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197 Cards in this Set

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What do Mb and Hb carry?
Oxygen
Where is Mb located?
Myocytes

Transport of O2 through cytosol to mitochondria
Where is Hb located?
Erythrocytes

Transport of O2 from lungs to peripheral tissues

Transport of CO2 and H+ from tissues back to lungs
Why does oxygen have low solubility in water?
Oxygen is nonpolar and has little opportunities for reacting with water
What is the oxygen carrying capacity of plasma?
5ml O2/liter plasma
What is the oxygen carrying capacity of whole blood?
250ml O2/liter plasma
What is the concentration of Hb in RBCs?
340 g Hb/L of cytosol
What is a simple protein?
Polypeptide only
What is a conjugated protein?
Polypeptide + cofactor
What is a cofactor?
aka: Prosthetic Group

NON-PEPTIDE group that is essential to a protein's function
What is a prosthetic group?
aka: cofactor

NON-PEPTIDE group that is essential to a protein's function
What type of protein are Mb and Hb?
conjugated proteins --> polypeptide + cofactor (heme)
What is the prosthetic group in Mb and Hb?
Heme
What is the apoprotein (polypeptide) and prosthetic group for Mb?
apoprotein: apoMb
prosthetic: (1) Heme
What is the apoprotein (polypeptide) and prosthetic group for Hb?
apoprotein: (2) alpha, (2) beta
prosthetic: (4) heme
In terms of the prosthetic group in Hb and Mb, what differs?
In Mb, only (1) heme is present.

Hb has (4).
Within each subunit of Hb, what is present?
(1) polypeptide chain and (1) heme unit

Polypeptide chain can be alpha or beta
How many subunits are needed for a functional unit?
(4) are needed-->(4) polypeptides, each with a heme unit
What is leghemoglobin?
Oxygen binding protein structure found in legumes in response to infection from parasites
How do you relate the Hb subunits to Mb?
The (4) Hb subunits each structurally resemble the Mb as a whole.
Within biology, what are the two types of metal bonding?
ionic
covalent
Describe ionic metal bonding:
*Electrons NOT shared
*ion-ion or ion-dipole interaction
*Transient Complexes
*Examples: Na+, K+, Mg 2+, Ca 2+ (alkali metals and alkaline earth metals)
Are ionic metal bonds long term or short term?
Transient
Describe covalent metal bonding:
*Electrons shared
*Coordinate covalent bond: both electrons from other (nonmetal) atom
*Long lived
*Examples: iron, zinc, copper (transitional metals)
What is a coordinate covalent bond?
both electrons from other (nonmetal) atom
Are covalent bonds short or long lived?
Generally long lived (stable) complexes
Describe Iron within the heme complex:
Oxidation State: ferrous
Symbol: Fe(II)
ionic equivalent: Fe 2+
Usual coordination #: 6
Describe Iron within the hemin complex:
Oxidation State: Ferric
Symbol: Fe (III)
ionic equivalent: Fe 3+
Usual coordination #: 6
What is the coordination number?
Number of atoms nearest the metal atom.
What is the oxidation reaction of iron?
heme (FeII)->hemin(FeIII)+1e-
What is the reduction reaction of iron?
hemin(FeIII)+1e- -->heme (FeII)
What is the organic portion of heme?
protophyrin
How large is heme?
>70 atoms
Describe the bond structure of heme and the results of it:
*alternating double bonds
*aromatic
*planar (flat)
*pi electrons: intensely colored
*non-polar except for (2) COO-
Is heme completely non-polar?
No, (2) COO- are present
Within heme, there are unpaired electrons of Nitrogen. Are they available for interaction?
No, they are delocalized in the ring system.
Iron is attached to ________ in heme.
(4) nitrogens

Iron is tightly bound at center of (4) Nitrogens

Covalent bonds
->Both electrons come from N
When iron is within heme, it is bonded to ____ atoms. It is capable of bonding to ___ more atoms.
4, 2
When iron is attached to heme, what state is it in?
Ferrous - Fe(II)
Spatially within heme, where are the two additional bonding positions on iron?
The heme molecule is planar, the two additional bonding positions are perpendicular to this plate.
Within heme, what are the non-polar interactions?
Folded peptide has a pocket complementary in size and shape to heme
Within heme, what are the coordinate covalent bond interactions?
Coordinate covalent bond exists between a histidine side chain and iron

