Metabolism of Heme- Lecture 82

Question 1

What is the structure of heme?

Answer 1

4 pyrrole rings linked together by methene bridges (to make a porphyrin ring) + Fe2+ or Fe3+

Question 2

Heme is the prosthetic group for _______.

Answer 2

hemoglobin/myoglobin
mitochondrial ECT cytochromes
cytochrome P450 enzymes
catalase and peroxidase

Question 3

Where is heme made?

Answer 3

largely in the liver and erythropoietic tissue (bone marrow) but can be produced in all tissues

Question 4

Describe the steps of heme synthesis.

Answer 4

1. succinyl CoA + glycine –> gamma-aminolevulinic acid
   via gamma-amino-levulinic acid synthesis (ALAS)
2. 2ALA –> porphobilinogen (PBG)
   via ALA dehydrogenase
   Last steps: protoporphryn IX –> Heme
   via ferrochelatase

Question 5

____ is sensitive to lead poisoning due to the fact that it out-competes the zinc that usually binds.

Answer 5

ALA dehydrogenase

Question 6

What is the rate limiting step of heme synthesis?

Answer 6

the first step (ALAS reaction)

Question 7

What are the important intermediates in the heme synthesis pathway?

Answer 7

hydroxymethylbilane
uroporphyrinogen II
coroporphyrinogen III
protoporphrinogen IX
protoporphryn IX

Question 8

How is heme synthesis regulated?

Answer 8

transcription of ALA mRNA, activity of ALAS, and transfer of ALAS into mito is inhibited by heme itself

Question 9

How is iron toxicity handled in the body?

Answer 9

Fe is transported in blood by transferrin and stored as ferritin in tissues until necessary for use (because both of these structures are very stable and cannot catalyze the Fenton reaction)

Question 10

What are porphyrias?

Answer 10

deficiencies in heme biosynthesis enzymes resulting in anemia and accumulation of porphyrins (either in the skin, GI tract, or brain/neuro tissue)

Question 11

What symptoms are associated with porphyrias mostly affecting the skin?

Answer 11

since porphyrins have many double bonds they promote oxidation by singlet oxygen –> light sensitivity, rashes, dermatitis, tingling

Question 12

How do you treat the symptoms associated with porphyrias affecting the skin?

Answer 12

treat with vitamin A (quenches singlet oxygen)

Question 13

What symptoms are associated with porphyrias mostly affecting the GI tract?

Answer 13

GI irritation, nausea, emesis, abdominal pain, constipation

Question 14

What symptoms are associated with porphyrias mostly affecting neuro tissue?

Answer 14

lethargy, neurological disturbances, weakness in arms/legs

Question 15

How do you treat porphyrias that present with mostly neurological symptoms?

Answer 15

treat symptoms

Question 16

What is the lifespan of RBCs?

Answer 16

120 days

Question 17

What is the lifespan of cytochrome t1/2?

Answer 17

10-20 days

Question 18

Describe the breakdown of heme.

Answer 18

Heme + NADPH + O2 –> Biliverden (BV) + CO2 + Fe3+ + NADP+
via heme oxygenase
BV + NADPH –> bilirubin (BR) + NADP+
via biliverdin reductase

Question 19

Bilirubin is transported to the liver as _____.

Answer 19

albumin complex/”indirect BR” (“insoluble BR”)

Question 20

In the liver, BR is conjugated with ______ to make _____ which is _____.

Answer 20

two glucuronic acids
conjugated “direct BR” (“soluble BR”)
secreted into bile

Question 21

What is jaundice?

Answer 21

accumulation of bilirubin (BR) which has a yellowish coloration due to hemolysis, bile duct blockage, decreased conjugation enzymes –> accumulation of indirect BR (poorly soluble)
leads to toxicity of the nervous system

Question 22

Why are newborns prone to jaundice?

Answer 22

they lack expression of these enzymes

Question 23

How is jaundice in infants treated?

Answer 23

blue light (which fragments the BR)

Question 24

What is Gilberts Syndrome?

Answer 24

decreased activity of UPD-glucuronyltransferase leading to an increase in unconjugated bilirubin, mild jaundice during illness