Lecture 11: Heme, Bilirubin, Porphyria I

Question 1

Heme synthesis intermediates

Answer 1

1. Glycine + succinyl-CoA
2. ALA (C5)
3. PBG (C10)
4. Bilane (C40)
5. Uroporphyrinogen III (cyclic C40)
6. Coproporphyrinogen III
7. Protoporphyrinogen IX
8. Protoporphyrin IX
9. Heme

Question 2

Heme synthesis steps

Answer 2

1. G+S -ALA synthase-> A
2. A -ALA dehydrase-> P
3. P -PBG deaminase-> B
4. B -uro’gen III cosynthase-> U
5. U -uro’gen III DC-> C
6. C -copro’gen III DC-> P
7. P -proto’gen IX DH-> P
8. P -ferrocheletase-> heme

Question 3

Porphyria

Answer 3

Inability to convert porphyrins into heme

Question 4

Porphyrin

Answer 4

Colored, fully conjugated, oxidized compound

Question 5

Pyrrole ring

Answer 5

5-member ring with amide (NH). Heme is a cyclic tetra-pyrrole, bilirubin a linear one.

Question 6

Porphyrinogen

Answer 6

Reduced, colorless heme precursor. Can be oxidized.

Question 7

Heme synthesis mnemonic

Answer 7

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Question 8

How is heme synthesis regulated?

Answer 8

Heme is self-regulating in 4 ways:
1. Heme inhibits ALA synthase activity
2. Heme inhibits ALAS mRNA transcription
3. Heme inhibits ALAS mRNA translation
4. Heme inhibits ALAS transport into the mitochondria

Question 9

Where does heme synthesis occur? Why?

Answer 9

Macro: heme synthesis happens where it is needed; bone marrow (RBCs) and liver (cytochrome P450s)

Micro: heme synthesis occurs both in and out of the mitochondria; moving compartments means lots of regulation can occur

Question 10

Conversion of heme to bilirubin

Answer 10

Heme oxygenase cleaves alpha carbon on heme, then biliverdin reductase converts to bilirubin (bile pigment)

Question 11

Which cells process heme?

Answer 11

-Mononuclear phagocytic system cells (tissue macrophages)
-Splenic phagocytes (spleen filters RBCs)
-Kupffer liver cells

Question 12

What’s wrong with excess heme?

Answer 12

Excess heme synthesis means heme intermediate buildup:
-Porphyrins generate free radicals and cell/tissue damage
-Porphyrinogens can be oxidized to porphyrins

Question 13

Bilirubin excretion pathway

Answer 13

Transport by blood to liver for conjugation, secretion into bile, and excretion by urine or stool

Question 14

How is bilirubin transported to the liver?

Answer 14

By blood bound to albumin. BR is totally insoluble, albumin required for transport

Question 15

How and why is BR conjugated in the liver?

Answer 15

UDP-glucuronyl transferase (UGT) aka BRGT uses 2 UDP-glucuronic acid to conjugate BR w/ 2 sugars; also serves to solubilize for excretion into bile

Question 16

Hepatocyte transporters for bile

Answer 16

OATP transporter brings BR in from blood/albumin, ABCC2 secretes BRDG into bile

Question 17

What happens to BRDG in bile normally?

Answer 17

Gut bacteria unconjugate BRDG into urobilinogen. 10% is reabsorbed and excreted by the kidneys, 90% is converted to stercobilinogen and ends up in stool.

Question 18

Possible causes of hyperbilirubinemia

Answer 18

1. Prehepatic (buildup of unconjugated, e.g. hemolysis)
2. Hepatic (issue with conjugation or secretion; intrahepatic cholestasis)
3. Post-hepatic (issue with bile ducts; extrahepatic cholestasis)

Question 19

UGT mutations

Answer 19

Gilbert’s (common, promoter)
Crigler-Najjar (rare, coding region)

Question 20

Gilbert’s

Answer 20

UGT mutation that is common and usually asymptomatic; might be set off by sudden insult to BR metabolism

Question 21

Crigler-Najjar

Answer 21

UGT coding region mutant. Type I = fatal, total lack of functional protein
Type II = reduced protein levels, jaundice