Lecture 28: Heme Metabolism

Front 1

Where are the major sites of heme synthesis

Back 1

bone marrow and liver, does occur in virtually all cells EXCEPT mature erthrocytes

Front 2

What are the two structural comonents of heme

Back 2

Fe2+ and protoporphyrin IX

Front 3

Porphyrins can have substituent groups attached to the pyrrole rings that modify what proteins they associated with. There are three different substituents and fifteen positional isomers. What are the three possible substituents? Which isomer is of physiological significance

Back 3

substituents= methyl, vinyl, propionyl
Significant= ferroprotoporphyrin

Front 4

What is the difference between heme and hemin

Back 4

Oxidation state of iron
Fe2+=ferroprotoporphyrin IX
Fe3+=ferriprotoporphyrin IX

Front 5

In general, where do the steps of heme biosynthesis occur

Back 5

1st and last three are in the mitochondrion, intermediate are in the cytosol

Front 6

What is the commited step of heme biosynthesis? How is it regulated

Back 6

Commited step is ALAS. Regulated kinetically by glycine levels. ALAS 1 inhibited by excess heme at transcription, translation, and translocation

Note that heme biosynthesis in erthyroid cells occurs via ALAS 2 which is NOT inhibited by heme

Front 7

What is the first step of heme biosynthesis? Where does it occur?

Back 7

Glycine and succinyl-CoA condense to form ALA (5-aminolevulinate). This occurs via ALAS 1 (hepatic) or ALAS 2 (erthroid)
the reactio occurs i the matrix

Front 8

What is the second step of heme biosynthesis? Where does it occur?
(just made ALA)

Back 8

Occurs in the cytosol
Two ALAs condense to form 1 porphobilinogen (PBG), catalyzed by ALA dehydratase (ALAD)

Front 9

How does lead interfere with heme
(lead poisonin mimics acute porphyrias)

Back 9

1. ALAD-requires zinc complexed to active cysteine, lead displaces zinc and eliminates catalytic activity
2. Ferrochelatase

Front 10

What is the third step of heme biosynthesis? Where does it occur?
(Just made PBG)

Back 10

Occurs in the cytosol
Four PBGs condense head to tail to form hydroxymethylbilane which cyclizes to uroporphyrinogens I and III (UROS directs the reaction to III)

Front 11

What is the purpose of UROS in the heme biosynthetic pathway

Back 11

Hydroxymethylbilane (from 4x PBG condensation) can spontaneously cyclize to uroporphyrinogen I which is not the correct sterochemical form. UROS directs the reaction so that uroporphyrinogen III is made instead.

Front 12

What is the 4th step of heme biosynthesis? Where does it occur?
(just made uroporphyrinogen III)

Back 12

The acetate side chains on uroporhyrinogen III are decarboxylated to methyl groups to yeild coprophorphyrinogen III. This occurs in the cytosol and is catalyzed by UROD

Front 13

What is the 5th step of heme biosynthesis? Where does it occur?
(just made coproporphyrinogen III)

Back 13

Occurs in the matrix. Coproporphyrinogen III is converted to protoporphyrinogen IX by CPO. Propionic acid side chains are converted to vinyl groups.

Front 14

What is the 6th step of heme biosynthesis? Where does it occur?
(just made protoporphyrinoge IX)

Back 14

Protoporphyrinogen IX is converted to protoporphyrin IX by PPO. This occurs in the mitochondrion.

Front 15

What is the final step of heme biosynthesis? Where does it occur?
Just made protoporphyrin IX

Back 15

Fe 2+ is inserted by ferrochelatase. Note that this enzyme is inhibited by heme, lead, and iron deficiency.

Front 16

Give three examples of species that modify ferrochelatase activity

Back 16

Heme-inhibts
Lead-poisoning
iron deficiency-inhibits

Front 17

When will person with a porphyria exhibit cutaneous photosensitivity

Back 17

only when the block results in build up of cyclic tetraphyrroles. If the deficiency is before this step (before PBG makes uroporphyrinogen) there will be no generation of ROS.

Front 18

Will a defiency in ALAD or PBGD cause photosensitivity

Back 18

No. These steps occur prior to the formation of porphyrins so there is no increases in ROS due to UV irradiation

Front 19

Which two enzymes in the heme biosynthetic pathway will lead inhibit? What products will accumulate in the urine?

Back 19

Ferrochelatase and ALAD
Protoporhyrin and ALA will accumualte

Front 20

Which enzyme defiency causes Variegate porphyria? What accumulates in the urine? Is there photosensitivity?

