Erythrocyte Biochemistry Flashcards
when is the majority of the Hb synthesized?
before the extrusion of the nucleus from the normoblast
what does the normoblast become when the nucleus is extruded?
a reticulocyte
what is the composition of fetal hemoglobin?
alpha2 gamma2
what is the composition of adult hemoglobin?
either alpha2beta2 or alpha2delta2
what happens to the iron in heme once the O2 binds to it?
there is a conformational change in the Hb; the iron moves into the plane of porphyrin in heme
what effect does the conformational change of the hemoglobin have?
it pulls down the proximal histidine of Hb and changes the interaction with the associated globin chain
what effect does 2,3-BPG have on Hb?
it reduces the O2 affinity so the Hb gives up more O2 to the tissues
what is the Bohr effect?
the stimulation of O2 release by CO2 and H+
what is the relationship between CO2/H+ and Hb?
they are allosteric effectors
what does the fetus require in regards to Hb?
the fetus needs Hb that has higher affinity for O2 than maternal Hb
how does the fetal Hb have a higher affinity for O2 than the maternal Hb?
the fetal Hb does not bind well to 2,3-BPG
what causes sickle cell anemia?
mutation at amino acid position #6 in the beta globin
what is the effect of the mutation that causes sickle cell anemia?
the glutamic acid changes to valine
what is currently being researched to treat sickle cell anemia?
induction of expression of HbF- using hydroxyurea
where is iron stored?
in cells that line the intestines, liver, spleen, and bone marrow
how is iron stored?
it binds to a protein-ferritin- as Fe3+
what is a product of ferritin breakdown?
hemosiderin
how is Fe2+ converted to Fe3+?
ferroxidase (aka cerruloplasmin)
how is Fe3+ converted to Fe2+?
ferric reductase (aka DCYTB)
what does ferric reductase (aka duodenal cytochrome B) require?
vitamin C
how does Fe2+ enter the enterocyte?
via the divalent transporter 1 (DMT1)
how is Fe2+ exported out of the enterocyte?
via ferroportin
what does ferroportin require in order to function?
Hephaestin
what are ferroportin levels regulated by?
Hepcidin
how is iron transported in the blood to target tissues?
as Fe3+ and bound to transferrin
how does uptake of transferrin occur?
receptor-mediated endocytosis via transferrin receptor
how is the transferrin internalized?
via clathrin coated pits into endosomes
how does the transferrin get released from its receptor once in the endosome?
the low pH of the endosome releases the transferrin
where does the endosome transiently dock?
on the mitochondria
how does the iron get to the mitochondria?
via DMT1
How is iron content in the body regulated?
by modulating its absorption- through Hepcidin
What happens when hepcidin binds to ferroportin?
it causes the internalization of ferroportin and its subsequent degradation in lysosomes
what could cause iron deficiency?
overuse of aspirin or ulcers of the GI tract
what does iron deficiency cause?
hypochromic microcytic anemia
What is the disease of iron overload?
hereditary hemochromatosis (or HH)
where does iron accumulate in cases of hereditary hemochromatosis?
heart, liver, and pancreas
what does hereditary hemochromatosis lead to?
liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis, and heart failure
what causes hereditary hemochromatosis?
autosomal recessive; mutations in the hereditary hemochromatosis gene (HFE)
what is the typical body iron found in a patient with hereditary hemochromatosis?
15 g
what is RBC production dependent on?
folate and vitamin B12
why does megaloblastic macrocytic anemia occur?
occurs due to diminished synthesis of DNA in developing RBC in blood marrow
what does a blood smear of a patient with megaloblastic macrocytic anemia show?
macrocytic normochromic cells
what does the bone marrow of a patient with megaloblastic macrocytic anemia show?
large erythroblasts (megaloblasts) and hyper-segmented neutrophils
Folic acid has three parts. What are they?
pteridine ring, PABA, and glutamate residue
Folate can be reduced to what?
dihydrofolate (DHF)
what enzyme is responsible for folate–> DHF?
DHF reductase
what can DHF be reduced to and by what enzyme?
THF; by THF reductase
what is the active form of folate?
THF
what is THF important for?
synthesis of purines and the pyrimidine thymine; vital role in DNA synthesis
DHF is found in most foods like what?
liver, eggs, milk, legumes, wheat, leafy veggies
where is folic acid absorbed?
in the small intestine (jejunum)
where can folate be stored and for how long?
the liver stores 5-10 mg of folate for 3-6 months
once absorbed in the intestine, what is DHF converted to?
N5-methyl-THF (the primary circulating form of THF in the bloodstream)
what is methotrexate?
an antineoplatic agent; inhibitor of DHF reductase-therefore inhibitor of DNA synthesis
what happens if vitamin B12 is not available?
then folate is stuck as N5-methyl-THF–> the folate trap
what is the action of vitamin B12?
it removes a methyl group from N5-methyl-THF to make methyl-cobalamin and release THF
how do you get vitamin b12?
animal products
what are most cases of B12 deficiency caused from?
a lack of intrinsic factor
what does b-12 bind to?
R-binder proteins
what is the intrinsic factor-cobalmin complex carried by in the blood?
transcobalamin II
what is the gold standard of testing for pernicious anemia?
schilling test
what is the structure of heme like?
there are 4 five-membered rings containing nitrogen and iron is present in the ferrous state
where does the biosynthesis of heme primarily occur?
in the liver and the erythroid cells of bone marrow
How many phases are there of heme biosynthesis and where do they occur?
3 phases; phase 1: mitochondria, phase 2: cytosol, phase 3: mitochondria
defects in one or more stages of the heme biosynthesis cause what?
porphyrias
What occurs during the first stage of heme biosynthesis?
succinyl CoA and glycine are formed together to form amniolevulinic acid
what enzyme is responsible for phase 1 of heme biosynthesis?
ALA synthase
what inhibits ALA synthase?
heme and hemin
what does ALA synthase require and what happens if there is a deficiency of this?
ALA synthase requires vitamin B6 (PLP); if there is a deficiency of vitamin B6 there will be anemia
lead inactivates 2 important enzymes in the heme biosynthesis pathway. What are these 2 enzymes?
ALA dehydratase and ferrochelatase
what does lead poisoning lead to?
neurological symptoms (ALA builds up and is neurotoxic) and microcytic and hypochromic anemia; also impacts ATP synthesis
there are two different types of porphyrias, what are they?
acute hepatic (cause neurological symptoms) and erythropoietic (affect skin and photosensitivity)
what porphyria do you get when the prophobilinogen deaminase enzyme is defective?
acute intermittent porphyria (hepatic)
what porphyria do you get when the uroporphyrinogen III cosynthase enzyme is defective?
congenital erythropoietic porphyria (erythropoietic)
what porphyria do you get when the uroporphyrinogen III decarboxylase enzyme is defective?
porphyria cutanea tarda (hepatoerythropoietic)
what porphyria do you get when the protoporphyrinogen oxidase enzyme is defective?
variegate porphyria (hepatic)
what is the most common porphyria in the united states?
porphyria cutanea tarda
what does congenital erythropoietic porphyria result in a build up of?
uroporphyrinogen I and its oxidation product uroporphyrin I
what are the clinical signs of congenital erythropoietic porphyria?
red color in urine, red teeth, skin photosensitivity
when RBCs are broken down, hemoglobin is released in large quantities. How is this handled?
by the reticulo-endothelial system
what is globin broken down into?
amino acids
what is heme converted to?
biliverdin
what enzyme converts heme into biliverdin?
heme oxygenase
what is biliverdin converted into?
bilirubin
what enzyme convert biliverdin into bilirubin?
biliverdin reductase
