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93 Cards in this Set

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What are 3 functions of Heme?
1. Oxygen transport/storage
2. Electron transport
3. Redox reactions
What molecules contain heme?
1. Hemoglobin/myoglobin
2. ETC cytochromes
3. Cytochrome P450 enzymes
What are the 2 Major sites of Heme Synthesis?
-Liver - cytochrome enzymes
-Bone Marrow - hemoglobin
What cells do NOT make heme?
Mature RBCs
What is the structure of heme minus the iron molecule?
Porphyrin
What is a Porphryin molecule?
Cyclic tetrapyrrole
What is the IMMEDIATE product of the heme synthesis pathway?
Porphyrinogen
How do Porphryinogens give rise to Porphyrin?
Via spontaneous air oxidation.
What exactly does HEME consist of?
Protoporphyrin IX + Fe2+
What substituents are attached to the protoporphyrin IX molecule?
-4 methyls
-2 propionyls
-2 vinyls
What is the function of these substituents?
Binding of intermediate porphyrins to apoproteins.
What happens in heme synthesis after Protoporphyrin IX is made?
Makes Ferroprotophoryin IX, which is spontaneously autooxidized to Ferriprotoporphyrin IX.
What is a Porphyria?
Inherited or acquired heme synthesis disorder in which a specific enzyme is defective.
What are the 2 categories of Porphyrias?
-Hepatic
-Erythroid
Why are there tissue-specific porphyrias?
Because there are tissue specific isoenzymes of the synthetic pathway.
What heme precursor molecules are photosensitive?
Porphyrin RINGS
What heme precursor molecules are NOT photosensitive?
Linear precursors or Porphyrin rings chelated to metals.
What results from UV irradiation of porphryins in the presence of O2?
Generation of Reactive Oxygen Species (ROS)
What is the principal symptomatology associated with Porphyrias after the ring-closing step?
Cutaneous photosensitivity - due to UV generation of ROS.
Which porphyrias are NOT photosensitive?
-ALAD deficiency
-PBGD deficiency
What is the primary symptomatology assoc w/ PBGD or ALAD deficiency?
Neurovisceral
What is the degradation product of heme?
Bilirubin
Where is Heme synthesis located?
1st step = Inner Mitochondrial membrane.
Steps 2-5 = Cytosol
Steps 6-8 = Mitochondria Intermembrane Space
What is the rate-limiting reaction and enzyme of heme biosynthesis?
Glycine + Succinyl CoA make ALA via ALA synthase (ALAS)
Where is ALA synthase located?
In the inner mitochondrial membrane
Where does ALA go after it is made?
Into the cytosol.
ALA stands for:
5-Aminolevulinate
What cofactor does ALA synthase use?
PLP
What are the 2 isoforms of ALAS and to what tissue is each specific?
ALAS1 = liver