Back 20

Variegate porphyria is an acute disease caused by a deficiency in protoporphyrinogen oxidase (PPO). Protoporphyrinogen IX and other proxmial intermediates accumulate in the urine. Patiens are photosensitive because porphyrins have been made.

Front 21

Jaundice results from an accumulation of

Back 21

bilirubin, an orange pigment

Front 22

Where deos the majority of heme catabolism occur

Back 22

In senescent erthrocytes, dead RBCs are taken up by the reticuloendothelial system (liver and spleen)

Front 23

Describe the first reaction of heme catabolism where the ring is opened. Where does this occur?

Back 23

Ferroprotoporphyrin IX ring is cleaved at the a-methene bridge by microsomal heme oxygenase. Uses NADPH. The second step invovles the non-enzymatic oxidation by O2 and release of CO. This releases iron and leaves biliverdin which is green.
The ring opening occurs in the macrophage.

Front 24

What happens to the biliverdin that was generated after heme ring opening and iron release? Where does this occur?

Back 24

Biliverdin is converted to bilirubin by biliverdin reductase using NADH or NADPH. This occurs in hte macrophage. Note that bilirubin is less polar and can cross the membrane into the blood.

Front 25

How does bilirubin generated by biliverdin reductase reach the liver?

Back 25

Bilirubin binds to serum albumin which transports it from the spleen and bone marrow to the liver

Front 26

What happens to bilirubin after it arrives at the liver on albumin.

Back 26

Bilirubin dissociates from albumin and then associates with ligandins to temporary store it in the hepatocye.

Front 27

Efficient excretion of bilirubin from hepatocytes depends on its conversion to polar conjugates. How does this occur?

Back 27

UDPGT (ER) transfers glucuronic acid onto bilirubin yielding BMG or BDG.

Front 28

What is the purpose of MOAT in bilirubin excretion

Back 28

MOAT transfers the conjugated bilirubin (BMG or BDG) across the liver canalicular membranes

Front 29

What happens to conjugated bilirubin after it reaches the intestine

Back 29

It is degraded by intestinal bacteria into urobilinogen products which are decojugated

Front 30

What happens to the urobilinogen products that are made from conjugated bilirubin in the intestine by bacteria (3)

Back 30

1. oxidized to stercobilin (brown) and excreted in feces
2. Participates in the enterohepatic urobilinogen cycle
3. Transported in blood to kidney and converted to urobilin (yellow) and excreted in the urine

Front 31

What test is used to determine serum bilirubin

Back 31

van den bergh assay
(water soluble conjugated bilirubin reacts rapidly to give direct value, in methanol both forms react giving total. Subtracting direct from total gives indirect)

Front 32

Why are neonates vulnerable to jaundice

Back 32

Delayed maturation of UDPGT enzyme results in insufficient conjugation and impaired excretion of bilirubin

Front 33

What type of hyperbilirubinemia is neonatal jaundice

Back 33

unconjugated

Front 34

Untreated neonatal jaundice can lead to?
How is it treated?

Back 34

kernicterus, a discoloration of the basal ganglia which can lead to neurological problems

Tx with phototherapy to change configuration of bilirubin to an excretable form.

Front 35

Inherited unconjugated hyperbilirubinemias are the result of a disorder in which enzyme

Back 35

UDPGT
note that these span a spectrum of disorders from Crigler-Najar type I, Type II and Gilbert

Front 36

What type of hyperbilirubinemia is Crigler-Najjar/ Gilbert's

Back 36

unconjugated, results from UDPGT deficiency

Front 37

Give two examples of iherited disorders resulting in conjugated hyperbilirubinemia

Back 37

1. Dubin-Johnson=defective MOAT
2. Rotor syndrome
obstructive jaudice also causes cojugated hyperbilirubiemia

Front 38

Hemolytic jaundice is the result of build up of what form of bilirubin

Back 38

unconjugated (indirect), excessive ertythrocyte destruction results in the formation of bilirubin the amounts exceeding the conjugating ability of the liver. Free bilirubin increases in the plasma

Front 39

Obstructive jaundice is the result of build up of what form of bilirubin

Back 39

Conjugated (direct)-results from obstruction of the bile ducts, conjugation is working fine but the conjugated bilirubin can't get to the intestine so it appears in the plasma

Front 40

Hepatocellular jaundice is the result of build up of what form of bilirubin

Back 40

Unconjugated (indirect)-damage to the liver impair's its ability to conjugate and excrete circulating bilirubin so the unconjugated form builds up