Heme Metabolism

Question 1

What are the key components of heme?

Answer 1

Porhyrins; made of pyrrole. Contains substituents of acetate, propionate, methyl and vinyl groups

Question 2

What are the key steps in heme biosynthesis

Answer 2

Step 1 (Commited Step): Succinyl-CoA being turned into ALA via ALA synthase. (2 parts)
-occurs in mitochondria
Step 2: ALA dehydratase turning ALA into porphobilinogen.

Question 3

Which enzyme is a target for lead poisoning?

Answer 3

ALA dehydratase

Question 4

Which reaction requires vitamin B6 as a cofactor?

Answer 4

ALA synthase rxns

Question 5

What enzyme links 4 porphobilinogens together in a linear fashion?

Answer 5

hydroxymethylbilane synthase

Question 6

What happens once porphobilinogens are linked?

Answer 6

They form a ring structure in which iron will be placed in the center.

Question 7

Where is Heme biosynthesis most active?

Answer 7

Liver, Bone marrow and reticulocytes

Question 8

How is heme synthesis regulated?

Answer 8

Negative feedback inhibition by heme’s action on ALA synthase.

Question 9

Name the two ways Heme regulates heme synthesis.

Answer 9

Allosteric binding to ALA synthase.

Decreased transcription of ALA synthase via heme binding to the co-repressor of ALA synthase mRNA transcription.

Question 10

What is porphyria?

Answer 10

An autosomal dominant disorder that arises from genetic mutations of enzymes involved in heme metabolism. Results in accumulatino, and increased excretion of porphoryin.

Question 11

What happens if there is an enzyme mutation prior to the formation of porphyrinogens?

Answer 11

Accumulations of ALA and PBG; Toxic to nerves and ATPase which could cause paralysis.

Question 12

What happens if there is an enzyme mutation later in the pathway?

Answer 12

Accumulations of porphyrinogens; Oxidation of these yield photosensitive porphoryins resulting in skin damage.

Question 13

What are the 3 products of hemoglobin catabolism?

Answer 13

Globin polypeptides, porphyrin ring, ferrous iron

Question 14

What enzyme degrades hemin?

Answer 14

heme oxygenase

Question 15

Name the 2 functions of bilirubin

Answer 15

1. Can be reoxidized to bliverdin; An antioxidant

2. Can serve as a scavenger for oxidants.

Question 16

What is non-conjugated bilirubin?

Answer 16

Bilirubin not bonded to anything.
-With limited solubility in aqueous solution. Due to the hydrophobic nature of bilirubin, it must be transported through the blood using the carrier protein, albumin. This bilirubin-albumin complex is then transported to the liver for conjugation.

Question 17

Can bilirubin be excreted in its hydrophobic form?

Answer 17

No, it must first be converted into a water-soluble product via conjugation in the liver.

1) First glucoronic acid is created from UDP-glucose via UDP-glucose dehydrogenase twice.
2) Glucoronic acid is added to bilirubin via UDP-glucuronosyl-transferase.
3) Next, another glucuronic acid is added via UDP-glucuronosyl-transferase. Now it can be excreted (conjugated).

Question 18

Once bilirubin is conjugated, how is it excreted?

Answer 18

The intermediate stercobiliogen is excreted in urine; colorless
The other intermediate sterocobilin is excreted in feces; Brown in color

Question 19

How can serum bilirubin levels be tested?

Answer 19

The vanadate oxidation test; In the presence of NaVO3 (sodium vanadate) at pH 3, bilirubin is oxidized to biliverdin and loses the absorbance at 451 nm. Oxidation occurs with both conjugated and non-conjugated bilirubin. (see coursepack)

Question 20

How do you calculate the indirect bilirubin (non-conjugate bilirubin)?

Answer 20

Indirect Bilirubin = Total Bilirubin – Direct Bilirubin

Question 21

What happens when bilirubin can’t be excreted from the body?

Answer 21

Bile pigments are produced, jaundice

Question 22

Describe neonatal jaundice.

Answer 22

Bilirubin is unconjugated in the neonate because the hepatic system is immature and consequently is unable to filter and secrete bilirubin. Therefore, excess bilirubin accumulates in the blood, a condition known as hyperbilirbinemia.

Question 23

Which enzymes can cause hyperbilirubinemia

Answer 23

UDP-gluconyl transferase and UDP-gluconyl dehydrogenase.

Question 24

What happens when jaundice is not corrected?

Answer 24

The excessive amount of bilirubin may damage developing brain cells leading to learning disabilities or a number of developmental disabilities including vision, hearing, motor movements (kernicterus)

Question 25

What correlations can be made between types of jaundica and bilirubin levels?

Answer 25

See coursepack