Heme metabolism

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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.

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