O2 transported in blood in 2 forms
1) dissolved O2 (%of total blood O2) HbO2 (98% of total blood O2, most O2 is associated with Hb)
CO2 transport
HbCO2 ~15-23% total blood CO2
What if the NADPH in RBC is low?
NADPH produced in RBCs helps reduce free radicals (PPP), decreased NADPH = hemolytic anemia
Porphyrins
a family of chemicals containing cyclic tetrapyrrole produced in all O2 using cells, mainly in bone marrow, kidney, and liver
Heme
a member of the porphyrins family
Heme is hydrophobic or hydrophilic?
HYDROPHOBIC (it is symmetrical)
myoglobin and hemoglobin
(heme + polypeptide) Mb: 1 heme + Mb globin Hb: 4 heme + Hb globin<
what is a globin
polypeptide
Mb does what
carries O2 for red muscle, slow ATP release (oxydative phosphorylation)
Myoglobin primary structure
~17 kDa of amino acids
Myoglobin secondary structure
alpha helix, globular, 8 regions labeled A-H
Mb tertiary structure
globular polar residues on the surface nonpolar residues in the core (interior), with hydrophobic interactions packing and stabilizing the myoglobin exceptions: the proximal histidine (His F8) and distal histidine (His E7) are hydrophilic to interact with charged polar ferrous ion
Heme is located:
in a crevice inside the molecule
Myoglobin binding of O2
His F8 -Fe2+ - heme plane - O2 - His E7
Hemoglobin molecule is formed where
in bone marrow
Where in the bone marrow is Hb formed?
within developing RBC
Hb transports ___ from lungs to entire body and ___ from body back to lungs&
1) O2 2) CO2
Each Hb is a tetramer
Hb globin (a polypeptide) + 1 heme = 1 Hb subunitHb globins + 4 heme = 1 hemoglobin moleculeAdult Hb: HbA1 (alpha2beta2)Fetal Hb: HbF (alpha2gamma2)
Sickle cell Hb
Hb - HbS (alpha2omega2), point mutation, sticks to blood vessels and ruptures)
Hemoglobin structure
2o and 3o structure are similar to Mb
Hb quaternary structure
Hb: 4 subunits forms 2 identical dimers, (alphabeta)1 and (alphabeta)2The tetrameric Hb molecule is structurally and functionally more complex than Mb due to interactions among the 4 subunits
The deoxyHb is constrained by...
salt bonds among different subunits (T form, taut or tight) binding of first O2 is difficult
Accepting the first O2...
ruptures of weakens salt bonds, resulting in conformational changes of Hb to R state (relaxed, Hb-O2) binding of 2nd, 3rd, and 4th O2 is easier and easier
What kind of curve is the Hb dissociation curve
sigmoid curve (higher p O2 = higher saturation rate)
DeoxyHb is associated with
T form
OxyHb is associated with
R form
Methemoglobin
Normal condition myoglobin (dark red)Hb (purple blue)HbO2 (bright red)change in structure and color
During oxygenation of Hb..
most Fe2+ is not oxidized to Fe3+
1.5% of Fe2+ - Fe3+, called:
methemoglobin (MetHb)
MetHb is what color? Can it combine with O2?
brown, no
MetHb can be converted to:
back to Hb by methemoglobin reductase (normally present in RBCs)
When [MetHb] is abnormally high:
high [MetHb] - little Hb to carry O2 = impaired tissue perfusion with O2
Cyanosis
blue color, and death
MetHb toxicosis
hypoxia, hypotension (vasodilation)
Ingestion of certain agents which oxidize Fe2+ to Fe3+, examples include:&
cat: acetominophen (7-10x more susceptible than dogs)cattle: nitrite poisoning from ingesting forage with high nitrate
When blood glucose enters RBC, Hb
non-enzymatically glycosylated to lysine residue in -NH2 terminus
fraction of glycated HbA1c Hb is usually
3-5% (7% for diabetics)
Once a hemoglobin is glycated:
it STAYS THAT WAY
a buildup of glycated hemoglobin within RBC reflects avg level of glucose to which the cell has been exposed during its life cycle
~120 day life cycle, HbA1c reflects blood glucose levels or last ~8 weeks or so
An elevated [HbA1c] =
poor blood glucose control such as in diabetes mellitus
Increased glycosylation of Hb increases or decreases affinity for oxygen binding?
