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Flashcards in ch 7 Deck (50):

what is hemoglobin?

oxygen transport protein found in red blood cells; carreis oxygen from the lungs to the tissues and simultaneously transports carbon dioxide and hydrogen ions back to the lungs


what is myoglobin

oxygen storage protein; found in muscle, provides a reserve supply of oxygen in times of need


myoglobin structure

alpha helices that form globular structure


2 forms of myoglobin

deoxymyloglobin, oxymioglobin


what does ability of myoglobin and hemoglobin to bind o2 depend on?

bound prostetic group called heme


what gives blood and muscle distinctive color

heme group


structure of heme group

organic component (protoporphyrin) and a central iron atom bonded to four pyrrole nitrogen atoms


under normal conditions, what charged state is the iron in?

Fe2+ which can form an additional 2 bonds one on each side of heme plane (5th and 6th coordination sites)


what is the 5th coordination site of the heme group occupied by

imidazole ring of a histidine residue from a protein (called the proximal histidine)


what is the sixth coordination site used for?

binding to oxygen


how does binding of oxygen affect the heme group?

changes the position of iron which goes into the plane when oxygen is present


what happens when oxygen binds?

partial transfer of an electron from the ferrous ion to oxygen. this is a complex between Fe3+ ion and a superoxide ion


why is the superoxide ion sometimes damaging to living cells

if superoxide leaves, heme group containging Fe3+ cannot bind to oxygen again


how does myoglobin prevent superoxide from being released

binding pocket of myoglobin has additional histidine called distal histidine which hydrogen bonds to the bound oxygen


structure of hemoglobin

4 chains: 2 identical alpha chains and 2 identical beta chains . each subunit has similar structure to myoglobin


hemoglobin binds oxygen very efficiently (how much of carrying capacity?) and how is this compared to myoglobin

90 percent. myoglobin can only use 7percent under similar conditions


four chains in hemoglobin bind oxygen how?

cooperatively meaning the binding of oxygen in 1 site increases chances for remaning sites to bind o2


how does cooperativity happen?

hem globin undergoes large changes in quarternary structure alpha1beta1 and alpha2beta2 dimers rotate 15 degrees with respect to each other


what is the t state

quaternary structure observed in the deoxy form. tense state. quite rigid


what is the r state

relaxed state. quarternary structure in fully oxygenated form. relaex because more flexible to undergo structural changes


which state r or t binds o2 better?

r state binds o2 with higer afinity.


what are the 2 models of cooperativity?

concerted model
- hemoglobin molecules only exist in the R or T states
Sequential model
- hemoglobin can exist in partial R or T states
- at each state of oxygen loading, an equlibrium exists between 2 states, more oxygen shits equilibrium towards R state more.
there can be a mixture of R and T states within a hemoglobin tetramer
- binding of ligand changes conformation of subunit to which it binds which induces neighboring subunits to increase affinity for ligand.


how does hemoglobin behavior described by both forms of cooperativity?

follows concerted model when three out of 4 sites are bound to o2. quaternary structure consistent with the R state and the o2 affinity of the remaining site is 20 fold greater than completely deoxygenated hemoglobin

follows sequential model when one of the four sites is bound with o2. has quaternary stuructre assoicated with the tstate and the empty sites only bind o2 with 3 times greater affinity than deoxygenated hemoglobin


what happens to the sigmoidal curve when all the molecules are in the t state? when the fraction of molecules in r state increases? when all of the sites within r state molecules are filled?

The sigmoidal curve is shallow at low oxygen concentrations when
all of the molecules are in the T state
• Curve becomes steeper as fraction of molecules in R state
• Flattens when all of the sites within R state molecules are filled


how does the heme group transmit structural changes

firs the o2 binding causes the iron atom to move into the plane of the porphyrin. the histadine residue bound to the fifth coordination stie also moves with the iron atom. this histadine is part of an alpha helix that also moves. the c terminus of this alpha helix lies in the interface between 2 alphabeta dimers. this change in the position of the alpha helix favours the T to R transmision.


how does 2,3-bisphosphoglycerate alter oxygen affinity of hemoglobin?

it stablizes the T state by binding to the pocket in the center of the tetramer. the pocket is only present in the T form and collapses upon T to R transition.

