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CPR Test 2 > Erthryocyte biochem > Flashcards

Erthryocyte biochem Flashcards

1
Q

when is majority of Hb synthesized in erythropoiesis?

A

before extrusion of nucleus from normoblast to become reticulocyte

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2
Q

what is the structure of adult Hb?

A

multi-unit protein that has 2 alpha chains, 2 beta chains, 1 heme molecule that contains an iron atom (to which O2 binds)

hydrophobic

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3
Q

how does O2 bind to Hb?

A

iron ion undergoes conformational change when bound to O2 in relation to the plane of polyphrin in heme

–> pulls down proximal histidine of Hb and changes its interaction with an associated globin chain

—> distal histidine then stabilizes bound O2

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4
Q

what kind of oxygen dissociation curve (ODC) does myoglobin have?

hemoglobin?

A

myoglobin: hyberloic curve
hemoglobin: sigmoidal curve

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5
Q

how does Hb bind O2 in cooperative manner?

A

binding to one molecule of O2 to one heme causes the conformational change (with the proximal histidine being pulled down) in one globin–> causes the conformational change in the next globin—> allowing O2 to readily bind to another heme

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6
Q

how does the lowering of pH in tissues cause the release of O2 from Hb? (also known as Bohr Effect)

which area of the ODC is this reflected on (and what percent saturation)?

A

histidine in Hb picks up the H+ from tissue–> causes conformational change which favors release of O2

steep part- 66%

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7
Q

how does 2,3- BPG modulate release of O2 from Hb?

A

signals to Hb to let go of O2 and reduces its affinity for it

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8
Q

why does exercise cause release of O2 from Hb?

what part of curve reflects this?

A

drop in pO2 from 40-20 mmHg

falls into the range of the very steep part of curve

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9
Q

does fetal Hb have higher or lower affinity for O2 than mother? how is this so?

A

fetal Hb (HbF) has higher affinity for O2 than HbA (mother’s Hb)

this is due to 2,3 BPG not binding well to HbF

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10
Q

what is the mutated Hb in sickle cell anemia? how does this happen? what are the effects?

A

HbS

glutamic acid changes to valine in B globin—> causes polymerization–> impedes circulation and can cause hemolytic anemia

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11
Q

what are they currently researching to treat sickle cell anemia? side effects?

A

hydroxyurea to induce expression of HbF

inflammation and is a toxic chemotherapeutic agent

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12
Q

what two big roles does Fe have?

A
  1. role in oxygen transport because it is both a component of Hb (67% of Fe) and myoglobin (5%)
  2. role in ETC becaise its component of cytochromes
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13
Q

how is Fe regulated in the body?

A

modulating its absorption (need about 25 mg each day to support Hb production)

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14
Q

how is iron stored (about 27% of total)?

A

stored in the form of ferritin (protein that binds to ferric iron) in cells of the spleen, BM, liver, and intestines

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15
Q

what is the degradation product of ferritin?

A

homosiderin

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16
Q

what is the pathway that non-heme iron (Fe3 from plant products) takes to become stored in body?

A

Fe3 (form that is hard for enterocytes to absorb) converted to Fe2 by ferric reductase (duodenal cytochrome-like B protein (dcytb)) in presence of vit C—>

Fe2 enters enterocyte via divalent transporter-1 (DMT-1)—>

exported out of enterocyte by ferroportin—>

Fe2 is then converted back into Fe3 in the blood by ferroxidase (cerruloplasmin) for transport or storage

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17
Q

what does ferroportin require for its function?

how is it regulated?

when is this regulation high?

what regulates the regulator?

A

requires hephaestin

regulated by hepcidin- peptide made by liver and binds to ferroportin causing internalization of ferropotin and degrades it in lysosomes

regulation high when iron levels are high—> hepciidin expression up, ferroportin levels down, iron absorption high. vice versa for low iron levels

human homeostatic iron regulator prtoein (HFE)

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18
Q

what is the pathway that heme iron (Fe2) (from animal products) take to be stored in body?

A

enters enterocyte and oxidized to Fe3 by ferroxidase (cerruloplasmin)—>

stored in form of ferritin

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19
Q

how does transferrin transport Fe3 in the blood to target tissues?

A

Fe3 gets bound to transferrin—>

transferrin reaches the target tissues thru blood—>

binds to transferrin receptor and undergoes receptor-mediated endocytosis—>

its internalized into endosomes via clathrin coated pits—>

pH in the endosome releases transferrin from its receptor so it can travel thru the cell in the endosome—>

endosome docks onto the mitochondria and tranfers iron via DMT1

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20
Q

what is the cause of hypochromic microlytic anemia?

what is the treatment?

