11. Heme Synthesis Flashcards

1
Q

What is heme made of?

A

Each heme subunit is made of a porphyrin ring and an iron.

(Porphyrin rings are made up of four pyrrole rings)

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2
Q

Where do the three stages of heme synthesis occur generally? (Organs)

Where does each of the three steps occur?

A

Primarily in the liver and erythroid cells of the bone marrow

  1. Mintochondria
  2. Cytosol
  3. Mitochondria again
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3
Q

What happens overall in phase 1 of heme synthesis?

A

Glycine + Succinyl CoA form delta-aminolevulinic acid (ALA)

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4
Q

What vitamin does the first phase of heme synthesis need to continue?

What happens if it doesn’t get this?

A

B6 - Pyridoxal phosphate

Heme synthesis is diminished, red blood cells look pale and iron stores back up and become elevated.

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5
Q

What are the players in heme synthesis’s feedback inhibition to phase 1?

A

Heme itself blocks ALA synthase in step one

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6
Q

What heme synthesis enzymes do lead inactivate?

What does this cause?

A

Inactivates ALA dehydratase (phase 2) and ferrochelatase (phase 3 / final step)

Backup of Protoporphoryn IX and ALA as well as Anemia

(This also will impact energy production by disabling synthesis of cytochromes)

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7
Q

What enzyme defect is associated with:

Acute Intermittent Porphyria?

Is this Hepatic or Erythropoietic?

A

Porphobillinogen Deaminase

Bill is known for being unreliable, so his porphyria is intermittent

Hepatic

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8
Q

What enzyme defect is associated with:

Congenital Erythropoietic Porphyria?

Is this Hepatic or Erythropoietic?

A

Uroporphyrinogen III Cosynthase

Congenital defects happen as a child is being made, so the porphyria is a cosynthase

Erythropoietic

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9
Q

What enzyme defect is associated with:

Porphyria Cutanea Tarda

Is this Hepatic or Erythropoietic?

A

Uroporphyrinogen Decarboxylase

Most common in America - Americans could eat less carbs - de_carb_oxylase

Hepatoerythropoietic

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10
Q

What enzyme defect is associated with:

Variegate Porphyria

Is this Hepatic or Erythropoietic?

A

Protoporphyrinogen Oxidase

Variegate means “different colors”, oxides are often different colors than their precursors: protoporphyrinogen oxidase

Hepatic

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11
Q

Which of the porphyrias is most common in the US, and what enzyme deficiency causes it?

A

Porphyria Cutania Tarda (PCT)

Uroporphyrinogen decarboxylase

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12
Q

What does a deficiency in uroporphyrinogen III synthase cause a buildup of?

A

Uroporphyrinogen I and it’s product, Uroporphyrin I

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13
Q

What system handles the breakdown of hemoglobin?

A

The Reticulo-Endothelial system

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14
Q

What enzyme breaks down heme’s bridges?

A

Heme oxygenase

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15
Q

What toxic compound does heme oxygenase release?

A

Carbon monoxide

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16
Q

What enzyme converts Biliverdin into Bilirubin?

A

Biliverdin Reductase

17
Q

What carries insoluable billirubin through the bloodstream?

A

Albumen

18
Q

Where is billirubin taken up?

What keeps it soluable in those cells?

What do we call the complex?

A

The liver (mediated by a protien carrier)

Glucuronic acid

Conjugated / Direct Billirubin

19
Q

What enzyme takes UDP-Glucose and makes UDP-glucuronate?

Why does it do this?

A

UDP-Glucose dehydrogenase

It is the first step of billirubin conjugation.

20
Q

What enzyme takes ready-to-go UDP-glucuronate and attatches it to bilirubin?

What does the glucuronate become when attached to bilirubin?

What does the enzyme do next?

A

Bilirubin UDP glucuronyltransferase

UDP-glucuronic acid

It attaches another one. (Monoglucuronide bilirubin → Diuronide bilirubin)

21
Q

When bilirubin is conjugated in the liver, where is it sent?

