Heme Synthesis and Degradation Flashcards
Structure of Heme
Ferrous protoporphyrin IX
4 Pyrrole rings linked via mehenyl bridges,
Side chains of Heme b: methyl, vinyl, methyl, vinyl,
methyl, propionyl, asymmetric ring D: propionyl, methyl
Location of Heme Synthesis
85% in bone
15% in liver for cytochrome P450
General Overview of Heme Synthesis
Succinyl CoA and Glycine (In mitochondria)
To
Delta-aminolevulinic Acid (ALA)
Two ALA combine to form Porphobilinogen (In Cytosol)
4 Porphobilinogen are alligned to form Hydroxymethylbilane
Ring closure forms Porphyrin Ring III
Modification of side chains to eventually form Protoporphyrin IX (in mitochondria)
Insertion of Ferrous Iron to form Heme
ALA Synthase
Converts Succinyl CoA annd Glycine to d-aminolevulinicacid (ALA) in the mitochondria. Requires PLP
First step in Heme Synthesis
ALA Dehydratase
AKA - Porphobilinogen Synthase
Joins two ALA in the cytosol to form Porphoilinogen. Requires Zn+ as a cofactor
Second step in Heme Synthesis
HMB Synthase
AKA - porphobilinogen deaminase
Aligns 4 porphobilinogens to form the linear hydroxymethylbilane
Third step in Heme Synthesis
Uroporphyrinogen III Synthase
Forms ring structure Urophorphyrinogen III from the linear hydroxymethylbilane
Forth step in Heme Synthesis
Uroporphyrinogende carboxylase
In cytosol decarboxylates all acetyl chains of the pyrrol rings to methyl groups. Forms Coporphyrinogen III which enters the mitochondria
Fifth step in Heme Synthesis
Fate of Coporphyrinogen III
Enters the mitochondria and undergoes further modification of side chains (decarboxylatedto vinyl groups)
Ultimately forms Protoporphyrin IX
Ferrochelatase
Inserts Ferrous Iron into porphoryn ring to form Heme. Requires Zn+ as a cofactor.
Lead Poisoning
Interacts with the Zinc cofactors of ALA dehydrotase and Ferrochelatase
ALA and Protoporphyrin accumulate in the urine
Acute Intermittent Porphyria
AIP
Deficiency of hydroxymethylbilane synthase (porphobilinogen deaminase)
Genetic defect autosomal dominant trait
Accumulation of ALA and porphobilinogen
Change of normal urine color to dark purple color of urine after 24 hrs exposure to light and air.
Characterized by:
- very severe abdominal pain, abdominal colic
- highly agitated state, tachycardia, respiratory problems, nausea
- confusion, mental disturbance
- weakness of lower extremities
Congenital Erythropoietic Porphyria
CEP
Deficiency of uroporphyrinogen III synthase
Genetic defect autosomalrecessive trait
HMB is spontaneously converted to Uroporphyrin I and coproporphyrinI that accumulates in tissues and blood and urine (red):
Extremely severe photosensitivity!
Characterized by:
- severe damage to skin beginning in childhood
- blisters, poor wound healing
- ulcers
- infections
- hypertrichosisis often severe
- can include reddish-brown teeth
- “werewolf” features, hairy front and arms
Treatment: bone marrow transplantation
( hemin infusion would not help, erythroid cells contain ALAS2 which is not inhibited by hemin)
Porphyria Cutanea Tarda
PCT
Deficiency of uroporphyrinogen III decarboxylase
Type I (sporadic, 80%) Type II (familial, autosomaldominant trait, 20%)
most common porphyriaand often due to a chronic disease of the liver
Characterized by:
Erosions and Bullous lesions in sun-exposed areas
Treatment: avoidance of sun-light, alcohol and iron
Heme Degradation
RBCs life span of ~120 Days
Senile RBCs are sequestered by reticuloendothelial system (RES) (Spleen, Kupffer cells of liver, macrophages)
Hemoglobin broken down to Heme which is further broken down to bilirubin, and globin which forms AA for the AA pool.
Heme Oxygenase
Opens heme ring to form biliverdin. Fe++ is converted to Fe+++ and CO is formed.
