Poryphyrins

Question 1

• Porphyrins are cyclic molecules formed by the linkage of _# ____ _____ through methenyl bridges.

Answer 1

4 pyrrole rings

Question 2

The central pocket can be occupied by a metal ion.

Answer 2

Iron ==> heme
Cobalt ==> cobalamine (vitamin B12)
Magnesium ==> chlorophyll in plants

Question 3

What are four examples of physiological heme functions?

Answer 3

• Mitochondrial cytochromes
• Hemoglobin and myoglobin
• Cytochrome P450 enzymes
• Catalase: antioxidant enzyme hydrolyzes H2O2

Question 4

Mitochondrial cytochromes: generate membrane H+ gradient required for ATP synthesis via electron transport chain. Cyanide poisoning causes irreversible inhibition of mitochondrial cytochrome a3.

Answer 4

Mitochondrial cytochromes: generate membrane H+ gradient required for ATP synthesis via electron transport chain. Cyanide poisoning causes irreversible inhibition of mitochondrial cytochrome a3.

Question 5

What do Cytochrome P450 enzymes do? (note there are 50 different types)

Answer 5

metabolism of fat-soluble compounds

formation of cholesterol, steroids, and arachidonic acid metabolites.

Question 6

Why are CYPs (especially CYP3A4) relevant in pharmacology?

Answer 6

CYPs (particularly CYP3A4) are medically relevant because their activities are responsible for many serious drug interactions.

Question 7

What does heme Catalase do?

Answer 7

antioxidant enzyme hydrolyzes H2O2

Question 8

What is the cause of acute porphyrias?

Answer 8

Autosomal dominant disorders characterized by blockade of the early, rate limiting steps of the heme biosynthetic pathway, causing decreased production of heme (and hemin).

Question 9

What the cause of acute intermitten poryphyria?

Answer 9

A prototypical disease for this group is acute intermittent porphyria (AIP), caused by deficiency of hydroxymethylbilane synthase.

Question 10

What are the symptoms and acute causes of symptoms in acute intermittent porphyria (AIP)?

Answer 10

• intermittent attacks of abdominal pain and neuropsychiatric symptoms.
• precipitated by ingestion of drugs and other chemicals.
• These compounds induce the production of CYP enzymes, consuming heme. This exacerbates the relative shortage of heme, triggering an increase in ALA synthase levels and subsequent accumulation of ALA and PBG.

Question 11

What are the specifics that cause abdominal pain in AIP? What causes Neuropsychiatric symptoms?

Answer 11

• Abdominal pain is caused by accumulation of ALA in the liver.
• Neuropsychiatric symptoms are caused by the structural similarity between ALA and the neurotransmitter γ-amino-butyric acid (GABA), which causes ALA to antagonize GABA receptors.

Question 12

How is AIP diagnosed?

Answer 12

• excess PBG in urine.
• Upon standing (oxidation), urine from AIP patients turns purple.
• Can identify affected family members by PCR.

Question 13

What is the treatment for AIP?

Answer 13

• Exogenous I.V. hemin and glucose.

* avoid precipitating drugs.

Question 14

What are the causes of non-acute porphyrias?

Answer 14

• Primarily acquired diseases associated with liver damage, but some diseases are genetic
• steps beyond the formation of hydroxymethylbilane, causing accumulation of abnormal porphyrin derivatives in the liver and skin, leading to liver damage and photosensitive skin rashes, respectively.

Question 15

What are the Heme and ALA levels in non-acute porphyrias? Are there neuropsychiatric symptoms?

Answer 15

• Heme and ALA levels are normal
• ALA synthase and hydroxymethylbilane synthase activities are increased through compensatory regulation mechanisms and alternative downstream products.
• There are no neuropsychiatric symptoms since ALA levels are normal.

Question 16

What is the cause of Poryphyria cutanea tada (PCT)?

Answer 16

• reduced uroporphyrinogen decarboxylase activity (one of the enzymes involved in the synthesis of protoporphyrin IX), leading to accumulation of uroporphyrins, which are abnormal metabolites.

Question 17

Note PCT is the most common and prototypical non-acute porphyrias

Answer 17

Note PCT is the most common and prototypical non-acute porphyrias

Question 18

What is the treatment of Poryphyria cutanea tada (PCT)?

Answer 18

• regular phlebotomy ==> removes excess porphyrin metabolites
• avoid alcohol, other liver toxins, and excess sunlight.

Question 19

What occurs with Lead Poisoning? What are the symptoms?

Answer 19

• Inhibits ALA dehydrase and ferrochelatase
• all the symptoms of AIP (due to inhibition of liver ALA dehydrase)
• anemia (due to inhibition of bone marrow heme synthesis).

Question 20

What is the mechanism of Iron-Deficiency Anemia?

Answer 20

• In bone marrow
• The translation of erythroid ALA synthase mRNA is stimulated by iron (Iron Response Element) Therefore, the lack of iron leads to a decrease in erythroid heme synthesis, causing anemia.

Question 21

In addition to ALA synthase, what do some other common Iron Response Elements code for?

Answer 21

Iron transport and storage

Question 22

Explain the degradation of Heme to its excretion in the feces and the kidneys. Pg 283 Lippincott

Answer 22

• Senescent RBCs are major Heme source
• Heme to biliverdin to bilirubin via macrophages in spleen and LV
• Bilirubin is taken up by LV and conjugated with glucuronic acid
• Conjugated Bilirubin ==> into bile
• Intestines: Conjugated Bilirubin ==> Urobiligen (unconjugated)
• Urobiligen has several fates
o Intestines: oxidized to brown stercobilin
o Kidneys: urobilin excreted as yellow pee
o Portal system sends urobiligen to KD or recycles to Intestine

Question 23

What is the main feature of Jaundice? How does it affect the brain?

Answer 23

• Bilirubin in blood

* Crosses blood-brain barrier and causes encephalopathy

Question 24

What is the van den Bergh reaction?

Answer 24

• Assay that measures conjugated and unconjugated bilirubin in blood

Question 25

Compare and contrast in terms of cause and conjugated state of bilirubin of
•	Hemolytic
•	Obstructive
•	Hepatocellular Jaundice
•	Neonatal Jaundice

Answer 25

• Hemolytic: RBC lysis (eg sickle cell anemia) ==> ↑ unconjugated bilirubin
• Obstructive: Bile duct blockage ==> ↑ conjugated bilirubin
• Hepatocellular: LV cell damage (eg hepatitis) ==> ↑ LV enzymes (eg AST aspartate amino transferase, ALT another transferase)
• Neonatal Jaundice: ↓ bilirubin glucoronyltransferase. Treated by blue fluorescent light to convert bilirubin into water soluble metabolites