5th coordinate position (proximal histidine)
At what coordinate covalent position does iron bond with the main polypeptide chain of heme?
5th
Within heme, what his does iron bond with?
Proximal his

Mb - #93??
Hb - #8??
Within heme, what ion pairing occurs?
heme COO- groups paired with (2) cationic side chains:

*arginine (R) - 45
*histidine (H) - 97
Where is the oxygen binding site on heme?
On the iron atom, 6th coordination position
How is the Fe-O bond formed?
Fe-O bond formed via an electron pair on oxygen
How is the distal his chain involved in oxygen binding?
distal his binds to O2, stabilizing Mb-O2 binding
Describe oxidation in heme:
irreversible
e is transferred
hemin unable to bind O2 (not an O2 carrier)

When heme is bound to Mb and Hb, oxidation occurs very slowly due to inhibition by apoprotein
What is the rxn of oxidation of heme?
heme-O2 → hemin + O2–*

*O2- is called superoxide, it is a reactive oxygen species
What is metHb?
Methemoglobin

Hb or Mb with hemin instead of heme
How does metHb occur and how is it taken care of?
metHb naturally forms via oxidation very slowly

Heme is ferric instead of ferrous

Unable to carry oxygen

It is normally reversed via enzymes & reductants (metHb->Hb)
What is methemoglobinia and how is it caused?
Clinically significant build up of metHb

Causes:
*Food additives (nitrites)
*drugs (sulfonamides, some local anesthetics)
*deficiency in reversing enzymes

Treatable with reducing agents such as Vitamin C
How is methemoglobinia treated?
Treatable with reducing agents such as Vitamin C
Within Mb, how much is alpha helix?
75%
How many alpha helix does Mb have and how are they arranged?
8

arranged in 2 layers
For Mb, where are the polar and non-polar side chains located?
Polar - Exterior

Non-polar - Embedded
What is important regarding heme and the folded structure of Mb?
The folded polypeptide has a pocket for heme

When heme is bonded to the folded Mb protein, it is less oxidizable
What about Hb over Mb gives it unique characteristics?
The tetrameric structure and lack of quaternary
When Hb and Mb go from oxygenated to deoxygenated state, how much O2 is released?
Hb - 4 O2
Mb - 1 O2
How do you define fractional saturation of oxygen?
Y= pO2/[pO2+P50]

P50 - pO2 where 50% is saturated
What is the descriptive word used to describe the shape of the graph of pO2 v. saturation in Hb and Mb?
Hb - Sigmoidal
Mb - Hyperbolic
For Mb, what is the p50?
1 torr

similar to Hb
What is the significance of p50?
Defines O2 affinity of an O2 binder
Does a higher p50 value correspond to higher or lower O2 affinity?
lower O2 affinity
Describe the affinity curve of Mb vs Hb:
Mb has a hyperbolic shape

Hb has a sigmoidal shape

Implications:
Hb curve is steeper in middle
Hb more sensitive to changes in pO2 in middle
What is the saturation of blood as it leaves healthy lungs?
.98

Same in tissue arteries
What is the saturation of blood as it leaves the tissues?
.62
During exercise what is the saturation of blood as it leaves the tissue?
.26
What is the relationship between changes in pO2 and changes in saturation?
small changes in pO2 doubles change in saturation
What is cooperative binding in hemoglobin?
Binding of oxygen to hemoglobin increases affinity of molecule to bond the next molecule of oxygen

Likewise for release of Oxygen
Define allosterism in regards to hemoglobin:
change in one site of a structure leads to changes elsewhere in the molecule

*Increased affinity as more Oxygen binds
What is degree of cooperativity?
Can range from 1-># of binding sites/molecule
How are the subunits in Hb joined?
Via:
ionic (salt links)
H-bonds
nonpolars
Why is Hb a dimer of dimers?
dimer 1 - alpha1beta1
dimer 2 - alpha2beta2
When O2 binds, how does the Hb molecule shift?
The dimers shift relative to each other, not within though

Relative to one dimer, the other dimer:
rotates 15 degrees counterclockwise and translates .8 angstrums
What happens to the interactions between dimers as oxygen binds?
several intersubunit salt bridges break
What happens during the iron movement due to O2 bonding?
*in deoxyHb, iron is out of plane of heme, towards proximal his (dome shaped)

