Porphyrins

Question 1

General structure of a porphyrin?

Answer 1

Think heme: 4 pyrrole rings linked by bridges with asymetrical side chains.

Question 2

Why can porphyrins bind a + ion?

Answer 2

Negative charge in center of ring due to N: create - charged binding pocket.

Question 3

Describe cobalamin

Answer 3

Vitamin B12: porphyrin ring with a cobalt (metal) ion in center.

Question 4

Three physiological roles for heme?

Answer 4

Oxygen transport
Cytochrome enzymes in ETC
Cytochrome P450 enzymes in liver (for detox)
Removal of H2O2

Question 5

What are the 2 starting materials for porphyrin synthesis?

Answer 5

Succinyl CoA and glycine

Question 6

Succinyl CoA + Glycine –>

Answer 6

ALA

Question 7

ALA then –>

Answer 7

PBG

Question 8

PBG –>

Answer 8

Hydroxymethylbilane

Question 9

Hydroxymethylbilane –>

Answer 9

Uroporphyrinogen

Question 10

Uroporphyrinogen –>

Answer 10

Protoporphyrin IX

Question 11

Protoporphyrin IX –>

Answer 11

Heme

Question 12

What is first committed step of porphyrin synthesis pathway?

Answer 12

Succinyl CoA + glycine –> ALA

Question 13

ALA resembles what neurotransmitter?

Answer 13

GABA

Question 14

Acute Intermittent Porphyria: disease resulting from a problem with what enzyme/step? Leads to buildup of what?

Answer 14

insufficient hydroxymethylbilane synthase. Cannot go from PBG –> hydromethylbilane. Leads to buildup of ALA.

Question 15

Buildup of ALA results in what?

Answer 15

Acute Intermittent Porphyria

Question 16

Effect of alcohol consumption on AIP?

Answer 16

AIP worsens with alcohol consumption: uses CYPs in liver to detox, which decreases heme levels, which induces the synthesis pathway further, which yields greater ALA buildup.

Question 17

What is the major feedback for this pathway?

Answer 17

Heme/hemin blocks first step (Succinyl CoA + glycine –> ALA). “Product Feedback control”

Question 18

Treatment for AIP?

Answer 18

Avoid CYP inducers (anything that you’d need to detox from)

Inhibit ALA synthase with hemin or glucose to prevent ALA buildup

Question 19

Porphyria Cutanea Tarda: acquired or inherited disease?

Answer 19

Acquired. Can be due to alc/drug abuse, damage to liver cells.

Question 20

What are levels of ALA and Heme in Porphyria Cutanea Tarda?

Answer 20

Both normal

Question 21

What is the pathway problem leading to Porphyria Cutanea Tarda?

Answer 21

Reduced liver uroporphyrinogen decarboxylase activity. Uroporphyrinogen can’t go to Protoporphyrin IX, so it is shuttled to side pathway –> uroporphyrins. Accumulate in skin, blood, urine. Yields photosensitivity.

Question 22

How can you diagnose Porphyria Cutanea Tarda?

Answer 22

Urine sample. Upon sitting for a few hrs, urine will turn purple due to accumulation of porphyrins.

Question 23

What is the difference between AIP and lead poisoning?

Answer 23

AIP: genetic, only affects liver.

Lead poisoning: environmental, affects liver and blood. Inhibits heme synthesis in liver and BONE MARROW.

Question 24

What is the main problem in lead poisoning?

Answer 24

Anemia due to decr synthesis of heme. Also, confusion due to AIP.

Question 25

What is the mechanism of lead poisoning?

Answer 25

inhibits ALA -> PBG (buildup of ALA). Also inhibits ferrochelatase, so Protoporphyrin IX won’t –> Heme.

Question 26

How would one diagnose Iron Deficiency Anemia?

Answer 26

Blood smear will show pale, thin-rimmed RBCs

Question 27

What is the mechanism of iron def anemia?

Answer 27

Reduces ALA synthase levels in blood cells (same enzyme as AIP).
Also, Iron Response Elements block translation of iron-metabolizing genes, so cannot metabolize iron if Fe2+ not present to remove IRE.

Question 28

Heme and bilirubin: water soluble? can they travel through plasma alone?

Answer 28

NO. Need to be bound to albumin to travel through plasma.

Question 29

At what point does bilirubin become soluble/excretable?

Answer 29

When it is conjugated in liver (conjugated with glucuronic acid, which is later removed from fecal matter by bacteria for re-use).

Question 30

Different colors in a bruise reflect what?

Answer 30

Different oxidation states of the heme in the bruise. Bruise disappears when macrophages enter and take up peripheral heme.

Question 31

Jaundice is caused by what?

Answer 31

Excessive bilirubin in blood, due to problem in heme degradation pathway.

Question 32

List the various types of jaundice

Answer 32

Hemolytic
Obstructive
Hepatocellular
Neonatal

Question 33

Hemolytic jaundice results in increased conjugated or unconjugated bili?

Answer 33

Unconjugated. Due to red cell lysis (ie, sickle cell anemia).

Question 34

The van den Burgh reaction measures what?

Answer 34

Biochemical assay that measures levels of both conjugated and unconjugated bilirubin in blood.

Question 35

Obstructive jaundice results in increased conjugated or unconjugated bili?

Answer 35

Conjugated. Due to block of bile ducts (ie, gallstones).

Question 36

Hepatocellular jaundice: increased conjugated or unconjugated bili?

Answer 36

BOTH conj and unconj bilirubin levels will be high. Also will see increased liver enzymes: AST, ALT. due to liver cell damage (hepatitis, toxin abuse)

Question 37

Neonatal jaundice caused by what? How to treat?

Answer 37

Caused by low levels of bilirubin glucuronyltransferase activity during early infancy (neonate). Treatment is blue fluorescent light which converts bili into water-soluble metabolites and clears it.