Anemia

Question 1

difference between heme and hemin

Answer 1

oxidation state of iron atom - heme contains reduced iron (Fe2+), while hemin contains oxidized iron (Fe3+)

Question 2

5-aminolevulinate synthase (ALAS)

Answer 2

enzyme located in the inner mitochondrial membrane; catalyzes first step of heme synthesis; condenses glycine and succinyl-CoA into 5-aminolevulinate; requires H+ and produces CO2 and CoA as products; uses pyridoxal phosphate (PLP) as a cofactor; ALAS1 is ubiquitously expressed in most tissues while ALAS2 is specific to erythrocytes

Question 3

regulation of ALAS

Answer 3

ALAS1 is regulated via negative feedback of heme at levels of enzyme transcription, translation, and translocation to inner mitochondrial membrane; ALAS2 is regulated at the level of enzyme translation by iron availability via iron responsive element (IRE) in 5’ UTR of ALAS mRNA; drugs that require CYP450 metabolism can increase ALAS1 expression but do not affect ALAS2 expression

Question 4

5-aminolevulinate dehydratase (ALAD)

Answer 4

enzyme located in the cytosol; catalyzes second step of heme synthesis; condenses two molecules of 5-aminolevulinate to form porphobilinogen (PBG), which contains a pyrrole ring; enzyme uses Zn2+ as a cofactor; can be inhibited by Pb2+, which displaces Zn2+

Question 5

lead poisoning

Answer 5

inhibits second and seventh steps of heme synthesis; in first step, lead displaces zinc cofactor in ALAD, eliminating its catalytic activity; in seventh step, lead inhibits ferrochelatase; leads to increased ALA and protoporphyrin IX in urine and blood; symptoms mimic acute porphyria, both ALA and Pb are neurotoxic (ALA mimics GABA and generates ROS)

Question 6

porphobilinogen deaminase (PBGD)

Answer 6

enzyme located in the cytosol; catalyzes third step of heme synthesis; condenses four molecules of porphobilinogen to form linear hydroxymethylbilane; liberates NH4+ with each condensation

Question 7

uroporphyrinogen III cosynthase (UROS)

Answer 7

enzyme located in the cytosol; works alongside PBGD to direct stereochemistry of hydroxymethylbilane cyclization towards uroporphyrinogen III (as opposed to spontaneously-forming uroporphyrinogen I)

Question 8

uroporphyrinogen decarboxylase (UROD)

Answer 8

enzyme located in the cytosol; catalyzes the fourth step in heme synthesis; converts uroporphyrinogen III into coproporphyrinogen III

Question 9

coproporphyrinogen III oxidase (CPO)

Answer 9

enzyme located in the inter membrane space of the mitochondria; catalyzes the fifth step of heme synthesis; converts coproporphyrinogen III into protoporphyrinogen IX

Question 10

protoporphyrinogen IX oxidase (PPO)

Answer 10

enzyme located in the cristae of the mitochondria; catalyzes the sixth step of heme synthesis; converts protoporphyrinogen IX into protoporphyrin IX

Question 11

ferrochelatase

Answer 11

enzyme located in the cristae of the mitochondria; catalyzes seventh step of heme synthesis; converts protoporphyrin IX into ferroprotoporphyrin IX by catalyzing chelation of Fe2+; inhibited by Pb2+ and iron deficiency; also capable of chelating Zn2+ in place of iron, forming a highly fluorescent molecule

Question 12

acute porphyria

Answer 12

acute attacks of porphyria induced by nutritional changes, smoking, certain drugs, and steroid hormones (i.e. progesterone during second half of menstrual cycle); symptoms include abdominal pain, neurologic deficits, psychiatric symptoms, and reddish-colored urine

Question 13

chronic porphyria

Answer 13

dermatologic diseases; may or may not include liver and nervous system dysfunction

Question 14

most important parameter for assessment of oxygen-carrying capacity of blood

Answer 14

hemoglobin concentration

Question 15

calculation of hematocrit

Answer 15

centrifugation or MCV x RBC; usually 3X hemoglobin

Question 16

differential dx: microcytic anemia

Answer 16

iron deficiency, thalassemia, anemia of chronic disease

Question 17

heme oxygenase

Answer 17

cytosolic enzyme in macrophages associated with ER membrane (active site faces cytoplasm) that converts heme to biliverdin; uses oxygen, NADPH, and electrons from CYPOR; releases Fe and CO as waste products; HO-1 is inducible, highest levels in spleen, protects cells from oxidative stress; HO-2 is constitutive, highest levels in brain and testes; rate-limiting step in heme catabolism

Question 18

biliverdin reductase

Answer 18

cytosolic enzyme in macrophages that converts biliverdin to bilirubin; uses either NADH or NADPH

Question 19

common features of hemolytic anemias

Answer 19

normocytic, reticulocytosis, elevated LDH, elevated AST, elevated potassium, bilirubinemia (unconjugated/indirect, can cause jaundice or pigment gallstones), hemoglobinemia (more pronounced in intravascular hemolysis), low haptoglobin