*O2 binds, drawing iron into heme plain

*proximal his is pulled along

*parts of the polypeptide chain attached to proximal his move as well
As oxygen binds to hemoglobin, shifts occur and bonds break? How many and of what kind break?
8 intersubunit ion pairs break
Describe O2 binding energy and how it changes as more oxygen binds:
Some O2 binding energy is used in polypeptide movement/breakage

First O2 requires more breakages-->weaker bond

Later O2 requires less breakages-->stronger bond
What two forms does Hb exist in?
Tense and Relaxed

Tense (T):
low O2 affinity
many intersubunit interactions

Relaxed:
high O2 affinity
few intersubunit interactions
How does the affinity of Hb for O2 change?
Changes with metabolic needs
What does BPG directly do?
BPG lowers O2 affinity by binding to deoxyHb, not oxyHb
What state is Hb when BPG binds?
Binds only to tense state
Can Hb bind BPG and O2?
No, only one of a kind
What type of molecule is BPG classified as?
Allosteric effector

binds at a seperate site than O2 (allosteric site)

Acts as a regulator of O2 affinity
At physiological pH, what is the charge of BPG?
4-5 negative charges
How and where is BPG manufactured?
synthesized and degraded in RBCs by side reaction of glycolysis
How many BPG binding sites are available per Hb?
Only 1 is available per HbT

None are available in relaxed state
Is the BPG binding site cationic or anionic?
Cationic
What subunits create the BPG binding site?
(2) beta chains

(or gamma in fetal)
Why is Hbr have little affinity for BPG?
The conformational changes result in the BPG being covered up
Within Hb, what are the most important characteristics of the BPG site?
Arrangement of cationic groups:

N-terminal of alpha-NH3+ grou

(3) basic side chains from each beta chain
When oxygen binds, what happens to the bonded BPG?
The ion pairing breaks
Name some ways fetal Hb is different than adult Hb:
BPG site differs

P50 of fetal Hb is lower than adult

No matter the pO2, transfer to fetal Hb occurs
What are the isoforms of Hb in adults and fetus?
HbA: alpha2beta2
HbF: alpha2gamma2
Does HbF has lower or higher affinity for BPG, and chemically why?
Lower

Due to fewer cationic groups at BPG site

his 143 of each betachain replaced by ser in each gamma chain
Does Hb and Mb's affinity for Oxygen change with pH?
Hb - YES
Mb - NO
Describe the bohr effect:
lowering pH increases P50, promoting O2 release, while raising pH decreases P50
Why does the bohr effect take place?
Increase in [H+] is due to increase in metabolism --> increase in Oxygen needs of muscles and increased Oxygen unloading
How is some H+ removed from the tissue?
carried by deoxyHb
What are the (3) antagonists for O2 binding?
BPG
H+
CO2
For various groups, what is the affinity (pKa) based upon?
local environment
is H+ affinity higher for HbT or HbR, and why?
HbT

pKa values of a few basic groups are higher on HbT than on HbR
Does CO2 react preferentially with HbT or HbR?
HbT is more likely to react
What groups does CO2 react with on Heme?
amino groups
Where does CO bind to Hb?
On the Oxgyen binding sites
What are the relative affinities of Oxygen and CO with hemoglobin?
Hb=200xs
Free Heme=25,000xs
Within free heme, the affinity for CO is much higher than in physiological form.

Why is this?
Steric hindrance by distal his, preventing optimal CO binding
How much CO does it take to become fatal?
.1% CO for ~1hr ties up ~50% of the Hb
The dissociation of CO from Heme is catalyzed by?
light
Comparing T vs. R forms:

Binds?
Salt Bridges?
Temperature?
T:
*binds H+, CO2 & BPG
*contains 8 salt links that break on oxygenation
*favored by ↑ temperature

R:
*binds O2, CO
*fewer intersubunit interactions
What are the signs and symptoms of Sickle Cell Disease?
*susceptibility to infection
*recurring pain
*chronic fatigue
*swollen lymph nodes
*cardiac enlargement
*kidney damage
*jaundice
*anemia
*misshapen erythrocytes
What are the codons for HbA and HbS?
A: GAG
S: GTG
What are the sticky patches on Heme?
Differing side chains on Beta chain:

HbA has a surface glu
HbS has a surface val
What are complementary patches on Heme?
deoxyHb (on both HbA and HbS) have surface sites complementary to the val on each Betachain