increases, this is BAD because then it is very difficult to unload O2 from the blood to the body
Carbon monoxide toxicity
HbCO2 has 220x more affintiy than HbO2 (prevents oxygenation of Hb in the lungs)
CO can also bind to:
cytochromes in the mitochondria of cells, blocking electron transfer and ATP prod. (% Hb that can bind to O2 decreases)
Cyanide poisoning
CN- affects oxidative phosphorylation in cells and decreases utilization of O2
Venous blood is still..
highly oxygenated (bright red venous blood)
Catabolism of Hb in MM cells
after 100-200 days, the ages/damaged RBC are removed by monoculear phagocyte system (macrophage/monocyte)
Removal of aged RBC by:
Spleen - bone marrow&
Within the MM cells
globin and heme are separated protein catabolism heme catabolism
Protein catabolism
globin is hydrolyzed to amino acidsAA can be reused or metabolized in the liver into NH3-urea
Heme catabolism
iron and porphyrin are separatediron is stored, reused, or eliminatedporphyrin is converted into biliverdin
Catabolism of porphyrin in MM cells
(monocyte/macrophage)>dissociation from globin and Fe2+removal of side chains on the pyrrole rings of porphyrin formation of biliverdin by heme oxygenationforamtion of bilirubin by reduction
Biliverdin
oxidative cleavage of porphyrin ring by heme oxygenase (requires O2 and release CO) to form biliverdinbiliverdin is a dark green pigmentbile pigment in birds and amphibiansin mammals, it is converted to bilirubin
Bilirubin
central methylene bond is reduced by biliverdin reductase to give unconjugated bilirubin (UCB)bilirubin is a yellow pigment
Transport of free bilirubin (UCB)
bilirubin released into the blood from MM cells
Is bilirubin water soluble?
NO
What is bilirubin bound to?
albumin when transported in the blood, called UCB or free bilirubin
Albumin acts as a carrier for:
both hydrophobic and hydrophilic materials
the albumin-UCB complex is too large to pass through:
glomerular capillary wall into the renal tubular lumen
Does UCB pass into urine?
NO
Free bilirubin are released from ___ into the blood and taken up by ____
1) MM cells 2) liver (hepatocytes)
In the hepatocyte, how is bilirubin diglucuronide formed?
conjugation with glucuronic acid by bilirubin UDP glucuronyltransferase - formation of bilirubin diglucuronide
Conjuation adds ____ to ___ solubility in water
polar (charged) groups to increase solubility in water
What can also conjugate with bilirubin in horse, dog, cat, mouse, and rabbit?
SO4 glucose (bilirubin monoglucoside)
Does conjugated bilirubin need to bind albumin in the blood?
NO
transport of bilirubin diglucuronide in bile to:
most conjugated bilirubin passes into intestinal lumen via biliary systemconjugated bilirubin escapes from hepatocytes back into the blood and again taken up by hepatocytesa very small amt escapes into urine
proximal tubules of kidney have weak or strong ability to conjugate bilirubin?
weak
what percent of AA and glucose is absorbed by liver
95%
A portion of the urobilinogen is reabsorbed from ___ to ___
1) gut 2) blood
Enterohepatic circulation is?
reabsorption of some products by gut ->portal blood -> pass to liver ->back to gut
How much product is excreted in the feces?
85%
When are old RBC broken down
constantly
constant breakdown of RBC accounts for what percent of bilirubin formed?
80%
Normal blood levels of bilirubin are high or low?
low
Normal bilirubin levels are too low to cause skin coloration? T or F
True (total <1.0 mg/dl)
Conjugated and unconjugated each
<0.5 mg/dl
Bile pigments excreted in urine or feces?
feces
Affinity for ___ tissue?
BRAIN (UCB more likely to pass through BBB bc UCB has higher affinity for brain tissue, albumin:UCB complex cannot pass thru glomerulus bc pores are too small, but in BBB albumin can be released and pass thru BBB which may cause damage to brain tissue)