Heme Synthesis And Breakdown Flashcards
Heme has a heterocyclic ____________ with _______ in the center
Heme has a heterocyclic PORPHYRIN with IRON present in the center
What are two key features of the porphyrin ring?
- Have four 5-membered rings with nitrogen
2. Iron in the center is in a ferrous state. Fe2+
What are the four 5 membered rings called?
Pyrrole ring
Where in the body is heme synthesized? A
And in what parts of the cell?
In liver and erythroid cells of bone marrow.
Phase 1 and 3 occur in mitochondria
Phase 2 occurs in cytosol
Defects in one or more stages of heme synthesis cause what type of diseases?
Porphyrias
ALA synthase needs what as a cofactor?
B6, pyridoxal phosphate
There are two isoforms of ALA synthase. Describe the difference
ALAS I: ubiquitous, inhabited by heme
ALAS II: (only in erythroid cells of bone marrow) has an iron response element in mRNA, presence of iron increases its transcription and translation.
How does lead poisoning work?
Lead inactivates ALA dehydrogenase and ferrochelatase.
Leads to accumulation of LAL and protoporphyrin.
ALA is neurotoxic because it resembles GABA
Causes anemia
Impacts energy production as cytochromes are not synthesized.
What is porphyria
- inherited metabolic disorder
- caused by defects in heme synthesis
- two types: acute hepatic»neurological symptoms; erythropoietic»skin, photosensitivity
What is deficienct in ACUTE INTERMITTENT PORPHYRIA
What does it cause
Type of porphyria
PBG deaminase
Causes a build up of PBG and ALA»neurological dysfunction
Hepatic
AUTOSOMAL DOMINANT
Congenital erythropoietic porphyria
Defective enzyme
What does it cause
Type
Uroporphyrinogen III synthase (erythrocytes)
Accumulation of uroporphyrinogen I and fluorescent red product of air oxidation»>red urine and teeth
Erythropoietic
AUTOSOMAL RECESSIVE
Porphyria cutaneous tarda (PCT)
Defective enzyme
What does it cause
Type
Uroporphyrinogen decarboxylase
Accumulation of uroporphyrinogen III»>photosensitivity, red wine colored urine.
Most common in US,
Hepatoerythropoietic
AUTOSOMAL DOMINANT
Variegate porphyria
Defective enzyme
What does it cause
Type
Protoporphyrinogen IX oxidase
Photosensitivity and neurological symptoms
Hepatic
AUTOSOMAL DOMINANT
What system degrades heme, and how often do RBC break down
Reticulo-endothelial system
Every 120 days
What enzyme completes the first step in heme degradation?
What is synthesized?
Heme oxygenase»>removes the bridge between pyrrole rings of heme.
This enzyme requires oxygen.
Carbon monoxide is released,
Fe2+»>Fe3+
Bilirubin is synthesized
Free bilirubin (unconjugated/indirect) is insoluble. How does it get to the liver?
Albumin binds it and carries to the liver.
Once in the liver, what happens to bilirubin?
They are conjugated»>2 UDP glucose are added to bilirubin by BILIRUBIN UDP GLUCURONYLTRANSFERASE to make bilirubin diglucuronide=more soluble.
What happens to bilirubin diglucuronide?
Transported to gall bladder for bile storage.
Is released into small intestine in response to food.
Microbes reduce it to bilirubin then to urobilinogen
Urobilinogen can do two things
Can be reabsorbed and transported to kidney and made into urobilin which makes urine yellow.
Can be unreabsorbed and reduced by microbes to sterocilin, which makes feces brown.
What are the three classes of jaundice
Prehepatic
Intrahepatic
Posthepatic
Describe prehepatic jaundice
Due to increased production of unconjugated BR.
Blood is being lysed faster than the body can deal with the heme.
Findings: elevated levels of conjugated BR
- normal ALT/AST because liver is functioning normally.
- urobilinogen present in urine
- direct BR not found in urine
Describe intrahepatic jaundice
Caused by impaired hepatic uptake, conjugation, or secretion of conjugated BR.
Generalized hepatic dysfunction
Findings: variable increase in unconjugated and conjugated BR
- increase in serum ALT/AST»>indicate liver Disfunction
- conjugated BR in urine
Describe post hepatic jaundice
Problems with BR excretion
Caused by obstruction to biliary drainage
Findings: elevated blood levels of conjugated BR
- conjugated BR is present in urine (dark)
- no urobilinogen in urine
- no stercobilin in feces (pale stool)
Describe neonatal jaundice
- newborns yellow
- UDP-GT enzyme not fully functional
- lot of fetal hemoglobin destruction
- treat with blue fluorescent light
- forms soluble dimers
Crigler-najjar syndrome
Deficiency of UDP-GT (cannot make bilirubin soluble
Type I- complete absence of the gene»>severe hyperbilirubinemia.
BR accumulates in brain of babies»brain damage, encephalopathy/kernicturus
Therapy: blood transfusion, phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, liver transplant.
Type II-UDP-GT is less active (10%) because of mutation
Gilbert syndrome
Common
Reduced activity of UDP-GT, formed normally, just not fully functional.
Occasional jaundice with stress or alcohol.
Hepatitis
V general term for inflammation of the liver
Can be caused by viral infection, alcoholic cirrhosis, liver cancer
Cause increased level of unconjugated and conjugated BR in blood
Dark tea colored ruin
Sclera icterus
