Heme Synthesis And Breakdown

Question 1

Heme has a heterocyclic ____________ with _______ in the center

Answer 1

Heme has a heterocyclic PORPHYRIN with IRON present in the center

Question 2

What are two key features of the porphyrin ring?

Answer 2

1. Have four 5-membered rings with nitrogen

2. Iron in the center is in a ferrous state. Fe2+

Question 3

What are the four 5 membered rings called?

Answer 3

Pyrrole ring

Question 4

Where in the body is heme synthesized? A

And in what parts of the cell?

Answer 4

In liver and erythroid cells of bone marrow.

Phase 1 and 3 occur in mitochondria
Phase 2 occurs in cytosol

Question 5

Defects in one or more stages of heme synthesis cause what type of diseases?

Answer 5

Porphyrias

Question 6

ALA synthase needs what as a cofactor?

Answer 6

B6, pyridoxal phosphate

Question 7

There are two isoforms of ALA synthase. Describe the difference

Answer 7

ALAS I: ubiquitous, inhabited by heme
ALAS II: (only in erythroid cells of bone marrow) has an iron response element in mRNA, presence of iron increases its transcription and translation.

Question 8

How does lead poisoning work?

Answer 8

Lead inactivates ALA dehydrogenase and ferrochelatase.
Leads to accumulation of LAL and protoporphyrin.
ALA is neurotoxic because it resembles GABA
Causes anemia
Impacts energy production as cytochromes are not synthesized.

Question 9

What is porphyria

Answer 9

• inherited metabolic disorder
• caused by defects in heme synthesis
• two types: acute hepatic»neurological symptoms; erythropoietic»skin, photosensitivity

Question 10

What is deficienct in ACUTE INTERMITTENT PORPHYRIA

What does it cause

Type of porphyria

Answer 10

PBG deaminase

Causes a build up of PBG and ALA»neurological dysfunction

Hepatic

AUTOSOMAL DOMINANT

Question 11

Congenital erythropoietic porphyria

Defective enzyme

What does it cause

Type

Answer 11

Uroporphyrinogen III synthase (erythrocytes)

Accumulation of uroporphyrinogen I and fluorescent red product of air oxidation»>red urine and teeth

Erythropoietic

AUTOSOMAL RECESSIVE

Question 12

Porphyria cutaneous tarda (PCT)

Defective enzyme

What does it cause

Type

Answer 12

Uroporphyrinogen decarboxylase

Accumulation of uroporphyrinogen III»>photosensitivity, red wine colored urine.
Most common in US,

Hepatoerythropoietic

AUTOSOMAL DOMINANT

Question 13

Variegate porphyria

Defective enzyme

What does it cause

Type

Answer 13

Protoporphyrinogen IX oxidase

Photosensitivity and neurological symptoms

Hepatic

AUTOSOMAL DOMINANT

Question 14

What system degrades heme, and how often do RBC break down

Answer 14

Reticulo-endothelial system

Every 120 days

Question 15

What enzyme completes the first step in heme degradation?

What is synthesized?

Answer 15

Heme oxygenase»>removes the bridge between pyrrole rings of heme.

This enzyme requires oxygen.

Carbon monoxide is released,
Fe2+»>Fe3+

Bilirubin is synthesized

Question 16

Free bilirubin (unconjugated/indirect) is insoluble. How does it get to the liver?

Answer 16

Albumin binds it and carries to the liver.

Question 17

Once in the liver, what happens to bilirubin?

Answer 17

They are conjugated»>2 UDP glucose are added to bilirubin by BILIRUBIN UDP GLUCURONYLTRANSFERASE to make bilirubin diglucuronide=more soluble.

Question 18

What happens to bilirubin diglucuronide?

Answer 18

Transported to gall bladder for bile storage.

Is released into small intestine in response to food.

Microbes reduce it to bilirubin then to urobilinogen

Question 19

Urobilinogen can do two things

Answer 19

Can be reabsorbed and transported to kidney and made into urobilin which makes urine yellow.

Can be unreabsorbed and reduced by microbes to sterocilin, which makes feces brown.

Question 20

What are the three classes of jaundice

Answer 20

Prehepatic

Intrahepatic

Posthepatic

Question 21

Describe prehepatic jaundice

Answer 21

Due to increased production of unconjugated BR.

Blood is being lysed faster than the body can deal with the heme.

Findings: elevated levels of conjugated BR

• normal ALT/AST because liver is functioning normally.
• urobilinogen present in urine
• direct BR not found in urine

Question 22

Describe intrahepatic jaundice

Answer 22

Caused by impaired hepatic uptake, conjugation, or secretion of conjugated BR.

Generalized hepatic dysfunction

Findings: variable increase in unconjugated and conjugated BR

• increase in serum ALT/AST»>indicate liver Disfunction
• conjugated BR in urine

Question 23

Describe post hepatic jaundice

Answer 23

Problems with BR excretion

Caused by obstruction to biliary drainage

Findings: elevated blood levels of conjugated BR

• conjugated BR is present in urine (dark)
• no urobilinogen in urine
• no stercobilin in feces (pale stool)

Question 24

Describe neonatal jaundice

Answer 24

• newborns yellow
• UDP-GT enzyme not fully functional
• lot of fetal hemoglobin destruction
• treat with blue fluorescent light
• forms soluble dimers

Question 25

Crigler-najjar syndrome

Answer 25

Deficiency of UDP-GT (cannot make bilirubin soluble
Type I- complete absence of the gene»>severe hyperbilirubinemia.

BR accumulates in brain of babies»brain damage, encephalopathy/kernicturus

Therapy: blood transfusion, phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, liver transplant.

Type II-UDP-GT is less active (10%) because of mutation

Question 26

Gilbert syndrome

Answer 26

Common

Reduced activity of UDP-GT, formed normally, just not fully functional.

Occasional jaundice with stress or alcohol.

Question 27

Hepatitis

Answer 27

V general term for inflammation of the liver

Can be caused by viral infection, alcoholic cirrhosis, liver cancer

Cause increased level of unconjugated and conjugated BR in blood

Dark tea colored ruin

Sclera icterus