(val is substituted for the correct one)
What has both sticky patches and complementary patches?
deoxyHbS
How does the aggregation occur in Sicke Cell Disease?
deoxyHbS has both sites and so they aggregate together

binding causes precipitation as fibers

this occurs where increase in [deoxyHbS]
Aggregation of deoxyHbS is based upon:
aggregation rate is extremely
concentration-dependent:
proportional[deoxyHbS]10


e.g., 7%↑ [deoxyHbS] produces rate doubling
Where does deoxyHbS increase?
deoxyHbS increases at regions where there is a decrease in [O2]
Is precipitation of HbS self regulating?
No, it is amplifying, vicious cycle
What is one positive thing of the heterozygous sickle cell trait?
Protection against malaria
What is the heterozygous sickle cell trait and characteristics?
1/2 - HbA
1/2 - HbS

Protection against Malaria
Minimal SCD symptoms
What is the treatment for Sickle Cell Disease?
Marrow transplant - RBC progenitor cells replaced
What is the functional relationship between oxygen binding by myoglobin and oxygen concentration?
Y=pO2/(pO2+p50)
What is the HbS sticky patch?
a surface anionic side chain (glu) on b chains of HbA is replaced by a nonpolar side chain (val )

On beta chain:
glu (anionic)-> val (nonpolar)
What is the HbS complementary site?
also on b chains ala 70 & leu 88
What two sites interact on HbS?
occurs via intermolecular binding of surface val of one. HbS to a complementary site on another HbS
What is the relationship between O2 consumed and CO2 expired?
For each O2 consumed,
.8 CO2 is produced
How is most O2 in blood carried?
Bound to protein Hb
How is most CO2 transported?
12% is bounded to Hb in form of carbamino groups

Majoraty is soluble in H2O
Compare the solubility of O2 and CO2 in water:
CO2 is 20xs more soluble in water than O2
Does O2 react with water?
No
Does CO2 react with water?
Yes

CO2 (gas) <--> CO2 (liq) + H2O
<--Carbonic Anhydrase--> H2CO3 <--> HCO3-
What is the enzyme involved in CO2 transport?
carbonic anhydrase
Where is carbonic anyhdrase located?
RBC cytosol

NOT in plasma
For every HCO3- produced, how many H+ are produced?
1 for 1
When attempting to measure CO2 levels, which ones are hard to measure seperate?
CO2liq & H2CO3

Together, they are called disolved CO2
What is dissolved CO2 composed of?
CO2liq and H2CO3
What is the simplified equilibrium equation for CO2 dissolving?
CO2gas <--> disCO2 <--> H+ + HCO3–
What is the H-H equation for CO2 dissolving?
pH = pKa + log([HCO3– ]/[disCO2])
What is the ratio of basic:acidic form in CO2?
19-20
What form of dissolved CO2 is the highest?
HCO3-
What are the percentages of the dissolved CO2?
HCO3- - 84%
carbaminoHb - 12%
disCO2 - 4%
Can dissolved CO2 levels change w/o detremental effects on health?
Yes, pH (dissolved H+) must stay constant though
What are some harmful effects of pH change?
malfunction of enzymes, receptors, neurons
How much of H+ is carried bound by buffers?
60% is carried bound to buffers
Isohydric carriage of CO2:
CO2 is carried with minimal change of pH

pKa shifts of Hb side chains upon O2 dissociation
(deoxy-Hb/ HbT formation) enable Hb to bind & carry more H+
If pH rises, what is likely to happen to excitable cells and why?
hyperexcitability likely

due to effects on membrane proteins
If pH lowers, what is likely to happen to excitable cells and why?
hypoexcitability likely

due to effects on membrane proteins
What are some important buffers in blood and their pKas?
***buffers
What are the important buffers for intracellular and extracellular regions?
Intracellular:
Protein (Hb in RBC)
CO2-bicarb
Pi
Phosphesters

Extracellular:
CO2-bicarb (in plasma, protein also)
What are (3) key things of buffers?
Act Instantaneously

Only minimize pH changes

Are overwhelmed with continuous base or acid production
Does ventilation adjust pH quickly or slowly?
Quickly, usually within seconds
What are lungs capable of excreting?
They only DIRECTLY extrect CO2

