Heme Synthesis Review Flashcards
List proteins that use heme as prosthetic group.
- -.>Cytochrome P450 enzymes
- ->Catalase: antioxidant enzyme hydrolyzes H2O2
What are the steps of heme synthesis?
1) Committed step – first rate-limiting step:
• Succinyl CoA + glycine –(ALA synthase)→ ALA+ CO2 + CoA-SH
• Committed step of pathway
• Primary rate-limiting step
o Regulated by feedback inhibition: heme, hemin (oxidized heme), and glucose
o Succincyl CoA is from the CAC
• ALA= delta-aminolevulinic acid
2) Condensation forms pyrrole compound:
• ALA + ALA –(ALA dehydrase)→ PBG + 2H2O
• Diagnostic tests measure PBG (Porphobilinogen)
• First 5-membered ring with a nitrogen in it (pyrrole)
3) Condensation forms a linear tetrapyrrole – second rate-limiting step:
• 4 x PBG –(Hydroxymethylbilane synthase)→ 4NH4 + Hydroxymethylbilane
• IF THERE IS AN OBSTRUCTION BEFOR THIS STEP YOU CANNOT MAKE ENOUGH HEME
4) Ring closure:
• Hydroxymethlybilane –(Uroporphyrinogen synthase) → Uroporphyrinogen I + H2O
• Not a porphyrin yet, it is symmetrical
5) Isomerization forms an asymmetrical compound:
• Uroporphyrinogen I –(Uroporphyrinogen cosynthase)→ Uroporphyrinogen III
• Uroporphyrinogen III cosynthase isomerizes the D ring side chains of uroporphyrinogen I to form uroporphyrinogen III.
• Uroporphyrinogen III is the common precursor of chlorophyll, cobalamine, and heme, in organisms that make those compounds.
6) Successive decarboxylation and oxidation reactions: Uropophyrinogen III → → Protoporphryin IX
• Porphyrins are purple and fluorescent (conjugated double bonds)
• All atoms w/in a system share electrons, these are very fluorescent
7) Introduction of Iron:
• Protoporphyrin IX + Fe2+ –(Ferrochetalase)→ Heme
What is the etiology of AIP?
AN ACUTE PORPHYRIA: AIP- Acute Intermittent Porphyria
–>Cause: Genetic insufficiency of liver hydroxymethylbilane synthase
Condensation forms a linear tetrapyrrole – second rate-limiting step:
• 4 x PBG –(Hydroxymethylbilane synthase)→ 4NH4 + Hydroxymethylbilane
• IF THERE IS AN OBSTRUCTION BEFORE THIS STEP YOU CANNOT MAKE ENOUGH HEME
o Congential: inherited in an autosomal dominant manner
What is the pathophysiology of acute intermittent porphyria?
• Result: Decreased heme leads to accumulation of ALA, some PBG accumulation,
o ALA antagonizes GABA receptors in the brain, causing psychosis
o PBG is oxidized to pyrrole which will fluoresce if left out at the bedside
What is the clinical presentation of AIP?
o Psychosis
o Low sodium
o Abnormal neuro exam
o Neuropathic pain–Burning abdominal pain
o High bp, high pulse
o Sometimes hard to breath
o Blistering rash caused by sunlight: PBG oxidize to fluorescent pyrrole compound
How do you diagnose acute intermittent porphyria?
Diagnosis:
o Measure PBG in urine—PBG oxidation will result in fluorescent urine if left out at bedside
o PCR test for gene mutation in family members
How do you treat acute intermittent porphyria?
Treatment:
o Avoid CYP inducers
o Inhibit ALA synthase with IV hemin or glucose
List famous AIP patients
Famous Patients
–>Vincent Van Gogh – Starry Night!!
–>Dracula
• inhibit ALA synthase by ingesting heme? – “I want to drink your blood!”
• Photosensitivity: PBG oxidation to pyrrole – “No, not the light!!”
–>King George III had repeated episodes of abdominal pain and psychotic paranoia
• Condition mismanaged: administration of arsenic induced increased CYP formation
What are the possible etiologies of porphyria cutanea tarda?
AN EXAMPLE OF A NON-ACUTE PORPHYRIAS: Porphyria Cutanea Tarda
–>Cause: Reduced LIVER Uroporphyrinogen decarboxylase activity (one of the enzymes involved in the synthesis of protoporphyrin IX)
–>Acquired phenotypic condition
Associated with liver toxins: alcohol, steroids, and iron
What is the pathophysiology of porphyria cutanea tarda?
Result
o Heme and ALA levels normal due to compensatory regulation
o High levels of abnormal porphyrins accumulate in skin and urine
o leading to liver damage and photosensitive skin rashes, respectively.
• accumulation of abnormal porphyrin derivatives in the liver and skin
o Heme production and ALA levels are normal, because both ALA synthase and hydroxymethylbilane synthase activities are increased through compensatory regulation mechanisms.
• There are no neuropsychiatric symptoms since ALA levels are normal.
How do you diagnose porphyria cutanea tarda?
o Increased urine uroporphyrins
How do you treat porphyria cutanea tarda?
o Regular phlebotomy, which helps to remove the excess porphyrin metabolites from the body. – bleed the patient
o Patients should avoid alcohol, other liver toxins, and excess sunlight.
Describe the pathophysiology of lead poisoning.
–>Lead inhibits ALA dehydrase and ferrochelatase
–> resultant inhibition of heme synthesis in both liver and blood cells
What is the clinical presentation of lead poisoning?
o Abdominal pain
o Confusion
o Anemia
• Clinical profile includes all the symptoms of AIP (due to inhibition of liver ALA dehydrase) plus anemia (due to inhibition of bone marrow heme synthesis)
How do you diagnose lead poisoning?
o Basophilic stippling on blood smear – immature blood cells in circulation