What will it do there?

A

Gall bladder (as bile)

Be secreted into the small intestine in response to food.

22
Q

After bilirubin is secreted into the small intestine, what does it become?

What two paths can it take from there?

A

Urobilinogen (microbes reduce it for us)

It can become Urobilin in the urine

or it can become stercobilin in the feces

23
Q

What might be a cause of pre-hepatic jaundice?

A

Hemolytic anemia

Internal hemorrhage

Reduced capacity of liver to conjugate bilirubin

Erythroblastosis fetalis

24
Q

What might you find clinically in pre-hepatic jaundice?

A

Elevated production of unconjugated BR

Normal levels of ALT and AST

Normal levels of conjugated bilirubin

Direct bilirubin absent in urine (normal)

25
Q

How might Glucose 6 Phosphate dehydrogenase deficiency cause jaundice?

What kind of jaundice would it cause?

A

Decreased replenishment of glutathione means more ROS - which can cause hemolytic anemia

Pre-hepatic jaundice

26
Q

What can cause Intra-Hepatic Jaundice?

A

Deficiency in liver uptake of bilirubin, conjugation of bilirubin, or release of conjugated bilirubin. (Basically all of the things the liver does)

Examples: Liver trauma, hepatitis, cirrosis,

Criggler-Najjar syndrome

Gilbert Syndrome

27
Q

Clinically, what will you see in intra-hepatic jaundice?

A

Either unconjugated or conjugated bilirubin will be elevated, depending on the issue.

Increase in serum AST and ALT!

Urobilinogen levels are still normal, because nothing is affecting that area.

28
Q

What is the common factor for post hepatic jaundice?

A

Problems with conjugated bilirubin secretion

29
Q

What are the clinical findings for post-hepatic jaundice?

A

Elevated blood levels of conjugated bilirubin

Conjugated bilirubin is present in urine (dark)

Sercobilin is absent from feces (pale)

30
Q

What gene is absent in Type 1 Crigler-Najjar Syndrome?

What are affected individuals unable to do?

A

UDP-Glucuronyltransferase

Conjugate bilirubin

31
Q

What are the symptoms of Type 1 Crigler-Najjar syndrome?

A

Jaundice

Kernicturus (jaundice related brain damage and encephalopathy)

32
Q

What is physiological jaundice in newborns?

What is the treatment?

A

Jaundice related to the conversion of fetal hemoglobin to adult hemoglobin

Phototherapy and possibly injection of tin-mesoporphyrin

33
Q

What is Gilbert syndrome?

When might someone see symptoms?

A

Benign disorder reflecting a reduced UDP-Glucuronosyltransferase

34
Q

Describe Lead Poisoning

A

inactivates ALA dehydratase and Ferrochelatase

ALA and Protoporphyrin IX accumulate and are neurotoxic (ALA) acting like GABA

causes anemia (microcytic, hypochromic)

impacts ATP synthesis and energy metabolism

35
Q

What are the two key enzymes that turn Heme into Billirubin

A

Heme oxygenase (to biliverdin)

Biliverdin Reductase (to bilurubin)

36
Q

Bilirubin is super insoluble in it’s unconjugated/free form. What enzyme adds sugar to it so that it can be more soluble?

A

UDP glucuronyl transferase adds glucuronates to the bilirubin and is the RATE limiting enzyme in this process

37
Q

Hepatitis

A

inflammation of the liver leading to liver dysfunction

caused by viral infections, ETOH or cancer

causes increase in level of unconjugated and conjugated bilirubin in blood

BR accumulates in skin, sclera causing yellow (jaundice)

dark brown urine

38
Q

What is the stage of hemoglobin breakdown seen in bruising?

A

initially: hemoglobin to heme (redish blue/purple)

biliverdin (green)

bilirubin (yellow)

iron (hemosiderin/reddish brown color)