Fixed "non-volatile" acids must be extreted by the kidneys
Why are the lungs considered open system for buffering?
The rate of excretion can be varied
What basis are used for excretion of H+ by the kidneys?
***kidney
What are the characteristics of renal compensation to pH?
slow (hrs->days)

permanent
Respiratory Acidosis:
Hypoventilation

Cause: Lung disorders

Compensation: Increased renal acid excretion

Note: [HCO3-] & pCO2 still high
Respiratory Alkalosis:
Hyperventilation

Cause: anxiety

Compensation: decrease renal acid excretion
Metabolic Acidosis:
Causes: diabetes mellitus, renal failure

Compensation: increase excretion of CO2 from lungs
Metabolic Alkalosis:
Cause: vomiting, antacids

Compensation: Decrease excretion of CO2 by lungs
What are genes made of?
DNA
A complete copy of all DNA is in which cells?
All Cells
What does DNA determine?
cellular structure and function.
What is the diameter and length of a single round of DNA double helix?
Diameter - 20 angstrums
Length - 34 angstrums
What is the backbone of DNA?
Deoxyribose Phosphate
What is the sugar in DNA?
Beta-D-2-deoxyribose
On the DNA sugar, where are the hydroxal groups?
1',3',5'
Why is it deoxy instead of oxyneucleic acid?
2' position has a hydrogen instead of a hydroxal
What connects the sugars within DNA?
Phosphate
What are the purine bases?
Adenine
Guanine
What are the Pyrimidine bases?
Thymine
Cytosine
What is a deoxynucleoside?
A deoxynucleoside is a deoxyribose with a base (purine or pyrimidine) attached at the 1' carbon by an N-glycoside bond

1' hydroxyl group has been replaced by a hydrogen
What is a deoxynucleotide?
Deoxynucleoside that is phosphorylated at the 5' hydroxyl

There are deoxynucleoside mono-, di-, and tri- phosphates
What type of deoxynucleoside phosphates are there?
Mono, Di-, Tri phosphates

dNTP's (where N is base [T,A,G,C])

dNTP's are relatively unstable
DNA is a polymer of:
deoxynucleotide monophosphates
What is the backbone a repeating unit of?
Repeating identical units of deoxyribose and phosphate connected by a diester linkage
What are the ends of DNA called?
3' (bottom)
5' (top)

called 3' and 5' hydroxals of the deoxyriboses
How are complementary bases paired?
Via Hydrogen bonds
How are the phosphates within DNA arranged?
They are arranged on the outside of the helix to maximize their distance from each other

also helps reduce hydrolysis of the phosphate ester bond
What does cooperativity do for the DNA molecule?
Cooperativity makes small changes in structure energetically unfavorable
How many degrees does each base pair rotate the helix?
36 degrees
What type of replication is DNA?
Semiconsurvative
What end is the dNMP added?
3' end via the 5'->3' polymerase
Addition of dMNP to DNA requires how much energy?
zero, addition of dMNP to DNA is energetically neutral

Hydrolysis of pyrophosphate drives the reaction
What are the polymerization energetics?
1
dATP+H20<->dADP+Pi (-7.3kcal/mole)

2
dATP+DNA<->DNA-dAMP+PPi (0)

3
PPi+H2O<->2Pi
What is the DNA polymerase III?
Both strands of parental DNA bind to alpha subunits of DNA polymerase III

Moving in 3'->5' direction on both templates, the polymerase places the next bases on the active sites

Fast (2000/sec)
Processive (thousands at a time)
Big (~900 kD)
Can a DNA polymerase III start a chain?
NO

Requires enzyme primase
What is sequence of starting a chain?
Enzyme primase uses the template to synthesize a primer (5 base RNA using NTPs, not dNTPs)

DNA Polymerase III uses dNTPs to add DNA to RNA primer
What is DNA polymerase I?
Removes RNA primer and replaces it with DNA

Does not attach it to the original DNA segment though...still has gap requiring DNA ligase
What does the DNA ligase do?
Connects DNA fragments
The lagging strand contains short segments called:
Okazaki's fragments
The leading and lagging strands have new DNA replicated in what direction?
The DNA is built in a 5'->3' only

==>
Both are in 5'-3' direction
What does helicase do?
Unwinds the double helix DNA
What does the primase do?
synthesizes RNA primers
What does ssb do?
stabilizes DNA single strand regions