hemoglobin

what bonds join globin chains?
hydrophobic
what bonds join dimers in hemoglobin?
ionic
what types of alpha globins are there, and what chromosome are their genes on?
alpha 1 and 2, zeta
what types of beta globins are there and what chromosome are their genes on?
beta, epsilon, delta, and gamma, chromosome 11
why does RBC gene transcription occur early? why is their mRNA particularly stable
because RBC enucleation happens, and the mRNA needs to remain intact for further translation
what is the significance of hemoglobin F?
HbF is produced as a smaller portion of adult hemoglobin, it has a higher affinity for O2 than HbA. HbF contain usually a very small number of gamma globins which are not produced in high levels after 6 months of age
what is the major adult form of hemoglobin?
HbA or HbA2
what is mutated in sickle cell, and what is one goal of therapy?
the beta globin chain is mutated, and one of the goals of therapy is increasing the number of F cells
what other proteins contain heme? why does heme have to be tightly controlled in the body?
cytochromes. it can be a lipophilic pro-oxidant, causing toxic oxidation
where does the heme bind in a globin?
between the F and E helices
what does the iron bind to in hemoglobin?
the 4 nitrogens in the porphyrin rings, the E histidine amino acid histidine, and an oxygen. it associates with the F helix as well which keeps the iron from oxidizing and reduces the Hb affinity for CO
where does hemoglobin get its color from?
the double bonds
where is iron absorbed and what state is it in?
the small intestine, as free iron or heme
what reduces Fe2+ to Fe3+ and where? what increases this activity?
in the intestinal mucosal cells, by reductase. acidic pH and reducing substances, such as vitamin C help
what regulates Fe absorption? how does it happen?
Fe requirement and synthesis of apoferritin. heme is directly absorbed through a heme transporter, iron is absorbed through a “divalent metal transporter” which is upregulated by vit C
what is apoferritin, what does it do?
a storage protein which binds Fe in the capillaries, (name changes to simply “ferritin”), and is taken to bone marrow and liver
how is Fe excreted?
bleeding, slough-ed off cells, urine, feces – no physiological pathway
what is transferrin?
single chain glycoprotein with 2 binding sites for Fe3+, (oxidized by ceruloplasmin). it carries iron through the blood and to cells which receive it via receptor mediated endocytosis.
how saturated are transferrin binding sites usually? why?
~ 30%, protects against infection by iron dependent pathogens. also it can increase in iron deficient states and function as an indirect method of determining iron levels
what subunits make up ferritin? where do they predominiate?
apoferritin, in 2 isoforms: L and H. L is usually in liver and spleen, and H is in nucleated blood cells and the heart. there is a small amount in blood, good indicator of Fe reserves.
what happens when ferritin capacity is exceeded?
iron deposits form in tissues called hemosiderin
how does iron starvation affect ferritin and transferrin receptor synthesis?
the iron responsive binding protein binds to a hairpin loop in the mRNA 5′ region for ferritin, blocking it from being transcribed, (no ferritin needed if no iron). however, the IRBP stabilizes the transferrin receptor in the 3′ region, so that any available iron can be recieved by cells. iron binds to the IRBP in excess iron situations, leading to the reverse of the actions described
where do the rxns of heme synthesis take place?
bone marrow and liver. 1st (rate limiting)and last 3 happen in the mitochondria, all others in the cytosol
what are the 2 organic substrates of heme synthesis? what is its feedback inhibitor?
glycine and succinyl CoA, (from TCA – prob why in mitochonria) (8x each). heme
what is the first rxn of heme synthesis?
ALA is formed from glycine and succinyl CoA, by ALA synthetase, along with cofactor vit B6. (mitochondrial)
what is the 2nd heme synth rxn?