2,3-BPG means more oxygen binding sites must be occuped in order to induce the T to R transition (hemoglobin remians in lower affinity T state until high o2 concentrations are reached)


how do carbon dioxide and hydrogen ions regulate activity of hemoglobin?

act as allosteric effectors.


what amino acids contribute to the bohr effect? and why?

1. alpha amino group at the n terminus of the alpha chain
2. side chain of histadine beta146

all have pH around 7 and are very sensative to small pH changes near 7


what stabilizes T state in deoxyhemoglobin?

3amino acids form salt bridges to stabilize t state quaternary structure


at low pH, how does the protonation state of histadine beta146 change, and what does this do?

added proton allows histadine beta 146 to form a salt bridge with the asp of b94 which stabilizes t state and allows release of o2 into the tissuse


at high pH what happens to histadine beta 146?

loses a proton resulting in disruption ofsalt bridge and favores o2 binding


how does co2 stabilize the T state

1. causes a drop in pH because it reacts with water to produce moderately strong acid carbonic acid (accelerated by carbonic anhydrase) which dissociates into bicarbonate ion and H+ ions
2. reacts with terminal amino group to form caramate which is negatively charged in contrast to the typical postively charged n-terminal amino goups. the negatively charged carbamate group form salt bridges that further stabilize the t state


how is co2 transported

carbon dioxide released from red blood cells is transported to lungs in the form of bicarbonate ion. bicarbonate leaves red blood cells using a membrane transport protein that exchanges hco3- for cl-. in the lungs hco3- is converted back to co2 and exhaled


what mutation is responsible for sickle cell anemia?

a single amino acid substitution in the beta chain. valine residue is substituded for a glutamate residue at position 6


what is this mutated version of hemoglobi called?

hemoglobin S or HbS


how does the HbS mutation affect solubility of deoxyhemoglobin?

it decreases solubility of deoxyhemoglobin but does not alter oxyhemoglobin


how does the mutant valine residue do to the T state?

it is on the surface of the T state HbS which forms a new hydrophobic patch that interacts with an existing hydrophobic patch on a neighborning beta chain from another hemoglobin molecule and initiates agregation


what is a single hemoglobin s fiber made of

14 chains of interlined hemoglobin s molecules.


why do hemoglobin s agregates not form in oxygenated state?

hemoglobin s is in the r state resulting in residues phe 85 and val 88 being burried in the protein and unable to aggregate with mutant val


what causes thalacemia?

loss or reduction in production of a single hemoglobin chain


what are symptoms of thalassemia

anemia, fatigue, pale skin, liver, and spleen problems


what are the 2 basic types of thalassemia

alpha thalassema
beta thalassemia


alpha thalacemia structure and effects

only contain beta chain. bind oxygen with high affinity but do not display cooperativity: low oxygen carying capacity and poor release of o2 to the tissues


beta thalassemia structure and effects

alpha chains form insouble aggregates that precipitate insid immature red blood cells. loss of red blood cells leads to anemia.


how many genes produce the alpha and beta chains respectively?

alpha: 4
beta: 2


symptoms of varying amount of inactivated genes:

1 gene: no symptoms
2 genes: mild symptoms
3 genes: moderate to severe
4 genes: fetus dies before birth

1gene: mild signs
2genes: babies healthy at birth but develop symptoms within 2 years


why does the alpha chain not precipitate even though its formed in excess due to the 4 genes

red blood cells produce a protein calld alpha hemoglobin stabilizing protein (AHSP) which binds to alpha chian monomers to form a highly soluble complex


where does ahsp bind?

it binds to the same face as beta hemoglobin and can bind to both deoxygenated and oxygenated forms of the alpha chain


when does ahsp bind?

binds as alpha chain is being produced


when does ahsp unbind?

as beta hemoglobin is produced it displaces ahsp from alpha hemoglobin