Hemoglobin 1 Flashcards
1
Q
Which protoporphyrin is found in heme?
A
IX
it has 4 methyl, 2 vinyl, and 2 proprioante side chains on the tetrapyrrole ring
2
Q
Which part of rings open to bind? What do they bind to?
A
THere are two open positions on each side of the heme plane: 5th and 6th position
1 binds O2; 1 binds to side chain
3
Q
Heme vs Hemin
A
heme (aka ferroprotoporphyrin) is +2, Hemin (ferriprotoporphyrin) is +3
4
Q
What is Hb (ferrohemoglobin) ?
A
Oxygenated form of heme with +2 charge
ONly Ferrohemoglobin can bind Oxygen
5
Q
What is the ferric +3 oxgenated form?
A
methemoglobin (HbM) (aka Ferrihemoglobin)-
CANNOT BIND oxygen
ferribHb
6
Q
What is the structure of Hemoglobin?
A
A HETEROTETRAMER (2 diff types of chains, alpha and beta), circulating in RBC
7
Q
What is the structure of Myoglobin? How many heme groups?
A
(single polypeptide with ONE heme group) A monomer in muscle cells
O2 gets transproted to muscle cells, faciliatetes O2 transport within muscle cells
8
Q
What is Hemoglobin A?
A
Hemoglobin alpha2beta2 is normal
9
Q
What genes can be on Chromosomes #16
A
zeta, alpha, alpha
10
Q
What genes can be on Chromosomes #11
A
epsilon, Ggamma, Agamma, delta, beta
11
Q
What are the gene clusters encoding the alpha and beta chains of human Hb on chromosome 16
A
zeta psi zeta, psi alpha 2, alpha 2, alpha 1, theta 1
12
Q
GEne clusters encoding the alpha an beta chains of human Hb
A
Zeta epsilon, Ggamma, A gamma, Psibeta, , delta, beta
13
Q
How many exons and introns does each chromsomes have on 11 and 16?
A
3 exons
2 introns
14
Q
What are chains of Adult HbA1
A
alpha2 beta2
15
Q
What are chains of Adult HBA2
A
alpha2 delta2
16
Q
What is the name of fetal Hb? What are the chains?
A
HbF- alpha2 gamma2 (FETUS!)
17
Q
What are the three embryonic HB
A
Hb Gower 1
Hb Gower 2
Hb Porland
18
Q
Chains of Hb Gower 1
A
zeta2 epsilon2
19
Q
Chains of Hb Gower 2
A
alpah2 epsilon2
20
Q
Chains of Hb Portland
A
Zeta2 Gamma2
21
Q
What does a heme group consist of?
A
an organic part, protoporyphyrin IX and iron atom.
22
Q
Whawt does the porphyrin contain?
A
four pyrrole rings linked by 4 CH groups (methene bridges) in an alternating double-bond system.
23
Q
What does Fe bind to?
A
four N (1-4 coordination position) int eh center of protoporphrin ring
24
Q
What is the composition of the various normal hemoglobin molecules
A
two alpha (or alpha-like) polypeptide chains and two non-alpha polypeptide chains
Each polypeptide is the product of a separate gene, and is called the globin chain
25
how many Hemoglobin polypeptide chains are synthesized int eh life of a normal humanbeing?
6 distinct but chemically and functioanlly related chains
26
how many chains does each hb moleucle contin
either two alpha or two zeta cians
Zeta chains are ONLY syntehsized ruign first trimester of prenatal developetn
ti is replaced by alpha chain whos syntehsis contineus throughout fetal and adult life.
27
what ist the zeta chain synthesized?
only during first trimester of prenatal development. It is replaced by alpha chain
28
What are the four non alpha polypeptide chains
Beta, gamma, delta and epsilon
29
What two globins are the highest during embryonic development
zetaand epsilon
30
Which Hb coincides with teh shift in teh site of ERYTHROPOIESES form teh yolk sac to the liver and spleen?
HbF (alpha2 gamma2)
31
What is ratio of beta to gamma globin chains at time of birth
1/3- 1/2 beta chains compared to gamma
32
When has beta synthesis reached its maximim adult rate and gamma chain synteheis noramllay reduced to 1% or less of the toatl Hb?
y 6 months
33
What are F cells?
the small amount of HbF present in normal adults is confiend to limited population of red cells caled F cells which also contain HbA
34
What chromosome/gene responsible for Myoglobin?
Mb gene on chromosome #22
Few human variants
Non-essential in mice
35
HOw different are G-gamma and A gamma?
By one residue!
G= glycine
A= alanine
36
What is Hb1Ac
by post-translational modification of HbA. While a small amt is present in every individual, tlevel may be significantly eleavted in patients with diabetes mellitus whose blood glucose levels are not well-controlled
37
How is HbA1C controlled?
HbA1c is formed by NONENZYMATIC addition f glucose (or glucose-6-phosphate) to an alpha-amino group and termed GLYCATION
Stable adduct is formed by the Amadori rearrangment of the ALDIMINE to KETIMINE
38
HOw is HBA1c useful clinically?