A

iron deficiency either thru diet, low absorption, GI ulcers, aspirin overuse, excessive menstruation

iron supplement

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21
Q

what is hereditary hemochromatosis (HH)?

what diseases does it cause?

inheritance?

how much body iron do these patients have?

A

increased absorption of iron due to dysregulation of iron uptake and export by enterocytes that results in accumulation of it in the liver, heart, pancreas

causes cirrohosis, hepatocellular carcinoma, diabetes, arthritis, heart failure

autosomal recessive- mutations in hereditary hemochromatosis gene (HFE)

15 g (normal patient has 3-5 g)

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22
Q

what is RBC production dependent on?

what can deficiencies in these cause?

how is this disease characterized?

what do blood smears show?

A

folate (folic acid) and vitamin B12 (cobalamin)

megaloblastic anemia due to diminshed synthesis of DNA in developing RBC’s in the BM

characterized by large (mega) erthyrocytes in bone marrow (MCV>100 fL while a normal patient has 80-100 fL), normal Hb, and hyper-segmented neutrophils (has more than 5 lobes)

RBC volume increases and blood smear shows macrocytic, normochromic cells

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23
Q

what is the structure of folate?

A

has 3 derivatives

has 3 parts:

  1. pteridine ring
  2. PABA (another ring)
  3. glutamate
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24
Q

how is folate metabolized?

A

first its reduced to DHF by dihydrofolate reductase—>

further reduced to THF again by dihydrofolate reductase—>

THF is active form that’s involved in synthesis of purines and pyrimidine thymine, and serves vital role in DNA synthesis

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25
Q

what does a folic acid deficiency lead to?

A

decreased DNA synthesis which can lead to megaloblastic microlytic anemia

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26
Q

what foods is folic acid found in?

how is it absorbed?

how is it stored?

A

liver, eggs, legumes, milk, yeast, green leafy vegetables, citrus fruits—> most folate present in DHF form

absorbed in the small intestine (jejunum)—> folic acid is reduced to N5-methyl-THF which is primary circulating form

liver stores 5-10 mg which can last 3-6 months

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27
Q

what is a strong inhibitor of dihydrofolate reductase?

what cannot convert into what?

A

methrotrexate—> antineoplastic (anti-cancer) agent and inhibitor of DNA synthesis (binds enzyme more tightly than DHF)

DHF cant convert into THF

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28
Q

what is the release of THF (FH4) from N5-methyl-THF dependent on?

A

B12 and DHF reductase

removes methyl group from N5-methyl-THF to make methyl-cobalamin (B12-CH3) and release THF

29
Q

what are suorces of one-carbon units?

what is the intermediate?

what is synthesized as the end product?

*I legit dont know what this has to do with anything

A

serine, glycine, choline, histidine, formate

THF (several forms)

serine, TMP, DNA, purines, methionine

30
Q

when B12 removes methyl group from N-methyl THF and releases THF, what in turn does it donate this methyl group to?

what role does this new molecule play?

A

donates it to homocysteine to create methionine

used in synthesis of thymine??

31
Q

what is the folate trap?

A

when B12 is not available to convert N-methyl THF into THF (folate is ‘trapped’ as N-methyl THF)

32
Q

what foods contain B12?

what does deficiency in it lead to?

what is it usually due to?

A

found in animal products (not plant products)

can also cause megablastic macrocytic anemia

lack in protein intrinsic factor

33
Q

how is dietary B12 absorbed?

A

binds to R-binder proteins in the gastric mucosa—>

proteases made by pancreas degrade R-binders and release B12—>

B12 binds to intrinsic factor (which is made by parietal cells in ileum)—>

forms complex which is released into blood and carried by transcobalamin II—>

intrinsic factor-cobalamin complex is taken up in cells via receptor-mediated endocytosis

34
Q

what is a type of megaloblastic macrocytic anemia that is due to unavailability of intrinsic factor and results in a failure to absorb B12?

A

pernicious anemia

35
Q

how do we determine if B12 deficiency is due to diet or absorption?

what is the procedure of this test?

what do the results mean?

A

Schilling test

give patients a butt load of radioactive B12 and watch them pee it out for a day

if radioactive B12 is in urine: diet

if B12 is absent from urine: absorption—> pernicious anemia

36
Q

what is done if radioactive B12 is not present in urine in Shilling test?

what does result mean?

A

give patients more radioactive B12 plus intrinsic factor

if radioactive B12 is now present= prenicious anemia due to lack of intrinsic factor

37
Q

what is the structure of porphyrin rings?

A

four 5-membered rings that are connected, contain nitrogen, and have iron (ferrous state) in the middle

38
Q

what form is iron in for heme to be active?

inactive?

what molecules is heme present?

