Final: Heme + Iron Metabolism (Ben) Flashcards
What is heme composed of?
(2 main “ingredients”)
Where/how does it function?
Protoporphyrin IX and Fe2+
- present as a prosthetic group in hemoglobin, myoglobin, cytochrome catalase, peroxidase and NO synthase
- functions mostly in transport of diatomic gases and electron transfer for redox reactions
Describe the structure of protoporphyrin IX.
- 4 pyrrol rings (5 atoms = 4 C + 1 N )
-
Methyl (-CH3) Vinyl (-CH=CH2) and Propionate (-CH2-CH2-COOH) groups attached to the pyrrols
- clockwise order from top left = MVMVMPPM
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Describe the structures of myoglobin and hemoglobin.
What can change the O2 affinity of hemoglobin?
-
Myoglobin
- a monomer with a single hem__e at its center
-
Hemoglobin
- a tetramer of 2 alpha and 2 beta subunits each with own Heme B
- 2,3-BPG binds to heme to decrease O2 affinity of Hb in tissues where O2 is required
- there is a “positive cooperativity” of O2 binding, where affinity increases with each O2 bound
What is the first and rate-limiting/committed/regulatory step in synthesis of protoporphyrin IX for heme?
Where does it take place?
ALA Synthase
- Succinyl-CoA + Glycine –> δ-aminolevulinate + CoA + CO2
- has a 6C intermediate (alpha-amino-beta-keto-adipate)
- is mitochondrial
How is the rate-limiting step in Heme synthesis regulated?
ALA Synthase has two isoforms
-
ALAS-L (liver)
- Heme inhibits transcription, mRNA export, mitochondrial uptake AND enzyme activity (allosterically)
-
ALAS-E (marrow)
- Erythropoietin stimulates transcription
- heme does not inhibit ALAS-E but does inhibit iron release from ferritin + stimulates globin synthesis
How many aminolevulinate substrate molecules go into the 2nd reaction of heme synthesis?
Whats the enzyme and its co-factor?
Cellular location + product?
What important functional groups are added?
Inhibition?
ALA Dehydratase
- requires 2 ALA** molecules plus **Zn2+
- located in cytosol
- makes porphobilinogen
- has added acetate and propionate groups which become methyl and vinyl groups later
- inhibited by Pb2+
How many porphobilinogen molecules go into the 3rd reaction of heme synthesis?
What is the enzyme and product?
What two things can happen to the product?
Porphobilinogen Deaminase
- requires 4 porphobilinogens to make hydroxymethylbilane
- OH-methylbilane is an unstable linear intermediate which can:
- Spontaneously close - which is slower and results in false endproduct uroporphyrinogen I excreted in urine
- Continue on to become uroporphyrinogen III
After the tetrapyrrole ring structure is formed via uroporphyrinogen III synthase…
What are the next 3 steps in heme synthesis?
-
Uroporphyrinogen Decarboxylase
- makes coproporphyrinogen III
- decarb. acetyl -> methyl
-
Coproporphyrinogen III Oxidase
- oxidizes 2 propionyl grps -> vinyl
- makes protoporphyrinogen IX
-
Protoporphyrinogen Oxidase
- oxidizes interpyrrole bridges + 2 nitrogens
-
Ferrochelatase
- adds Fe2+ ….. (inhibited by Pb2+)
What molecule transports iron in blood?
In what form?
How does it enter cells?
And how is the form changed for use?
-
Transferrin transports two Fe<strong>3+</strong> per molecule (note it’s 3+ !!!)
- this “diferric” transferrin binds to transferrin receptors and is absorbed into endosomes in which the lower pH triggers iron release
- Fe3+ binds to Ferritin** and is reduced to usable Fe2+ by **Ferritin Reductase
- empty “apotransferrin” leaves cell
Where and how is heme degradation started?
2 steps
In macrophages…
-
Heme Oxygenase
- Heme B + 3 NADPH + 3 H+ + 3 O2 –> Biliverdin + etc. + H2O + Fe2+ + CO
- destabilizes methinyl bridges via hydroxylation to linearize rings
-
Biliverdin Reductase
- **Biliverdin + NADPH + H+ –> **Bilirubin
- converts central methinyl bridge from =CH- to -CH2-
What is special about bilirubin that makes some disorders of heme metabolism benefical to health?
Bilirubin can act as an antioxidant…
- Bilirubin + H2O2 –> Biliverdin + 2 H2O
What is the next two-step process in heme degradation after bilirubin is formed?
Where does it take place?
Conjugation in the liver…
-
UDP-glucose DH
- UDP-Glucose + 2 NAD+ + H2O –> UDP-Glucuronic Acid + 2 NADH + 2 H+
-
UDP Glucuronosyl Transferase
- Bilirubin + 2 UDP-glucuronic acid –> Bilirubin Diglucuronide + 2 UDP
- 2 steps… first monogluc then digluc
- Makes the bilirubin more polar and thus water-soluble
What results from issues with pumping heme degradation products out of the liver?
What 2 mechanisms can cause this?
Post-hepatic Jaundice / Direct Hyperbilirubinemia
- means conjugation is working, but liver secretion is not
- Mechanisms:
- Obstructred bile duct
- Dysfunctional MRP2 transporter (Dubin-Johnson/Rotor Syndrome)
- conjugated bilirubin increases in urine/plasma
What results from abnormal increases in the amount of heme which must be degraded?
Prehepatic Jaundice
- caused by anything which increases hemolysi__s and thus heme breakdown
- sickle cell anemia, Pyr Kinase deficiency, G6P DH deficiency
- a form of indirect (unconjugated) hyperbilirubinemia
- __increased heme degradation overwhelms bilirubin conjugation capacity of liver
- increased unconj. bilirubin in blood
What results from issues with bilirubin conjugation in the liver?
What general condition and what two specific diseases?
Hepatic Jaundice
- a form of Indirect (Unconjugated) Hyperbilirubinemia
-
Crigler-Najjar Syndrome (Type I)
- congenital non-hemolytic jaundice
- total UDP-glucuronosyl transferase deficiency
- Phenobarbitol induces conjugation in partial deficiency (type II) but useless in type I
-
Gilbert’s Disease
- slightly reduced transferase activity, 5% of people, anti-oxidant capacity of increased bilirubin can be beneficial