Heme Metabolism Flashcards
What is the difference between heme and hemin
Heme = Fe2+ Hemin= Fe3+
Two main places where heme synthesis occurs?
However, heme synthesis happens in all cells EXCEPT
Site within the cell of heme synthesis?
Liver and bone marrow
RBCs
Mitochondria and cytoplasm
What assists in heme synthesis in the liver
Cytochrome p450
For our purposes, which 2 steps happen in the mitochondria?
1st step and last 3 steps; rest occur in cytoplasm
Two things required for heme biosynthesis
Glycine and succinyl CoA (these are the beginning substrates for first step)
First step of heme synthesis?
By which enzyme?
Glycine and succinyl CoA decarboxylate to form ALA by ALA synthase
First step of heme synthesis requires?
Vitamin B6 (pyridoxal phosphate)
What is the rate limiting enzyme in heme synthesis
What inhibits this enzyme?
ALA synthase
Heme/hemin
What happens in step 2 of heme synthesis
What does this enzyme require?
What is significant about the enzyme in this step
2 molecules of ALA condense to form porphobilinogen by ALA dehydratase
Requires zinc
It is inhibited by heavy metals (lead)
Lead poisoning will lead to what two things?
Anemia and elevation of ALA and zinc protoporphyrin
Besides ALA dehydratase, what other enzyme is inhibited by lead?
Ferrochelatase
~so these 2 enzymes are the cause of anemia in lead poisoning
Deficiency in any of the other enzymes of heme synthesis that have not been mentioned cause what?
A condition known as porphyria
Name the following enzyme used for the last 3 steps of heme synthesis:
- Coproporphyrinogen III -> protoporphyrinogen IX
- Protoporphyrinogen IX -> protoporphryrin IX
- Protoporphyrin IX -> heme
- Coproporphyrinogen III oxidase
- Protoporphyrinogen oxidase
- Ferrochelastase
- Disorders in any of the beginning steps of heme synthesis will have what kind of symptoms?
- Disorders in the ending steps?
- Either GI or neuro/psych
2. Either photosensitive or skin
Porphyrias:
- Caused due to a defect in?
- Reduced heme formation will lead to increase function of which enzyme?
- Cells of which two organs will be most affected by these disorders
- Heme sythesis
- ALA synthase
- Bone marrow (erythropoietic) and liver (hepatic)
Erythropoietic porphyria:
1. Characterized by
- Complications
- Skin rashes and blisters that appear early in childhood
2. Liver cirrhosis/progressive hepatic failure
Two subsections for hepatic porphyrias
Acute and chronic
Acute (intermittent) porphyria:
- 2 other types
- Symptoms
- Hereditary coproporphyria, variegate porphyria
2. Acute attacks of GI, neuro/psych, and cardiovascular symptoms
Chronic porphyrias:
- 2 types
- Symptoms
- Porphyria cutanea tarda and hepatoerythropoetic (rare)
2. Sensitivity to sunlight and blisters on the skin
Acute intermittent porphyria:
- Deficiency in what enzyme? (Give both names for the enzyme)
- Leads to accumulation of
- Symptoms
- What can cause an acute attack
- PBG deaminase / HMB synthase
- ALA and PBG
- Abdominal pain and neuro/pysch
- Barbiturates and ethanol (induction of cytochrome p450)
Porphyria cutanea tarda:
- Deficiency in what enzyme
- Chronic disease of __ and __
- Onset?
- Clinical expression is influenced by?
- Leads to accumulation of
- Clinical symptoms?
- Uroporphyrinogen decarboxylase
- Liver and erythroid tissue
- Late; 40s-50s
- Iron overload, exposure to sun, and infection
- Porphyrins
- Skin / urine will turn from red to brown; “werewolf” appearance
What two things can repress ALA synthase?
High carbs and administration of hemin
Patients with photosensitivity may benefit from?
Beta carotene (lessen production of free radicals)
Catabolism of heme occurs in what type of cells? In what two organs, mainly?
~85% get degraded this way, how do the other 15% get degraded?
Reticuloendothelial cells; liver and spleen mainly
From turnover of immature RBCs and cytochromes from extraerythroid tissues
Two parts of heme?
What is globin composed of?
Which of the above answers can be reused?
Porphyrin and iron
Amino acids
Iron and amino acids can be reused; porphyrin cannot
Name 3 functions of carbon monoxide (CO)
Anti-inflammatory, signaling molecule, and vasodilator
What is indirect/unconjugated bilirubin
Orange/yellowish bilirubin that is formed in extra-hepatic tissues
Main difference between conjugated and unconjugated bilirubin
Conjugated is soluble in water so can be secreted in the urine/blood
Tissues in the reticuloendothelial system that these extra-hepatic processes can happen in
Spleen, macrophage, lymph tissue
Formation of indirect bilirubin requires what two things?
What does formation of indirect bilirubin produce?
NADPH and oxygen
Biliverdin, CO, iron, and NADP+
Next step is converting biliverdin to bilirubin - what enzyme does this?
Biliverdin reductase
Bruises change color based on biliverdin/bilirubin - what are the colors of each
Biliverdin- green
Bilirubin - yellow/orange
If indirect bilirubin is formed outside of the liver, what does it require in order to get into the liver?
Facilitated transport via albumin
What are the two sites that albumin has for bilirubin?
High affinity and low affinity sites
What happens once indirect bilirubin enters the liver?
It gets converted to direct/conjugated bilirubin (bilirubin diglucuronide) by bilirubin glucuronyl-transferase which uses 2 UDP-glucuronic acid
How does conjugated bilirubin leave the liver and go into bile?
What is significant about this
Active transport - requires energy
Rate limiting for the entire process of hepatic bilirubin metabolism
Bilirubin glucuronyltransferase can be induced by ?
Phenobarbital
3 inherited unconjugated hyperbilirubinemias?
All 3 of these disorders have to do with a deficiency in which enzyme
Crigler-Najjar 1, Crigler-Najjar 2, and Gilberts syndrome
UDP glucuronyl transferase deficiency
Main difference between the 3 disorders
CN1 is complete deficiency of enzyme-poor survival
CN2 is partial deficiency- medium severity
Gilberts is minimal deficiency- not clinically significant
2 inherited conjugated hyperbilirubinemia disorders?
Both occur when there is a defect in?
Dubin Johnson syndrome (major effect) and Rotors syndrome (minor effect)
Excretion of bilirubin into the bile
Symptoms of dubin johnson?
Symptoms of rotors?
Black pigmented liver
Liver-no pigmentation
In the intestine, what happens to bilirubin
It goes back to unconjugated bilirubin and then converted to urobilinogen which is reabsorbed/reexcreted to the liver and excreted in urine
Small percentage of bilirubin does not convert to urobilinogen, instead it oxidizes to?
Stercobilin (excreted in feces - responsible for brown color)
Identify if the following is describing conjugated or unconjugated bilirubin:
- Soluble in methanol
- Absent in urine
- Excreted in bile
- Unconjugated (conjugated is soluble in water/blood)
- Unconjugated
- Conjugated
Total bilirubin= 1.0 mg/dl
Conjugated bilirubin=?
Unconjugated bilirubin=?
Conjugated= 0-0.2 mg/dl
Unconjugated=0.2-0.6 mg/dl
What is hyperbilirubinemia?
What sign/symptom can it result in
When bilirubin in blood exceeds 1 mg/dl
Jaundice (when serum bilirubin >2 mg/dl
Jaundice:
- Yellowing of what areas of the body?
- How do you measure this?
- What causes the yellowing?
- Skin, nail beds, and sclera
- Van den Bergh reaction
- Deposition of bilirubin