...to determine long term glucose levels in diabetic conditions since the STABLE GLYCATION BUILDS up over time, dependent on teh circulating glucose concentrations in blood
39
What percent of the globin poplypeptide chains are folded in a right handed alpha hleical conformation?
~75%
8 major helical segments (A-H) in both myoglobinand beta chains and 7 chains in alpha chain
40
Where do non-helical segments lie between?
the alpha helices and ends f chain
41
What does the insdie fo the globin chain consist of?
almost entirely non-polar resides. Helical segments exhibit a priodic pattern of polar (exterior) and non-polar residues (interior)
42
Where does Myoglobin have ioznied (polar) side chains ?
distributed all over the surface
43
What about alpha nd beta globin chians/
polar groups on the surface of the molecules but in addition to non-polar pathches that allow them to combin with each other to form the alpha2- beta2 tetramer.
44
How does large number of charged amino acids on the surface of Hb moleule, wtith hits spherical shape affet its solubliliy?
makes it very soluble
45
Where does the heme group reside?
wihtin a non-polar crevice in the chain
46
Describe the Hb structure
heme group in non-polar crvice in the chain
Highly polar proprionicacid side chains of heme lie on surface
rest of heme group is inside where it is surrounded by non-polar residues except for TWO HISTIDINES
47
What are the funtions of the 2 Histidines
Irone atom of the heme is directly bonded to one Histidine (F8) - PROXIMAL HIS (5th coordination positiion)
the second (E7)- termed the distal HIS. This resduces affinity of myoglobin and Hb for CO
48
What ist he fucntion fo the intricate folding of Hb and Mg
nature's design for an oxygen carrier. Places heme in an environment that enables it to carry oxygen reversibly
In water, ferrous heme is very rapidly oxidized to ferric form (cannot bind oxygen); the non-polar heme bidning site provided by polypeptide chain protects the ferrous state of Fe from oxidatin to Ferric form
49
What are the two interactions between teh alpha and beta chains
Little interaction b/w the two alpha hchains and two beta chains
1. alpha1 - beta1 contact (and identical alpha 2- Beta 2) is one tyepe
2. Alpha1- Beta 2, or Alpha2 -beta1
Majority of them are H-phobic in nature, although ionic interactions rae important in modualating the allosteric interactions
50
Hb Quarternary Struvture
Dimer of Dimers
1 dimer of alpha 1- alpah2
1 dimer of beta 1- beta 2
4 hemes/tetramer (one heme per subunit)
51
What are two ways oxygen is transported?
1. as oxygen in solution
| 2. in reversible chemical combination with the Hb of RBCs
52
HOw much oxygen can be transported in plasma? In whole blood?
In plamsa, due to limited solubility of oxygen
only 0.3 mL O2/ 100mL
Whole blood, 18-20 mL O2 (60x greater b/c of the presence of Hb in teh RBs
53
What is oxyhemoglobin and deoxyhemoglobin?
Hb comibned with O2 is oxyhemoglobin (Fe2+)
Deoxyhemoglobin (Fe2+) when oxyhemoblogin reversibly lose its O2
54
What are the required physiological properties of Hb?
1. Great Solubility (34% mg/100mL) or 5mM in RBC
2. Transport large quantities of O2
3. Uptake and release of Oxygen at apporpriate partial pressures of O2
- must be saturated with O2What in lungs
- -must release sufficient amounts of O2 in the tissues
4. Good Buffer
55
What gives Hb great solubility?
- spherical shape
| - polar groups on surface of molecule
56
How much O2 can be transported
-18-20 mL O2/100 mL blood (cf 0.3 O2/100 mL H20)
57
what kind of shape foes the hemogloglobin diss curve have?
sigmoidal shape
58
What kind of shape does the myoglobin shpae have?
Hyperbolic
59
order of Oxygen affinisty between Hb, Mb, cyt oxidase
Cyt Oxidase> Mb > Hb
60
What is P50 for Mb and Hb
Mb = 1-5 mmHg (1-5 torr)
Hb = 26 mm Hg (26 torr)
61
What is ARTERIAL Oxygen Tension
about 100 torrs
62
What is mixed venous oxygen tesnion
about 50 torrs
63
what is minimum oxygen tenstion for cytochrome enzymes?
4-5 torrs
64
What is the venous circulatio oxygen tenstion?
about 40 mmHG, oxyhemoglobin dissociates and oxygen is readily made avaialable to cells
65
What does the Hill coefficient measure?
The cooperativity of O2 binding
nH for Hb is about 2.8
the nH for Mb is 1.0 b/c there is single polypeptride chain and NO COOPERATIVITY
66
What are the required phsyiogical properties of Hb
1. Great Solubility 34% (mg/100mL) or 5mM in RBC
spehrical shape
polar gorups on surface of molecuels
2. Transport large quantities of O2 (free gas solubility)); 18-20 ml O2/100 mL blood
3. Uptake and release of oxygen at appropriate partial pressures of O2
- must be satruated with O2 in the lungs
- must release sufficient amounts of O2 in the tissues
4. Good buffer
67
What are two ways Oxygen is transported in the blood
1. As oxygen in solution
| 2. in reversible chemical combination with the Hb of RBCs
68
How much oxyen can plasma transprot>
0.3 ml O2/100 mL
69
How much oxygen can WHOLE BLOOD transprot?
