Hem & Onc - Pathology (Heme synthesis, porphyrias, & lead poisoning)

Question 1

What 2 enzymes are affected by lead poisoning? What is the accumulated substrate in each instance? Where do they accumulate?

Answer 1

(1) Ferrochetelase - accumulation of protoporphyrin (2) ALA dehydratase - accumulation of delta-ALA; blood

Question 2

What are the presenting symptoms of lead poisoning in general? What about specifically in children? What about specifically in adults?

Answer 2

Microcytic anemia, GI & kidney disease; Children - exposure to lead paint –> mental deterioration; Adults - environmental exposure (battery/ammunition/radiator factory) –> headache, memory loss, demyelination

Question 3

What are the exposures for lead poisoning seen in children versus adults?

Answer 3

Children - lead paint; Adults - environmental exposure (e.g., battery/ammunition/radiator factory)

Question 4

What is the affected enzyme in acute intermittent prophyria? What substrate(s) accumulate(s) as a result? Where does it/they accumulate?

Answer 4

Porphobilinogen deaminase; Porphobilinogen, delta-ALA, coporphobilinogen (urine)

Question 5

What are the symptoms associated with acute intermittent porphyria?

Answer 5

(1) Painful abdomen (2) Port wine-colored urine (3) Polyneuropathy (4) Psychological disturbances (5) Precipitated by drugs, alcohol, and starvation; Think: “5 P’s”

Question 6

What is the treatment for acute intermittent porphyria, and why?

Answer 6

Glucose and heme, which inhibit ALA synthase

Question 7

What is the affected enzyme in porphyria cutanea tarda? What substrate(s) accumulate(s) as a result? Where does it/they accumulate?

Answer 7

Uroporphyrinogen decarboxylase; Uroporphyrin; Urine = tea-colored

Question 8

What are the signs/symptoms associated with porphyria cutanea tarda?

Answer 8

Blistering cutaneous photosensitivity, tea-colored urine

Question 9

What is the most common porphyria?

Answer 9

Prophyria cutanea tarda

Question 10

What is the rate-limiting step of the heme synthesis pathway?

Answer 10

dela-aminolevulinic acid synthase catalyzes the conversion of glycine + succinl-CoA to delta-aminolevulinic acid

Question 11

What is the first step in the heme synthesis pathway? Where does it take place? What enzyme catalyzes this step?

Answer 11

Conversion of glycine + succinl-CoA to delta-aminolevulinic acid; Mitochondria; dela-aminolevulinic acid synthase

Question 12

What 4 steps of the heme synthesis pathway take place in the cytoplasm? What enzymes catalyze them?

Answer 12

(1) delta-aminolevulinic acid (synthesized in mitochondria during first step of heme synthesis pathway) converted to porphobilinogen by delta-aminolevulinic acid dehydratase (2) Porphobilinogen converted to hydroxymethylbilane by Porphobilinogen deaminase (3) Hydroxymethylbilane converted to Uroporphyrinogen III (no enzyme specified in First Aid) (4) Uroporphyrinogen III converted to Coproporphyrinogen III by Uroporphyrinogen decarboxylase

Question 13

Where is protoporphyrin synthesized, and from what precursor in the heme synthesis pathway?

Answer 13

Mitochondria; Coproporphyrinogen III

Question 14

What is the final step in the heme synthesis pathway? Where does it take place? What enzyme catalyzes it?

Answer 14

Iron added to Protoporphyrin to synthesis Heme; Mitochondria; Ferrochetalase

Question 15

What effect do low versus high heme levels have on ALA synthase activity?

Answer 15

Low heme –> increased ALA synthase activity; High heme –> decrease ALA synthase activity

Question 16

Draw out the steps of the heme synthesis pathway, including precursors, enzymes, and locations of each major step.

Answer 16

See p. 388 in First Aid 2014 for visual at bottom of page

Question 17

Which step of the heme synthesis pathway is associated with sideroblastic anemia (x-linked)?

Answer 17

dela-aminolevulinic acid synthase catalyzes the conversion of glycine + succinyl-CoA to delta-aminolevulinic acid