ALA is made into porphobilinogen, (PBG) by ALA dehydratase in the cytosol
what other than heme can inhibit the 2nd and last heme synth reactions, potentially toxically?
lead, other heavy metals
what can happen if the 3rd rxn of heme synth doesnt occur correctly?
dead end intermediates can build up, causing photosensitivity
what happens in the final heme synth rxn?
ferrochetalase catalyzes the placement of Fe in the center of the porphyrin ring
heme synth is regulated mostly by reg of ALA synthetase, what activates or inhibits it?
heme and glucose inhibit, and Fe, steroid hormones, (esp those metabolized by cytochrome p450) activate
what are ALAS1 and 2?
isoforms of ALA synthase. ALAS1 is found in the liver, makes heme for cytochromes. ALAS2 makes 85% of daily heme – found in bone marrow, ALAS2 synthesis, (TL), responds to Fe levels, which are regulated by heme’s reg of Fe aquisition from transferrin. it is also subject to the same erythroid-specific transcription factors that reg globin synth. heme also can likely regulate ALAS1+2 by preventing translocation of either into the mitochondria.
how is heme synthesis coordinated with Fe levels and globin synth?
ALAS2 has an IRE in the 5′. ALAS2 TS is under control of the same TS factors as globin TS, erythropoietin increases both TS of ALAS2 and alpha/beta globins, and finally in erythroblasts, heme increases the TS of globins/stabilizes the mRNA
what is HCI?
heme-controlled inhibitor, a protein kinase that is inhibited by heme. when heme levels are high, the kinase is inhibited, eIF2 is nonphosphorylated and active – leading to translation of proteins, (globin)
what is a porphyria, what are symptoms?
a defect in heme synthesis, can be genetic or aquired. symptoms include: ALA in blood and urine, aneamia, neurological problems. lead poisoning is technically included
what are porphyrias classified as, how are they inherited, what are some precipitating factors?
erythropoitic or hepatic. most are dominately inherited, but with low penetrance. alcohol, certain drugs, fasting/severe dieting, hormones, and stress can precipitate the condition.
what are symptoms of porphyrias due to?
accumulation of toxic intermediates, porphyrins/porphrynogens can cause photosensitivity by reacting with sunlight, depletion of essential cofactors.
what treatment is given for porphyrias?
hematin, a stable heme-derivative, inhbits ALA sythase and serves in hemes place. a carb-rich diet will inhibit ALA synthase, as well as withdraw from any precipitating drugs
how does diet affect heme synthesis?
when glucagon is high, a coactivator of ALAS1 is activated, and when insulin/glucose is high it is inhibited
how do some drugs induce acute porphyria attacks?
some drugs induce synthesis of cytochrome p450, using more heme, so less is available to inhibit ALA synthase
what is the most common porphyria? what are some symptoms and tx options?
porphyria tarda. it is dominantly inherited, often seen expressed in conjunction with patients with liver damage. iron overload can also be a precipitating factor. symptoms are photosensitivity and pigmented urine. tx includes alcohol abstinence, blood iron removal, and sunlight avoidance
what characterizes acute intermittent porphyria?
intermittent attacks of abdominal pain, constipation, weak muscles, cardiovascular abnormalities, and neurological disfunction. also colored urine/stool. usually no symptoms until exacerbated. dominant, low penetrance
what is congenital erythropoietic porphyria?
extremely rare, accumulation of uroporphyrinogen I, leading to red urine, florescent teeth, photosensitivity, and and anemia
where does oxygen bind on the heme in relation to the histidine? how does this affect the shape of the hemoglobin?
opposite side, when it attaches to the Fe molecule, it straightens out the convex shape, which in turn pulls on the histidine, (relieving strain), which in turn changes confirmation of the hemoglobin
what is the net effect of the 4 hisidine’s movements in response to oxygen binding?
change from the T, (tight), to R, (relaxed), form. this incorporates a lessening of the number of ionic bonds, and a 300x increase in O2 affinity
how does hemoglobin’s affinity for O2 in the lungs and tissues compare?
in the lungs, hemoglobin has a high affinity for O2, (like myoglobin), with O2 essentially functioning as an allosteric activator. in the tissues, several allosteric inhibitors such as, 2,3 BPG, H+, and CO2 cause hemoglobins affinity for O2 to drop, (unlike myoglobin), so that hemoglobin can drop off O2 as opposed to receiving it. in the lungs, the high levels of O2 override all other inhibitors
where does 2,3 BPG come from, how does it affect hemoglobin?