A

active: ferrous state (Fe2)
inactive: ferric state (Fe3)

present in hemoglobin, myoglobin, cytochrome

39
Q

what organs does biosynthesis of heme occur in?

A

liver and erythroid cells of bone marrow

40
Q

where does phase 1 of heme biosynthesis occur? what happens in it?

A

in mitochondria

glycine and succinyl CoA are used to make ALA (decarboxylation reaction?) by ALA synthase

41
Q

where does phase 2 of heme biosynthesis occur? what happens in it?

A

in cytosol

two ALAs are condensed by ALA dehydratase—> porphobilinogen (PBG)—>

four PBG’s condensed to form hydroxy-methylbilane—>

uro-porphyrinogen III—>

corpo-porphyrinogen III (tetrapyrrole ring system)

42
Q

where does phase 3 of heme biosynthesis occur? what happens in it?

A

in mitochondria

corpo-porphyrinogen III undergoes oxidation reaction to install side chain vinyl groups to form porphyrinogen IX—>

another oxidation reaction to generate fully conjugated ring system and form proto-porphyrin IX—>

iron inserted by ferrochelatase—>

heme

43
Q

what do defects in one or more stages of heme synthesis cause?

A

porphyrias- inherited metabolic disorders

44
Q

what is the feedback inhibition in heme synthesis?

A

heme (and hemin) inhibits ALA synthase

45
Q

what does ALA synthase need to function?

what happens without it?

A

B6 (pyridoxal phosphate)

heme synthesis diminished, RBCs pale, iron stores elevated

deficiency causes anemia

46
Q

what are the two isoforms of ALA synthase?

A

ALAS I (ubiquitous)

ALAS II (only in erythoid cells of BM): has an iron response element in mRNA

47
Q

what up regulates ALA synthase?

A

presence of iron increases transcription and translation

48
Q

what two enzymes does lead inactivate?

what are the effects of each?

A
  1. ALA dehydratase—> ALA accumulates and can be neurotoxic–> neurological sx of lead poisoning (ALA resembles GABA)
  2. ferrochelatase–> protoporphyrin IX accumulates

overall effects: causes microcyctic and hypochromic anemia and impacts ATP synthesis/energy metabolism (cytochromes not synthesized)

49
Q

deficiency in what enzyme causes acute intermittent porphyria?

what type is it?

inheritence?

effects?

sx?

A

porphobilinogen (PBG) deaminase (porphobiligoen–> hydroxymethylbilane)

hepatic

autosomal dominant

excess production of ALA and PBG

occasional abdominal pain and neuro problems

50
Q

what are the two types of porphyrias?

A
  1. acute hepatic- neurological symptoms
  2. erythropoietic- affect skin, photosensitvity
51
Q

what enzyme deficiency causes congenital erythropoietic porphyria?

what type is it?

inheritance?

effects?

sx?

A

uroporphyrinogen III cosynthase in RBCs (hydroxymethylbilane–> uroporphyrinogen III)

erythropoietic

autosomal recessive

accumulation of uroporphyrinogen I and its oxidation product uroporphyrin I (red fluoresence)

skin photosensitivity, red urine and teeth, hemolytic anemia

52
Q

what enzyme defiency causes porphyria cutanea tarda?

what type is it?

inheritance?

effects?

sx?

A

uroporphyrinogen decarboxylase (uroporphyrinogen III–> corproporhyringen III)

hepatoerythropoietic

autosomal dominant

accumulation of uroporphrinogen III and converts to oxidation products

photosensitivity and bullae/vesicles on skin, red urine

** most common porphyria in USA

53
Q

what enzyme deficiency causes variegate porphyria?

inheritance?

what type is it?

sx?

A

protoporphyrinogen oxidase (protoporphyrinogen IX–> protoporphyrin IX)

hepatic

autosomal dominant

photosensitivity, neuro sx (delirium, hallucinations, convulsions), occasional abdominal pain, and developmental delay in children

** celebrity/king polyphria

54
Q

how is heme broken down?

A

RBCs undergo breakdown every 120 days

senescent RBCs phagocytosed by cells of spleen and BM–>

reticulo-endothelial system degrades hemoglobin into globin (broken down into amino acids) and heme–>

heme (poryphrin ring) is cleaved into biliverdin (tetrapyrrole rings) by heme oxygenase (this reaction releases ferritin?)—>

biliverdin converted to billirubin by biliverdin reductase (does this thru reduction of NADPH)

55
Q

what is required for heme oxygenase to break down heme into biliverdin?

what is it induced by?

what is a byproduct that is released?

what happens to the iron molecule in this reaction?

