Erythrocyte+Biochemistry

Erythrocyte Biochemistry

RBC development RBC function

3 main fucntions 1) carry Hb 2) Generate ATP (metabolism) 3) RBC degredation product catabolization

RBC development Erythropoeisis begins in RBC stem cells Colony forming unit erythrocyte

as develop, nucleus is lost last cell inbone bmarrow...reticulocyte cytoplasm turns red from hemoglobin

EPO main regulator of response

in the kidneys ontrol production of Epo stiulated by hypoxia inducible factors stimulate production of Epo in rbcs stimulates bone marrow make new RBCs proliferative response (EPO allows RBCs to continue to live)

as hb goes up, direct relationship as hormone levels go up

principle degredative products: globin heme heme->iron, bilirubin really needto remember

How does occur? PAY ATTENTION Macrophage ingests damaged/sensecent RBCs RBC membrane lysed hemoglobin is released? globin proteolyed to AAs heme oxygenase acts on heme to release CO2 also releases biliverdin and iron biliverdin --> bilirubin iron is recycled

where does this occur?

REVIEW REVIEW

free hemoglibin in plasma binds ot haptoglonbin acute hemolysis->decrease in haptoglobin-HgB complex binds to hepatocyte recpetor, internalized haptoglobin is degraded in liver RES system globin is degraded heme is catabolyzed into biliverdin, bilirubin what happens to iron iron is converted to ferritin/hemosiderin in RES System intracellula storage as ferritin increase over time, forms granules in RES hemosiderin: an amorphous, water-insouble many blood transfusions->increase iron absorption hemosiderin: amorphous, H20 insoluble iron storage cmpound hemosiderin can be do[osited many organs...kidney, lungs in iron overload hemochromatosis stain with prussion blue urine hemosiderin

methemoglobin/hemopein pathway hemopexin heme-heopexin complex heme-hemopexin binds hepatocyte rec & ointernalized also bind to albumin hethemalbunim complex binds to hepatocyte receptor and internalized chromosome 15 ebryonic alpha glbins are zeta predominatnt alpha globins alpha 1, alpha 2 paired with one beta globin gene on chromosome 11 alpha2gamma2 is hemoglobin F intermediate alpha2delta2 is A2 hemoglobin delta is only about 2% of all adult hb predominant hemoglobin is adult...alpha2 beta 2

four polypeptides 2 beta, two alpha globins blwon up picture of subunit heme pocket binds oxygen each Hb binds 4 oxygen binding pattern 2,3bisphosphoglycerol

developing embryo.......yolk sac primarily embryonic hemoglobin other hemoglobhin afterwards is primarily in liver, spleen adult hemoglobin is predominant after 12 weeks getation

functions of hemoglobin binds to O2 in sigmoid fashion

binds to CO2 while delivering O2 and releases CO2 awhen its bidning )2 Binds H+ efficiently @ low pH and releases it when encoutners a high pH affinity is modulated by allosteric effectors: 2,3 dbg, chloride, CO2

Oxygen dissociation curve HB bidning 4 oxygen when 2,3 DPG cuases conformational change relases oxygen why?

p50-partial presssure O2 @ which Bohr Effect: )2 dissociation curve hemoglobin has to release oxygen to tissues way to remember: P50 p)2 is 26.6 mmHg with Sa)2 50%

to right: decrease oxygen affinity pts: febrile, high fever, favor release of oxygen infection: deliver more O2 to tissue

in ICU: releases more O2 to tissue acidotic

increases in oxygen affinity increases in DBG fetal hemoglobin left shifted high affinity for O2 low affinity for 23DPG

HB exists in 2 shapes: T state: tense, nonaccepting/low affinity state R: Relaxed state

Higha ffinity vs low affinity hemoglobins

unstable hemoglobins when exposed to stress, have tendency to break down

hemoglobins with increases susceptibility to oxidative stress 75% beta globin 25% alpha avariants mutations modify/ewaken heme-globin interactions Hb zurich, Hb gun hill intraerythrocytic preicpated globular incluseions-heinz bodies congenital heinz body anemia

M hemoglobins each one facotrs oxidized or ferric state faovrs the 't' state pseudocyanosis brown-slate colored skin enough )2, justnot binding absense of repsiratory distress )2 affinity curve is right shifted almost like exposed to carbon monoxide HBG saskaton, hyde-park, milkawlkeee

heme synthesis occurs within, without heme center for heme biosynthesis in liver, heme enzymes cytochromes, P450s

fifrst step: glycine blus cusccinyl coa goes to ALA (aminolevulinate acid) calatyzed by ALA synthase rate limiting step under negative feedback by heme

ALA leaves mitochondira leaves mitochondira enters cytosol for is converted after 3 rxns to coproporphyringen III coproporphyrinogen III reeneters mitochondria

any defects within this glycine+csuccinly coa outside reenters to make protoporphyrin ring.... lus iron makes heme conditions seen.... porphyria

sideroblastic iron deposits ALAS deficiency

mature RBC doesn't have any see iron deposits

acute abdominal pain photosensitivity sunlight induced rash neurologic complications

RBC cytoskeleton allows to maintain integrity width is 2 microns has to change shape even though 8 microns in diameter, needs to deform to go through sinsoids, which are only 3 microns in diameter how does deform? RBC cytoskeleton nice, complex

1) lipid bilayer hydrophilic end, hydrophobic end peripheral proteins lay mostly in cytoplatic side all ianteract to maintain stability flippases allow proteins in/out

hereditary spherocytosis caused b y defect in ankyrin (AKA band III) increased osmotic fragility loss of central translucence RBCs lyse sooner in spherocytosis b/c cytoskeleton compromised loss of ability to maintain k+ gradient

spectrin is horizontal causes hereidtoary elliptocytosis

RBC metabolic pathways RBC cation transport Sodium/potassium ATPase pump without pump, tendency is to accept water high protein content RBCs swell, burst cation pump driven by ATP high intracellular levels of potassium los intracellular levels of sodium binds ouabain competes with ATP ends up shutting down ATPase RBCs burst

glucose metabolism

when glucose enters RBCs 3 main pathways glycolysis pathway pentose phosphate pathway glutathione pathway maintain ATP reducing oxidants within RBC

changes it from hydrogen peroxide to redicals causes oxidative damage G6PD deficiency....mothballs or fava beans will result in oxidative damage & hemolysis glutathione pathway glucoase going straight to ATP, lactate

Rapoport-luerbering shunt->2,3 DPG need for case of acidotic conditions embden-meyerhoff pathway

how are the RBC products processed? normal RBC live 120d abnormal live 90d

thalassemia-unpaired alpha, beta->break down comensate by increased production, circlation of reticulocytes

incongugated bilirubin congugated in liver b y bulrubin uridine diphosphage-glucuronlyl tranferase--adding esters to the UDP-glucuronic acid much more water soluble physiologic jaundice of thenewborn occurs when there is increased load of bilirubin to immature liver BUGT-reducted enzyme activity assoc with gilbert syndrome... sometimes found in pts with grigler-najjar syndrome

reduce in enzyme activity

Unconjugated bilirubin sythesisd in RES from bilirubin synthase IMPORTANT IMPORTANT release dfrom RES not water soluble released bound to albumin elevated in hemolytic anemais, jaundice less water soluble severely elevated levels assoc iwth kernicterus in newborn...>20mg/dl full term
 * heme oxygenase is rate limiting enzyme in bilirubin biosytehss**

use phototherapy->convert unconj bilirubin->water soluble form RBC stimllated by anemia/hyposia via EPO RBC has 3 main components membrane hemoglobin-transport oxygen important in oxygen transport