2,3 BPG is made from a glycolytic intermediate, and exists equimolar with Hb in rbc. it binds to deoxy Hb in a +charged pocket between alpha globins and stabilizes the T form, decreasing O2 affinity.
why does HbF have a higher affinity for O2?
it has less of +charged pockets than other Hb, (gamma chains have less +), this is important so that the fetus can get O2 from the mother
how does 2,3 BPG respond to higher altitude, and other conditions of hypoxia, (anemia, cardiopulmonary insufficiency)?
its levels increase, increasing hemoglobin’s O2 affinity quicker than other bodily changes
how do H+ ions affect hemoglobin’s affinity for O2?
as Hb is converted from the T to R form, H+ ions are released, therefore increasing the level of H+ pushes this rxn to the left, helping release O2
how does conversion of CO2 to bicarbonate help Hb in its function?
in the tissues, 70-80% metabolically produced CO2 is converted to bicarb, giving off an H+ that allows Hb to give off O2 easier. in the lungs, O2 binding to Hb gives off H+, which combines with bicarb to create CO2 which can be exhaled
what happens to the remaining 15-20% of CO2?
CO2 binds to the N terminal amino acid of globin chains, creating carbamino-hemoglobin. this also gives off an H+, allowing Hb to drop O2 in the tissues
what is a thalassemia?
partial or complete absence of one or more globin chains
what can result from alpha thalassemia? if 4 genes are deleted? if 3 are deleted? 2?
if all 4 alpha genes are deleted -> hydrops fetalis, only gamma globins that have too high of an affinity to give up O2s = fatal before birth. if 3 genes are deleted, there is an unstable tetramer formed with the beta globins = moderate to severe disease. if 2 genes are deleted, mild disease.
what can result from beta thalassemia? if both genes are deleted? 1?
thalassemia minor, when 1 gene is deleted is usually asymptomatic, except for minor anemia, which should not be treated with iron supplements. (heterozygous). thalassemia major is when both genes are deleted, and pts need many transfusions for sever anemia, often suffer from iron overload, skeletal deformities, and alpha chain precip. can build up, (homozygous)
what causes sickle cell anemia? what are the symptoms?
a point mutation in the beta globin, (glutamate to valine causing intracellular fibers), which causes decreased solubility, however only the deoxy form of Hb will sickle. usually only homozygotes have symptoms – hemolytic anemia, vaso-occlusion leading to infarction.
what is the most common aquired hemoglobinopathy?
CO poisoning, where it competes with O2 for binding
methemoglobinemia is caused by what? what level of methemoglobin is fatal?
methemoglobin, or Hb with Fe3+ bound to it is fatal if levels reach 70% of Hb. some drugs, such as anesthetics can cause it, along with some rare congential forms, (dominant hemoglobin M and recessive deficiency of NADH cytochrome b5 reductase). it is treated with methylene blue, a reducing agent
what is the rate limiting first step of heme degradation? what does it require? what does it produce
macrophages in the reticuloendothelial system, (spleen), pick up RBCs, (globin chains are removed), and heme oxygenase cleaves the pyrrole ring, producing biliverdin. this requires O2 and NADPH, and gives off CO and Fe3+
what produces bilirubin?
biliverdin is converted to bilirubin by biliverdin reductase in a rxn that requires NADPH
what are two uses for CO?
it can be measured on exhalation to monitor level of heme degradation, b/c it is the only physiological source of CO. it also acts as a signaling molecule in neural tissue, (vasodilatory, anti-inflamatory, cytoprotectant)
what is the goal of heme degradation?