A

requires oxygen

induced by heme, metal ions, phenylhydrazine

carbon monoxide released

iron oxidized from ferrous (active) to ferric (ferritin-inactive)

56
Q

once bilirubin is synthesized, how does it get to liver?

A

released into blood as free BR- its insoluble so it must bind to albumin to be transported to liver where protein carrier induces hepatic uptake

57
Q

what happens to free BR once its in liver?

A

converted to a conjugated form by being added with UDP-glucuronic acid (<– UDP-glucose <– glucose) by UDP glucuronyl transferase—>

makes bilirubin-monoglucuronide and UDP glucuronyl transferase acts one more time to create diglucuronide–>

conjugated BR then secreted by hepatocyte empties thru bile duct into gall bladder (energy-dependent)

** UDP glucuronyl transferase is rate limiting enzyme

58
Q

what happens to BR once it’s in the gallbladder?

A

undergoes reduction to urobilinogen—>

will either be reabsorbed and processed by kidneys to produce urobilin

OR

undergoes further reduction to become stercobilin found in feces

59
Q

what is the color of all the BR compounds?

A

heme-red

biliverdin: green
bilirubin: red-orange
urobilin: yellow

stercobilin and hemosiderin: red-brown

*think of a bruise! (unless its pee or poo)

60
Q

what is another name for jaundice?

what causes it?

how is it characterized?

what are the three types of jaundice?

A

hyperbilirubinemia

imbalance between production and excretion of bilirubin

elevated levels of BR in blood (either free or conjugated)

  1. pre-hepatic
  2. intra-hepatic
  3. post-hepatic
61
Q

what levels are increased in pre-hepatic jaundice?

cause?

clinical examples?

lab findings?

A

increased production of unconjugated BR

excess hemolysis

ex: internal hemorrhage, maternal-fetal compatibiltiy, liver capacity exceeded

normal levels of conjugated BR, normal ALT and AST (liver enzymes), urobilinogen present in urine

62
Q

what is intra-hepatic jaundice?

clinical examples?

lab findings?

A

impaired hepatic uptake, conjugation, or secretion of conjugated BR

ex: cirrohosis, hepatitis, Criggler-Najjar syndrome, Gilbert syndrome

variable for free and conjugated values, increase in ALT and AST, urobilinogen levels normal

63
Q

what is post-hepatic jaundice? aka cholestatic jaundice

caused by?

lab findings?

A

problems with BR excretion

physical barrier (gallstones, cancer, obstrution), infiltrative liver disease, lesions, drugs

increase levels conjugated BR in blood, small increase in free, normal AST and ALT, elevated ALP, conjugated BR found in urine (dark), no stercobilin in feces (pale stool)

64
Q

what is another name for physiological jaundice?

what physiological process causes it?

what aggravates it?

what effects can it have?

A

neonatal jaundice

newborns hepatic metabiolic pathways are immature—>

have defiency in UDP-GT enzyme–>

when fetal HB is broken down (to be replaced with HbA) we get more RBC’s broken down that liver can handle–>

increase in free BR–>

jaundice

premature birth

get into basal ganglie and cause encephalopathy

65
Q

what is used mainly to treat jaundiced newborns?

how does it work?

what’s another treatment that prevents breakdown of BR?

A

phototherapy

BR undergoes photo-conversion to become more soluble isomers when exposed to blue fluorescent light

tin-mesoporphryn- inhibitor of heme oxygenase

66
Q

what is Criggler-Najjar syndrome a deficiency from?

what are the two types?

what are the effects of each?

what is the therapy for each?

A

UDP-GT

type 1: complete abscence of gene- severe hyperbilirubinemia–> BR accumulates in brains of babies—> causes encephalopathy (kernicturus)… tx: blood transfusions, phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate (forms complexes with BR in gut), and liver transplant

type 2: benign form—> mutation in UDP-GT gene (enzyme there but less activity)

67
Q

what is Gilbert syndrome?

sx?

A

common, benign disorder resulting from reduced activity of UDP-GT

BR may increase with fasting, stress, alcohol

68
Q

what is hepatits?

causes?

effects?

lab findings?

sx?

A

inflammation of liver

viral infections (Hep A, B, C), alcoholic cirrohosis, liver cancer

can lead to liver dysfinction

increased levels of free and conjugaed BR in blood and dark urine

BR accumulates in skin and sclera–> yellow discoloration

69
Q

what is fetal Hb?

what is adult Hb?

how do they correlate with eachother?

A

a2y2 (alpha2gamma2)

a2B2

as HbF starts to decrease (around birth)–> HbA begins to increase

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