ALAS2 = RBCs
How is ALAS1 regulated?
At ALL LEVELS
-Transcription
-Translation
-Translocation to membrane.
-Feedback inhibition
-Substrate availability (Gly)
What causes the multi-level regulation of ALAS1?
Heme - product feedback inhibition.
What is Regulatory heme?
Heme produced in excess of its intended proteins.
What drug elevates ALAS1 activity markedly?
Phenobarbital
What is the main difference between ALAS1 and ALAS2?
ALAS2 is NOT inhibited by heme.
What occurs in the 2nd step of heme biosynthesis?
Condensation of 2 molecules of ALA -> Porphobilinogen (PBG)
What is the important thing to remember about ALAD (dehydratase)?
It requires ZINC in its active site
What can inactivate the Zinc in ALAD?
Lead poisoning
What would lead poisoning that deactivates ALAD result in?
Accumulation of ALA
What enzyme operates in Step 3 of porphryin synthesis?
PBGDeaminase
What does PBGD do?
Condenses 4 porphobilinogen molecules together to form LINEAR TETRAPYRROLE.
What is the name of this initial linear tetrapyrrole?
Hydroxymethylbilane
What happens to Hydroxymethylbilane?
2 Options:
-Spontaneous cyclization
-Enzymatic cyclization
What is an important determinor in whether heme synthesis will continue from this point?
If cyclization is enzymatic - only this option produces functional heme that will continue in the pathway.
What enzyme catalyzes cyclization of hydrxym.bilane?
Uroporphyrinogen III cosynthase (UROS)
What does UROS deficiency result in?
A photosensitive porphyria - because the ring is still cyclized SPONTANEOUSLY.
What do the next two steps of heme biosynthesis do?
Convert the side chains to what they should be (Methyl, Vinyl, and Propionyl groups)
Where is the location of CPO?(coproporphyrinogen 3 oxidase)
Mito intermembrane space - so its product goes back into the mitochondrial.
What is the product of CPO?
ProtoporphyrinOGEN IX
What does PPO do?
oxidizes protoporphyrinogen IX to protoporphyrin IX.
Where is HEME formed?
IN THE INNER MITOCHONDRIAL MEMBRANE.
What enzyme puts iron into protophoryin IX? What is the important thing to remember about it?
Ferrochetolase - the 2nd target of lead poisoning.
So the 2 targets of lead poisoning are:
-ALAD (step 2)
-Ferrochetolase (step 8)
What principally regulates Ferrochetalase?
Product inhibition - heme
What does Ferrochetalase do when Fe is absent?
Inserts a Zn to make a brilliantly flourescent compound.
What 2 intermediates accumulate in Lead poisoning?
-ALA
-Coproporphyrin III
Most common porphyria:
Intermediate that accumulates?
Enzyme deficient?
Porphyria cutanea tarda
-Uroporphyrin
-UROD
What enzyme deficiency causes Acute Intermittent Porphyria?
PBGD
What accumulates in Acute intermittent porphyria? How is it diagnosed?
PBG and ALA
Urine darkens when exposed to air and light
In which porphyria are patients NOT photosensitive?
PBGD deficiency - Acute Intermittent Porphyria
Steps of heme catabolism that occur in macrophage:
1 -Heme Ring opening
2 -Biliverdin converted to bilirubin
What is the 2-step mechanism of Heme Ring opening?
1. Cleavage at a-methene bridge in Heme
2. Oxidation w/ O2 and Release of CO
What enzyme catalyzes the cleaving step in heme ring opening? What is required?
Microsomal heme oxygenase
-NADPH or O2
What is the resultant product of the heme ring opening?
Biliverdin
What happens to Biliverdin? Where?
Conversion to bilirubin in Macrophage.
What enzyme converts Biliverdin to bilirubin? What is required?
Biliverdin reductase
-NADH or NADPH
Why is it good to make bilirubin in macrophages?
B/c it is less polar and can cross membranes to get into blood.
What happens to bilirubin after it's made in macrophage?
Crosses out into blood and binds albumin which takes it to the liver
What happens after albumin drops off Bilirubin at liver?
(4 things)
-Uptake
-Storage
-Conjugation
-Excretion
What happens to bilirubin immediately after it gets into the liver?
It gets bound by ligandins
What do ligandins do?
-Inhibit efflux of Bilirubin back out into circulation
-Temp storage form of bili
What happens to bilirubin-ligandin conjugates within the liver?
CONVERSION TO POLAR CONJUGATES via Esterification of propionic acid carboxyl groups
What donates the conjugating group to make bilirubin polar?
Glucuronic acid
What catalyzes the conjugation of bilirubin?
UDPGT
Where is UDPGT located?
Hepatocyte Endoplasmic reticulum
What are the resulting products of UDPGT conjugation of bilirubin?
Bilirubin Monoglucronide (BMG)
OR
Bilirubin Diglucuronide (BDG)
What does bilirubin conjugation allow?
Excretion from the liver to the bile duct -> intestine.
What allows Bilirubin (direct) to get out of the liver?
MOAT
What is MOAT?
ATP-dependent multiorganic anion transporter
What happens to bilirubin in the Intestinal tract?
-Degradation via bacteria to urobilinogen (feces/brown)
-Some reabsorbed into blood, goes to kidneys/urine (yellow)
What does an abnormality in any part of bilirubin catabolism result in?
Hyperbilirubinemia/Jaundice
What are the 2 classes of Hyperbilirubinemia?
-Unconjugated type
-Conjugated type
What assay allows for serum bilirubin determination?
Van den Bergh
What is the principle of the Van den Bergh assay?
1. Measure Soluble (direct) Bilirubin in water
2. Measure total bilirubin in methanol
3. Calculate indirect
What is the reactive group in the assay reagent for Van den Bergh assay?
Diazonium salt (diazo compound is generated)
What are the disorders resulting in UNCONJUGATED (INDIRECT) hyperbilirubinemia?
-Neonatal Jaundice
-Crigler-najjar type 1
-Crigler-najjar type 2
-Gilbert syndrome
Which of the inherited defects in this category is worst? Most common?
Worst = CN type I

Most common = Gilbert
What causes all 3 inherited disorders of unconjugated bilirubinemia?
Defective UDPGT expression (no conjugation can occur)
What are the 2 disorders resulting in Conjugated hyperbilirubinemia?
-Dubin Johnson
-Rotor Syndrome
What defect is associated with Dubin Johnson?
MOAT defect (multiorganic anion transporter)
What are 3 noninherited causes of hyperbilirubinemia?
1. Hemolytic syndrome
2. Obstruction of the bile duct
3. Hepatocellular injury
What type of bilirubinemia would result from a hemolytic process?
Indirect
What type of bilirubinemia would result from a bile duct obstruction?
Direct
What type of bilirubinemia would result from Hepatocellular damage?
Indirect - liver doesn't work.