18-20 ml O2
Oxygen carryign capacity of whole blood is >60x greater than that of plamsa b/c of the presence of Hb in teh RBC
70
For any given PO2, is the Y higher for myoglobin or for hemoblogin? Wha tis the P50 of each?
Y is higher for myoglobin (myoglobin has a higher affinity for Oxygen than does Hb);
Oxygn affinit can be characterized by qauantitiy called P50.
P50 Mb= 1-5 mm Hg (1-5 torr)
P50 Hb = 26 torrq
71
What is the oxygen tentsion in venous circulation when oxyhemoblogin dissociates an doxygen in readily made available to cells?
40 mm Hg
72
What factors decrease Hb Affinity for Oxygen?
```
H+ (lower pH)
CO2
BPG
Cl-
Temp
```
73
What is the effect of low pH (higher Hydrogen ion concentration) on oxygen affingty for Hb? For Mb?
Hb- decreases affinity
Mb- no effect
74
How can you distinguish affect of CO2 vs pH on Hb oxygen dissociation cuve?
maintain a constant buffered pH, which both contribute to the effect
75
In aerobic metabolism, how many equivalents of CO2 are produced per O2 consumed?
In aerobic metabolism, 0.8 equivalents of VO2 are produced per O2 consumed
About 75% of the shift caused by an increasess in pCO2 is the result of H+ generated in teh folloiwng reaction
76
Some CO2 is carried by Hb to the lungs in teh form of what???
CARBAMATE! the unionized alpha amion groups of HB cn react reversibley with CO2
77
What is the mechanism of the Bohr Effect?
About 0.5 H+ is taken up by Hb for each molecule of O2 that is released
Hb is an improtant physiological bufer and as a reuslt, pH of venous blood changes very little evne though in rapidly meatboizing tisseus much CO2 and acid are produced
78
What type fo Hb (oxygenated or not) is able to take up H+
Deoxygenated!
79
What three gorups int eh Hb molecule acct for much of the Borh effect?
Side chains of
1. His 146 bet
2. His 122 alpha
3. Alpha-amino group of the alpha chain
The immediate environents become more NEGATIVELY charnged in the Deoxyhemoglobin b/c of changes in quaternary sructure induced by rlease of O2.
80
If pKa higer or lower in deoxy Hb
pKA is higher in Deoxy Hb (affinity for proton is higher)
81
Is Deoxy Hb a stronger or weaker acid
Weaker!
82
When is BGP produced normally?
as an off-shoot of the glycolytic metabolism fo the red cell
Increases at high Altitudes, (low ambient O2) nd in certain metabolic conditions
83
How many binding sits are tehre for DPG on Hb
ONly ONE binding site
84
What is the net charge of DPG at physiologial level?
Minus 4-5 net negative charge
85
When is 2,3 BPG Elevated? (what conditions)
How is 2,3, BPG maintained?
Anemia
Hypoxia (high altitude)
2.3 BPG lost in blood stored in citrate-glucose
Maintained with inosine via ribose
86
Where is the single binding site of DPG on Hb
in the central cavity
87
What happens when Hb is oxygenated?
BPG is extruede bc central cavity becomes too small
88
Does HbF have stronger or weaker affinity for O2?
Stronger
89
Why does HbF have a higher affinity for Oxygen?
b/c it Binds to BPG less strongly than HbA and consequently has a higher oxygen affinity in red cells
Higher O2 affinity optimizes teh transfer of oxgen form teh maternal tot eh fetal circualtion
Gamma chain has a Ser substituted for His at position 143, losing pos charge and inteactino with negative DPG
90
What deos increase in Cl- concnetration affect Hb binding
shiftes O2 dissociation curve to teh right
Cl- ions may further brace the deoxy -state b forming additional salkt bridges
91
What does an increase in Temperature do to oxygen affinity and Hb and Mb
shift right!
Decreases Oxygen affinity and therefore incerases the P50.
Affects BOTH myoglobin and Hb.
92
Describe the characteristics of Hb alpha chain
like myoglobin
Alpha chain by itself has a high oxygen affinity, a HYPEBOLIC oxygen dissociation curve, and oxygen binding characteristics tha tare insensitive to pH, CO2 concentration and BPG levels
93
Dexcribe characteristics of isoalted Beta chain of Hb
form tetramer, B4, which is called Hemoblin H
B4 entirely lacks the allosteric prperites of Hb.
The cooperative effets also disappear if the Hb molecule is split n half to alpha beta units
94
Dexcribe characteristics of isoalted Beta chain of Hb
form tetramer, B4, which is called Hemoblin H
B4 entirely lacks the allosteric prperites of Hb.
The cooperative effets also disappear if the Hb molecule is split n half to alpha beta units
