Heme metabolism flashcards
Heme A
In cytochrome A
Heme B
In Hb and Mb
Heme C
In cytochrome C
ALA synthase
Converts succinyl CoA to dALA in mitochondria. 2 isoforms exist
2 isoforms od ALA synthase
- ALAS-E aka ALAS-2 (only in erythrocytes) 2. ALAS-N aka ALAS-1 (nonspecific)
What 3 enzymatic steps of heme biosynthesis occur in mitochondria?
- ALA-synthase converting succinyl CoA to dALA (succinyl CoA + glycine = heme) 2. Protoporphyrin-III oxidase making protoporphyrin IX 3. Ferrochelatase by oxidation mechanism inserting iron ion into polyporphyrin ring to make heme All other enzymatic steps are in cytosol
Heme ring system
Derived from 8 residues each of glycine (from cytosol) and succinyl CoA (from Kreb’s cycle). Iron atom also from cytosol.
delta-Aminolevulinic Acid Synthase (ALAS)
Rate-limiting and regulated enzyme in heme synthesis pathway
Synthesis od ALA synthase (4 steps)
- ALAS synthesized in cytosol with N-terminal signaling sequence directing to mitochondrion 2. Using ATP chaperone protein keeps ALA synthase unfolded to pass through mitochondrial membrane 3. N-terminal sequence cleaved by protease in matrix 4. Another chaperone catalyzes correct folding in 2nd ATP-dependent process
How is ALAS-E regulated?
By the availability of iron
Heme feedback loop
Heme is a feedback inhibitor, repressing transcription of gene and inhibits its own activity in most cells
Sideroblastic anemia
X-linked disorder caused by deficiency in ALAS-E
What are porphyrias?
Enzyme deficits in synthetic pathway. Caused by breakdown of heme biosynthetic control mechanisms. Classified by cause and symptoms.
2 acquired porphyria examples
- Lead poisoning: Inhibits several enzymes 2. Iron deficiency: protoporphyrin IX excreted in feces (water insoluble)
Acute intermittent porphyria
Type of neurologic porphyria. (deficiency in E3). Permanent nerve damage, fatal. Caused by elevated ALA (from de-repression of ALA synthase gene) which binds to GABA receptors. Treat by injection of hemin (form of heme) which repress transcription. Phenobarbital induces ALA-synthase which aggravates disease.
Cutaneous porphyrias
Photosensitivity
Mixed porphyrias
Both neurologic and skin issues
3 steps to catabolize heme-containing proteins
- Degrade globin 2. Process hydrophobic products or porphyrin ring cleavage 3. Retain/reuse iron
3 potential dangers of eliminating heme proteins
- Free heme is pro-oxidant (inflammatory) 2. Free iron is pro-oxidant 3. Protoporphyrin degredation products pro-oxidants
Products of heme catabolism
bilirubin + Fe3+
3 reticuloendothelial system steps
- In RBCs heme degraded by heme oxygenase which requires oxygen and NADPH. Produces CO (only endogenous source). Fraction of CO exhaled and can be used as measure of heme being degraded in individual 2. Iron released in ferric form and binds to ferritin 3. Biliverdin reduced by bilverdin reductase to bilirubin IX using NADPH
4 stages of bilirubin metabolism
- Uptake from circulation (where it needs albumin transporter) by liver 2. Intracellular storage 3. Conjugation with glucuronic acid (to make it soluble) 4. Biliary excretion
Unconjugated bilirubin
Non-covalently bound to albumin. High affinity for membrane lipids leading to impairment of cell membrane function, especially in nervous system.
Conjugated bilirubin
Very little should be in blood. Excreted by feces and urine.