Takes place in macrophages
(biliverdin has a green pigment)
Biliverdin Reductase
Converts Biliverdin to Bilirubin. requires NADPH
Takes place in macrophages
(Bilirubin has a orange-yellow pigment)
Transport of bilirubin in blood to liver
Bilirubin binds to Albumin for blood transport - unconjugated bilirubin.
Binding to albumin prevents the unconjugated bilirubin from crossing the blood-brain barrier
Many drugs can displace bilirubin from albumin eg: salicylates, sulfonamides
Ligandin
Intracellular protein in hepatocytes that bind bilirubin after transport into cell from blood
UDP-glucuronyl transferase
Conjugates bilirubin in hepatocytes by the addition of 2 molecules of glucuronic acid (from UDP-glucuronic acid)
Conjugated bilirubin = Bilirubin Diglucuronide
Secretion of bilirubin into bile.
Conjugated bilirubin is actively transported from the hepatocytes into the bile canaliculus AGAINST a concentration gradient by a specific ABC TRANSPORTER
Formation of urobilinogen
Conjugated bilirubin in large intestine undergoes deconjugation and is converted to urobilinogen (colorless) by bacterial flora
Formation of stercobilin
Bacterial action on urobilinogen in the large intestine forms stercobilin (brown color) that is lost in the feces
Urobilin
~10% of urobilinogen from the large intestine is absorbed and enters the liver.
Urobilinogen is converted to Urobilin (yellow color) and is excreted in the urin
Jaundice
Characterized by binding of bilirubin to connective tissue
Occurs with elevated serum bilirubin levels >2mg/dL (normal is <1mg/dL)
Van Den Bergh Reaction
Used to detect the type of serum bilirubin
Bilirubin reacts with diazo reagent (diazotized sulfanilic acid) to form a red colored complex
Conugated bilirubin acts quickly and is referred to as direct bilirubin
Unconjugated bilirubin reacts in the presence of methanol (slower) and is referred to as indirect bilirubin
Total bilirubin –Direct (conjugated) bilirubin = Indirect (unconjugated) bilirubin
Prehepatic Jaundice
Hemolytic Jaundice
Increased breakdown of RBCs. Increased serum unconjugated (indirect) bilirubin
Urine urobilinogen present
Hepatic Jaundice
Decreased capacity of conjugation in the liver and decreased excretion if bilirubin from hepatocytes.
Elevated Conjugated and unconjugated serum bilirubin
hepatocellular damage results in lower uptake of unconjugated bilirubin into liver
Conjugated bilirubin regurgitates into plasma (as it cannot be excreted into bile)
Urine bilirubin present
Posthepatic Jaundice
Obstructive Jaundice
Decreased excretion of bilirubin via bile. Increased conjugated serum bilirubin
Obstruction due to gall stones or cancer
Urine bilirubin present
Kernicterus
High levels of unconjugated bilirubin crosses the blood-brain barrier and deposits in basal ganglia of the brain
characterized in newborns by lethargy, altered muscle tone, high pitched cry
•Patients surviving kernicterus have severe permanent neurologic symptoms (choreoathetosis, spasticity, muscular rigidity, ataxia, mental retardation)
Crigler-Najjar syndrome I
Severe Deficiency in UDP-glucuronyl transferase
Serum bilirubinlevels can reach up to 50 mg/dL (unconjugated hyperbilirubinemia) and result in kernicterus and mental retardation
Arias syndrome
Crigler-Najjar syndrome II
Characterized by lower activity of bilirubin glucuronyl transferase (10-20% of normal)
–Characterized by jaundice, but less severe than type I (serum bilirubinlevels usually 6-22mg/dL)
–Children respond to phenobarbital(induces the enzyme)
–Regular phototherapy is used in patients with persisting high bilirubinlevels
Gilbert’s syndrome
Characterized by occurrence of mild jaundice (2-5 mg/dL) usually following an infection or stress or starvation
–UDP-glucuronyltransferase activity is about 50% of normal
–Characterized by a mild increase in unconjugated bilirubin
Present in 3-7% of population
Dubin-Johnson syndrome
Inherited deficiency of the ABC transporter that transports conjugated bilirubin from the hepatocyte into the biliary canaliculus
–Characterized by elevated levels of conjugated (direct) bilirubin in circulation
