Heme Metabolism

Question 1

Where does heme biosynthesis occur?

Answer 1

Heme biosynthesis occurs in most tissues, but is highest in the bone marrow and liver

Question 2

Heme synthesized in the bone marrow is incorporated into what?

Answer 2

hemoglobin

Question 3

Heme synthesized in the liver is incorporated into what?

Answer 3

cytochromes, particularly cytochrome p450

Question 4

What are the general structural features of heme?

Answer 4

Porphyrin ring with heme in the middle

Question 5

Name the two simple molecules that contribute all the atoms for the organic portion of heme.

Answer 5

Succinyl CoA and Glycine

Question 6

Describe the first step in heme biosynthesis, indicating the product of the reaction and the enzyme responsible

Answer 6

Succinyl CoA + Glycine –> ALA

Catalyzed by ALA synthase

Question 7

Describe the differences between porphyrinogen intermediates and porphyrins and indicate whether or not porphyrinogens can be non-enzymatically converted to porphyrins

Answer 7

Porphyrinogen: no double bonds at the bridging carbons
Porphyrins: double bonds at the bridging carbons –> colored

Porphyrinogens CAN be non-enzymatically oxidized to porphyrins by light

Question 8

Describe how heme biosynthesis is regulated in the liver.

Answer 8

increased heme has a negative feedback on the first step in heme synthesis (succinyl CoA + glycine).

This is only true in the liver

Question 9

What are porphyrias?

Answer 9

Genetic diseases resulting from abnormalities of the enzymes of heme biosynthesis

Question 10

Indicate which two intermediates of heme biosynthesis are increased in nerve damage

Answer 10

a

Question 11

What is the characteristic feature of porphyrias?

Answer 11

Nerve damage

Question 12

What happens to ALA synthase activity in acute intermittent porphyria?

Answer 12

Increase in ALA synthase activit

Question 13

Which factors exacerbate acute intermittent porphyria by inducing ALA synthase?

Answer 13

Increased ALA and PBG (porphobilinogen)

Question 14

Indicate how the feedback inhibition of heme can be used in the treatment of this disease.

Answer 14

Give them straight heme. Heme feedsback negatively on the process and inhibits ALA synthase.

Question 15

Indicate what causes the photosensitivity seen in many porphyrias

Answer 15

sunlight converts the deposited protoporphyrinogen to porphyrins. The porphyrins are then further degraded by light, a process that generates tissue-destroying singlet oxygen. This leads to blistering and other skin lesions.

Question 16

Name the cells that are primarily responsible for the degradation of hemoglobin

Answer 16

Catabolism of heme occurs in the phagocytic cells of the reticuloendothelial system (monocyte-macrophage system in the spleen, bone marrow and liver)

Question 17

Describe the fate of the constituents of hemoglobin: globin, iron and porphyrin

Answer 17

globin: free amino acids
Iron: re-utilized
Porphyrin: degraded

Question 18

Name the products of porphyrin degradation by heme oxygenase and biliverdin reductase

Answer 18

Heme –> Biliverdin –> Biliruben

Question 19

Describe how unconjugated bilirubin is carried in the plasma

Answer 19

Unconjugated bilirubin is carried in the plasma as a complex with albumin and is delivered to the liver where it is taken up by active transport and conjugated.

Question 20

Describe the process of uptake and conjugation of bilirubin and the secretion of conjugated bilirubin by the liver

Answer 20

Bilirubin is conjugated in the liver to UDP-glucuronate in the liver. Conjugated bilirubin is actively secreted into the bile canaliculus. In the intestine, bilirubin diglucuronide is deconjugated by bacterial flora and oxidized to colored stercobilins.

Question 21

Define hyperbilirubinemia

Answer 21

Elevated bilirubin in serum – can be either conjugated or unconjugated, or both

Question 22

Define jaundice

Answer 22

Elevated bilirubin diffuses into the tissues, making them appear yellow.

Question 23

Describe the clinical consequences of hyperbilirubinemia

Answer 23

Conjugated hyperbilirubinemia is benign. Unconjugated hyperbilirubinemia is benign at low concentrations, but above 25 mg/dL, free unconjugated bilirubin can enter the brain and cause toxic encephalopathy

Question 24

Describe some causes of hyperbilirubinemia and indicate whether unconjugated or conjugated bilirubin predominates

Answer 24

Hemolysis –> unconjugated
Biliary obstruction –> conjugated
Hepatitis or Cirrhosis –> mixed hyperbilirubinemia

Question 25

Describe a treatment for neonatal physiological jaundice

Answer 25

Blue light