to preserve Fe and convert protoporphyrin to excretable products
what carries bilirubin to the liver?
albumin
once bilirubin reaches the liver what happens?
bilirubin is bound to glutathione S transferase, and then conjugated to 2 molecules of UDP-glucuronate by glucuronyl transferase
how does conjugated bilirubin get to the bile?
conjugated bilirubin is then taken to the bile by Multidrug Resistance Protein 2, (MRP2)
what happens to conjugated bilirubins when they are taken from the liver to the small intestine?
bacterial hydrolases de-conjugate bilirubin, which is then reduced to form urobilinogens. most are oxidized to form urobilins -> feces, some are reabsorbed into the blood and urinated out
what are the 3 isoenzymes of heme oxygenase?
HO1, which is expressed constitutively in the liver and spleen, although inducible in most tissues; which essentially any kind of stress will do, (cytoprotective response). HO2, is expressed esp. in the liver and brain constitutively, (not inducible) HO3, not much is known.
what can bilirubin perform as in low levels in the body?
antioxidant
what is jaundice, and what can cause it?
deposits of bilirubin in the skin and sclerae, it is usually due to increased production of Br, either prehepatic, (hemolysis), hepatic, (neonatal, hepatitis, genetic), or post-hepatic, (bile duct obstruction)
how does the van den bergh reaction measure bilirubin?
the conjugated bilirubin will react with diazonium salts in a direct van den berg rxn, the unconjugated, (still attached to albumin), has to be treated with an organic solvent to react with the azo dye, this will give you the total. then use this equation: total-direct=indirect
define prehepatic jaundice
indirect hyperbilirubinemia. increased production of Br, past the liver’s ability to conjugate. there is no bilirubin in the urine. uncommon unless there are other problems with the liver.
name some general symptoms of intrahepatic jaundice, and what 3 types can it be broken down into?
impaired hepatic uptake, conjugation, or secretion of Br. usually a combination of direct and indirect hyperbilirubinemia. urobilinogen increased in urine, decreased in stool. conjugated bilirubin in urine. increase in liver enzymes, (AST/ALT). there can be neonatal, hepatitis, and genetic types.
describe neonatal jaundice
~50% of newborns, due to delay, (~ 4 wks),of adult levels of bilirubin glucuronyl transferase. caveat is if Br levels exceed albumin binding capacity, the accumulation of Br in basal ganglia can cause a toxic encepthalopathy called kernicterus
what treatment can be effective for neonatal jaundice?
phototherapy which converts bilirubin into more soluble isoforms
what is crigler-najjar syndrome?
rare deficiency with bilirubin glucuronyl transferase. type 1 = total deficiency, type 2 = less severe
define gibert syndrome
common elevation of indirect bilirubin, due to a mutation in the promoter of bilirubin glucuronyl transferase gene, (decreased expression)
define dubin-johnson syndrome
rare mutation in the MRP2 gene, resulting in defective transport of conjugated bilirubin out of hepatocytes
define posthepatice jaundice
due to bile obstruction, hyperbilirubinemia can result in bile acid accumulation in plasma, conjugated bilirubin in urin, and a lack of urobilinogens in stool/urine
what happens if RBCs lyse in the bloodstream outside of the normal pathway?
Free Hb dissociates into the alpha and beta dimers, and Haptoglobin binds to them, creating a complex too large to be filtered by the glomerulus, delivering them to macrophages via a specific receptor. this also prevents tissue damage by Fe
what does serum haptoglobin reflect?
degree of intravascular hemolysis
if haptoglobin is an acute phase reactant what can be inferred about its levels during different afflictions?
levels will increase with inflamation or infection, but will decline with sustained hemolysis
what is the action of hemopexin?
free heme not bound by haptoglobin is oxidized to metHb, which dissociates to globin and metheme, which hemopexin binds to. hemopexin delivers heme to the liver, which induces heme oxygenase -> normal pathway
can albumin bing metheme?
yes, with a low affinity
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