Flashcards in Heme metabolism flashcards Deck (43):
In cytochrome A
In Hb and Mb
In cytochrome C
Converts succinyl CoA to dALA in mitochondria. 2 isoforms exist
2 isoforms od ALA synthase
1. 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?
1. 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)
1. 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
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
1. 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.
Both neurologic and skin issues
3 steps to catabolize heme-containing proteins
1. Degrade globin 2. Process hydrophobic products or porphyrin ring cleavage 3. Retain/reuse iron
3 potential dangers of eliminating heme proteins
1. 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
1. 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
1. 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
Non-covalently bound to albumin. High affinity for membrane lipids leading to impairment of cell membrane function, especially in nervous system.
Very little should be in blood. Excreted by feces and urine.
Makes a 3rd kind of bilirubin which covalently binds to serum albumin
Deposition of conjugated and unconjugated bilirubin in skin and sclera. Looks yellow-green color
Elevation in either unconjugated or both conjugated and unconjugated bilirubin. Could be caused by hepatitis or cirrhosis. If unconjugated alone increased comes from inherited or acquired disorders affecting bilirubin uptake or glucuronidation by liver.
May be caused by increased production of bilirubin or decreased clearance of bilirubin. All are mutations of glucuronyl transferase gene.
Rare, autosomal recessive unconjugated hyperbilirubinemia caused by lucuronyl transferase deficiency. Bilirubin cannot be conjugated and stays in blood causing kernicterus (bilirubin-induced brain damage). Type I has severe jaundice and neurologic impairment. Type II causes lower serum bilirubin concentration and no neurologic impairment.
Bilirubin-induced brain damage
Neonatal jaundice. Temporary decrease in glucuronyl transferase deficiency which resolves itself as liver matures after birth. Treated with exposure to UV light which converts bilirubin to soluble form.
2 main reasons for anemia
1. Under-production of mature RBCs 2. Loss of RBCs
5 causes of underproduction of RBCs
1. Bone marrow disease 2. Deficiency in folic acid and/or vitamin B12 3. Underproduction of Hb 4. Underproduction of heme 5. Iron deficiency
Idiopathic aplastic anemia
Bone marrow fails to properly make RBCs. Fanconi's syndrome and Aase syndrome are 2 known reasons for this.
Abnormal gene that damages cells and keeps them from repairing DNA resulting in idiopathic aplastic anemia
Poor development of bone marrow resulting in idiopathic aplastic anemia
Type of vitamin deficiency anemia due to deficiency in folic acid or B12
Pernicious (megaloblastic) anemia
Type of vitamin deficiency anemia due to malabsorbtion of vitamin B12 in GI tract
Less Hb deposited in cells
Most common form from blood loss, poor absorbtion, diet, lead poisoning (lead replaces iron ions in proteins).
Premature destruction of RBCs. Could be for intrinsic (genetic) reasons or extrinsic.
Hypochromic and microcytic anemias