Metabolism: Heme Flashcards
What tissues have the highest rates of heme biosynthesis?
liver => cytochromes
bone marrow => hemoglobin
Describe the rate limiting reaction of heme synthesis.
First step; occurs in mitochondria
succinyl-CoA + Glycine => ALA (d-aminolevullinic acid)
via ALA synthase
Differentiate between porphyrinogens and porphyrins.
porphyrinogen - no double bonds; colorless;
porphyrins - double bonds; colored, fluorescent, photodegradable
How is ALA synthase regulated?
allosteric negative feedback by heme (works on ALAS1 in the liver)
Describe the 2 kinds of ALAS.
ALAS1 = all tissues ALAS2 = bone marrow erythroid cells
Define porphyrias.
diseases caused by partial deficiency of one of the enzymes involved in heme biosynthesis
- caused by increased heme metabolic intermediates
- typically 50% enzyme activity is present (haploinsufficiency)
Describe the inheritance pattern of acute intermittent porphyria.
- autosomal dominant
- incomplete penetrance (most people who inherit the trait never have symptoms)
What are some symptoms of acute intermittent porphyria?
- nerve damage
- acute attacks of abdominal pain
- tachycardia
- HTN
- muscle weakness
- tremors
- seizures
- agitation/hallucinations
What is the etiology of acute intermittent porphyria?
deficiency in porphobilinogen deaminase enzyme
- leads to increased ALA and PBG
- leads to decreased heme synthesis
- diminished feedback inhibition of heme on ALAS1
- increased ALAS1 activity => more ALA and PBG formed => exacerbation
What is the treatment of acute intermittent porphyria?
- low glucose diet, OH, steroids, and other drugs can increase ALAS and exacerbate the disease
- tx: glucose infusion, IV heme to suppress ALAS
What other porphyrias exhibit acute attacks like acute intermittent porphyria?
- variegate
- hereditary coproporphyria
==> causes skin sensitivity
Describe the inheritance pattern of variegate porphyria.
- autosomal dominant
- incomplete penetrance
- founder effect of South African whites
What is the etiology of variegate porphyria?
- deficiency in protoporphyrinogen oxidase
- increased levels of protophorphyrinogen III and coprotoporphyrinogen III in liver
- reduced heme synthesis
- increased ALAS activity
- increased ALA and PBG
- proto and coproto deposits in the skin => converted to porphyrins by light => further photodegradation => O2 => tissue degradation
What are some symptoms of variegate porphyria?
blisters
skin lesions
How does lead affect heme synthesis?
- inhibits 3 enzymes
- elevated ALA, coproporphryinogen, protoporphyrinogen III
Which 3 enzymes are inhibited by lead?
- ALA dehydratase
- coproporphyrinogen oxidase
- ferrochetalase
What is the diagnostic marker for lead poisoning?
increased levels of protoporphyrinogen in RBCs
Where does heme catabolism take place?
RBCs are phagocytized by RES cells (macrophages in spleen, liver, bone marrow)
Tracks the steps in heme catabolism leading to the formation of unconjugated bilirubin.
- hemoglobin => heme + globin
- heme => Fe (reutilized) + biliverdin
- biliverdin => unconjugated bilirubin
- unconjugated bilirubin-albumin => liver, active absorption
Describe the reaction by which bilirubin is conjugated.
2 glucuronic acids (UDP-glucuronate) are attached to bilirubin
What makes urine yellow?
urobilin
What is the cause of hyperbilirubinemia?
- > 1mg/dL bilirubin in serum
- either conjugated or unconjugated accumulation
- diffuses into tissue => yellow
- jaundice (>2-2.5 mg/dL)
What are clinical consequences of hyperbilirubinemia?
- conjugated is benign
- unconjugated => toxic encephalopathy after > 25 mg/dL (kernicterus)
List 4 causes of jaundice.
- hemolysis
- biliary obstruction
- hepatitis/cirrhosis
- neonatal
