Heme Synthesis and Degradation Flashcards Preview

2.b. Biochemistry II > Heme Synthesis and Degradation > Flashcards

Flashcards in Heme Synthesis and Degradation Deck (34)
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1
Q

Structure of Heme

A

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

2
Q

Location of Heme Synthesis

A

85% in bone

15% in liver for cytochrome P450

3
Q

General Overview of Heme Synthesis

A

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

4
Q

ALA Synthase

A

Converts Succinyl CoA annd Glycine to d-aminolevulinicacid (ALA) in the mitochondria. Requires PLP

First step in Heme Synthesis

5
Q

ALA Dehydratase

A

AKA - Porphobilinogen Synthase

Joins two ALA in the cytosol to form Porphoilinogen. Requires Zn+ as a cofactor

Second step in Heme Synthesis

6
Q

HMB Synthase

A

AKA - porphobilinogen deaminase

Aligns 4 porphobilinogens to form the linear hydroxymethylbilane

Third step in Heme Synthesis

7
Q

Uroporphyrinogen III Synthase

A

Forms ring structure Urophorphyrinogen III from the linear hydroxymethylbilane

Forth step in Heme Synthesis

8
Q

Uroporphyrinogende carboxylase

A

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

9
Q

Fate of Coporphyrinogen III

A

Enters the mitochondria and undergoes further modification of side chains (decarboxylatedto vinyl groups)

Ultimately forms Protoporphyrin IX

10
Q

Ferrochelatase

A

Inserts Ferrous Iron into porphoryn ring to form Heme. Requires Zn+ as a cofactor.

11
Q

Lead Poisoning

A

Interacts with the Zinc cofactors of ALA dehydrotase and Ferrochelatase

ALA and Protoporphyrin accumulate in the urine

12
Q

Acute Intermittent Porphyria

A

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
13
Q

Congenital Erythropoietic Porphyria

A

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)

14
Q

Porphyria Cutanea Tarda

A

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

15
Q

Heme Degradation

A

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.

16
Q

Heme Oxygenase

A

Opens heme ring to form biliverdin. Fe++ is converted to Fe+++ and CO is formed.

Takes place in macrophages

(biliverdin has a green pigment)

17
Q

Biliverdin Reductase

A

Converts Biliverdin to Bilirubin. requires NADPH

Takes place in macrophages

(Bilirubin has a orange-yellow pigment)

18
Q

Transport of bilirubin in blood to liver

A

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

19
Q

Ligandin

A

Intracellular protein in hepatocytes that bind bilirubin after transport into cell from blood

20
Q

UDP-glucuronyl transferase

A

Conjugates bilirubin in hepatocytes by the addition of 2 molecules of glucuronic acid (from UDP-glucuronic acid)

Conjugated bilirubin = Bilirubin Diglucuronide

21
Q

Secretion of bilirubin into bile.

A

Conjugated bilirubin is actively transported from the hepatocytes into the bile canaliculus AGAINST a concentration gradient by a specific ABC TRANSPORTER

22
Q

Formation of urobilinogen

A

Conjugated bilirubin in large intestine undergoes deconjugation and is converted to urobilinogen (colorless) by bacterial flora

23
Q

Formation of stercobilin

A

Bacterial action on urobilinogen in the large intestine forms stercobilin (brown color) that is lost in the feces

24
Q

Urobilin

A

~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

25
Q

Jaundice

A

Characterized by binding of bilirubin to connective tissue

Occurs with elevated serum bilirubin levels >2mg/dL (normal is <1mg/dL)

26
Q

Van Den Bergh Reaction

A

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

27
Q

Prehepatic Jaundice

A

Hemolytic Jaundice

Increased breakdown of RBCs. Increased serum unconjugated (indirect) bilirubin

Urine urobilinogen present

28
Q

Hepatic Jaundice

A

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

29
Q

Posthepatic Jaundice

A

Obstructive Jaundice

Decreased excretion of bilirubin via bile. Increased conjugated serum bilirubin

Obstruction due to gall stones or cancer

Urine bilirubin present

30
Q

Kernicterus

A

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)

31
Q

Crigler-Najjar syndrome I

A

Severe Deficiency in UDP-glucuronyl transferase

Serum bilirubinlevels can reach up to 50 mg/dL (unconjugated hyperbilirubinemia) and result in kernicterus and mental retardation

32
Q

Arias syndrome

A

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

33
Q

Gilbert’s syndrome

A

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

34
Q

Dubin-Johnson syndrome

A

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