells in the body have heme containing proteins (if you have mitochondria you have heme)
Functions of globular hemeproteins
May be found as part of an enzyme active site(chytochrom p450 enzymes in liver)
Transport of O2(Hb)
Storage of O2 (Mb)
Electron carriers (ETC in the mitochondria)
Storage of O2 by muscle cell myoglobin
- Globin protein monomer is mostly composed of alpha helix (few bends and turns present)
- Globin is unusual because it is devoid Beta sheet ( most proteins have alpha helix and beta sheet)
Heme is held in place with hydrophobic interactions and histidine
How many bonds does Fe2+ (Ferrous ion) form?
May form 6 covalent coordination bonds:
x4 bonds form to the N from the prophyrin ring
x1 bond links to the globin protein
x2 bond is free to reversibly bind O2
Why is Ferrous ion found protected by the prophyrin ring and found buried inside the globin protein?
Helps ensure that oxygen is released as O2 and not as some other species (like superoxide)
O2 entrance and exit is defined path through the globin protein
How many oxygen can bind to myoglobin (Mb)?
reversibly binds to only one oxygen
single monomer with tertiary structure
only function is to store O2 in the muscle
Function and Structure of Myoglobin (Mb)
single monomer with tertiary structure
only function is to store O2 in the muscle
Why is the Myoglobin dissociation curve hyperbolic?
If there is a lower partial pressure of oxygen then only about 50% of myoglobin receptors are turned on (enables oxygen to go to hemoglobin where it is needed)
In vascularized areas like capillaries the Mb-O2 saturation is increased since there is plenty of oxygen
Similarities and Difference between whale myoglobin and human beta-globin (monomer)
Primary sequence is remarkably different but conservation of important amino acids ensures correct shape
Structure of Hemoglobin
Hemoglobin A (HbA) is a pair of identical alpha beta dimers (called an alpha beta tetramer)
- Many hydrophobic interactions betwen alpha beta peptides form a strong dimer (do not change, stay tighly linked together)
- Few hydrogen bonds, ion-dipole bonds, and ionic interactions between alpha beta dimers (two dimers associate with each other, but may shift slightly)
- Acess to ferous ion is through channel in the protein
- Widely spaced heme groups
How many molecules of O2 can be carried on Hb?
4 globin monomers means that x4 O2 molecules may be carried on Hb
T- state (taut) of oxyhemoglobin
formed when no oxygen is presents; completely stripped of oxygen
Distal histidine is not interacting with oxygen; proximal histidine is covalently bonded to ferrous group
R-state (relaxed) of oxyhemoglobin
load hemoglobin with oxygen and some of the H-bonds are broken
Side chain may contribute to the hydroxyl group
Serine and Threonine
Side chain may contribute positive charge
Lysine and Arginine
Side has amide function group
Asparagine and Glutamine
Side chain may contribute negative charge
Aspartate and glutamate
Importance of histidine
Histidine exhibits acid base characteristics with a pka close to physiological range so it can act as a buffer
Only common amino acid that ionizable side chain whose pKa is close to physiological PH
Allows Hb to do two very important things:
Help buffer the pH of the blood
Regulate O2 affinity in response to pH
What are the branched chain amino acids?
Valine (Val), Leucine (Leu), Isoleucine (Iso)
hydrophobic side chains that stabilize the hydrophobic interaction between the globin alpha beta dimers
What are the amino acids that have aromatic side chains?
Phenylalanine (Phe), Tyrosine (Tyr), Tryptophan (Trp)
hydrophobic side chains that stabilize the hydrophobic interaction between the globin alpha beta dimers
Conformational change in the Hb molecule when O2 is attached
When O2 comes in it pulls down on the ferrous group and makes the ring flat (heme ring assumes planar shape which tugs on the proximal histidine, which then tugs the alpha helix, which then changes the shape of the globin monomer; this change in shape then alters the shape of the tetrameric protein)
Conformational change in the Hb molecule when O2 is not attached
When O2 leaves the proximal histidine tugs the ring up which creates the domed shape
How does conformational change in the Hb molecule affect the oxygen binding affinity of the heme sites in hemoglobin?
- When deoxygenated the hemoglobin is slightly bent and the affinity is low
- When the first O2 binds it sets off chain reaction and increases the affinity to promote the binding of more O2
Cooperativity
Binding of one O2 molecules promotes binding of another O2 molecule (cooperative ligand bonding)
How is sigmoidal O2 binding curve of Hb produced by cooperative binding of O2 to Hb?
- Cooperative ligand binding creates a sigmoidal curve when affinity is plotted against partial pressure
- When no oxygen at all bound the affinity for that O2 is relatively low; after first O2 binds then the “hunger” of the hemoglobin grows (affinity grows)
Why is O2 itself a positive allosteric regulator of oxygen binding?
O2 is a positive allosteric regulator of hemoglobin; binding of O2 at one site increases the affinity at another site
Note: decrease in pH causes a decrease in oxygen affinity for hemoglobin
Why does the O2 dissociation curve shift to the RT with decrease in pH and to the LT with increased pH?
- When pH is slightly elevated hemoglobin will experience LT shift and the affinity for O2 is increase
- When pH is slightly decreased there is decreased affinity
The affect of low pH on hemoglobin
Lower pH more protons in solution=more likely for histidine to become protonated= more areas to form salt bridges
Sets up driving force towards taut state
Carbonic anhydrase
Acts as a acid in solution; H+ ions protonate Hb, forms positive charges
Allow formation of additional salt bridges
Stabilizes the taut form of Hb
Promotes O2 delivery to tissues
Reaction of CO2 with amino terminus of the alpha chains
reacts with the amino acid terminus of the alpha chains
- allows for the formation of additional salt bridges, and also the release of H+ ions to strengthen the Bohr affect
Function of 2,3 biophosphoglycerate (2,3-BPG) in regulation of O2 binding to Hb
Formed from a side reaction of glycolysis
Potent regulatory of Hb oxygen affinity ; promotes formation of taut state–> decreases O2 affinity for Hb
–> promotes oxygen release to the tissues
Negative allosteric effector
Carries a lot of negative charges on the phosphates and carboxyl group
Positively charged side chains of amino acid groups form a pocket for 2,3 BPG to bind
When there is high pH is 2,3 BPG more or less likely to be present?
High pH= histamine less likely to be protonated
= more likely for 2,3 BPG to be present
When there is low pH is 2,3 BPG more or less likely to be present?
Low ph= histamine more like to be protonated which means its less likely that 2,3, BPG will be present
Bohr Effect (Mechanism of action and its significance in regulating O2 release from oxyHb)
Hemoglobin responds to pH to alter or change is O2 affinity
Allosteric effects & Hb
Regulation of O2 delivery by Hb depends on Allosterism (“other site”) effectors:
- pO2 (oxygen increases the affinity of the next O2 on hemoglobin)
- pH of environment (Bohr effect)
- pCO2 ( influences pH, and taut/relaxed state) ( acts as acid in solution)
- 2,3 BPG availability (negative allosteric regulator)
Why isn’t myoglobin allosterically regulated like Hb?
Myoglobin is not regulated in the same way because it only has 1 function (O2 delivery to muscles)
Where should O2 affinity be high?
In the lungs
Where should O2 affinity be low?
In the muscle tissues
Which tissues should have higher pH?
Higher pH should be in lung tissue
Which tissues should have lower pH?
Lower pH in muscle tissues
What type of shift is cause by increase in temperature?
Creates a right shift
Why do we need the prophyrin ring?
Hb purpose is to carry O2
oxygen always trying to take electrons from someone else and is very reactive
body has way to protect itself from the toxicity of the O2
