Heme Synthesis: Porphyrias Flashcards
Objectives: i.Describe in detail ALA synthaseand ALA dehydratasereactions ii.Outline hemesynthesis starting from glycineand succinylCoAto the formation of heme iii.Distinguish between the different regulatory processes of hemesynthesis in the liver and in the erythroidcells iv.Explain how pyridoxine deficiency affects hemesynthesis v.Discuss the effects of lead poisoning on hemesynthesis vi.Categorize the different types of porphyriasbased on clinical manifestations such as abdominal pain,
What are the major tissues for heme synthesis?
Bone Marrow
Liver
Besides hemoglobin and myoglobin, heme can act as a prosthetic group of what enzymes?
Cyctochromes P450
Cytochromes of ETC
Catalase
Nitric Oxide
The four pyrrole rings of Heme are linked via what?
Methenyl Bridges
Which amino acid is used for heme synthesis?
Glycine
In regards to heme synthesis, succinyl CoA and glycine are used to form what?
Gamma-aminolevulinic acid (ALA)
What are the two isoforms of ALA? Where are they found? What regulates them?
ALA synthase 1 - liver
ALA synthase 2 - RBC
ALA 1 is inhibited by heme
ALA 2 is inhibited by low intracellular iron
Both require PLP, which can be inhibited by Isoniazid
Regarding heme syntheis, 2 ALA’s form what in cytosol?
Porphobilinogen
What is used to form the linear hydroxymethylbilane (HMB)
4 porphobilinogens
Defiencies of ALAS2 leads to what disease?
Sideroblasticic anemia (x-linked)
The gene for ALAS2 is on which chromosome?
X-chromosome
Which enzyme combines to ALA to form porphobilinogen? What inhibits this enzyme?
ALA dehydrate (aka Porphobilinogen synthase)
Inhibited by: Lead
Note: Enzyme requires Zinc as cofactor
Which reaction does the PBG deaminase, or also known as HMB synthase, catalyze? What disease is related to the deficiency of this enzyme?
Combines 4 porphobilinogen to form hydroxymethylbilane.
Disease: Acute Intermittent Porphoria (NOT photosensitive)
Which of the diseases are related to severe photo-sensitivity in heme synthesis? Which enzyme is deficient?
1) Congenital Erythropoietic porphoria
Enzyme: UPG-3-synthase
2) Porphyria Cutanea Tarda
Enzyme: UPG-Decarboxylase
3) Erythropoietic Protophyria
Enzyme: Ferrochelatase
What is the treatment for porphyrias?
- Intravenous injection of glucose
- Hemin
Why is it a bad idea to administer barbituates to calm the patient down in Acute AIP?
Can lead to increased CYP450 synthesis and can worsen situation
