Heme metabolism flashcards

Question 1

Heme A

Answer 1

In cytochrome A

Question 2

Heme B

Answer 2

In Hb and Mb

Question 3

Heme C

Answer 3

In cytochrome C

Question 4

ALA synthase

Answer 4

Converts succinyl CoA to dALA in mitochondria. 2 isoforms exist

Question 5

2 isoforms od ALA synthase

Answer 5

1. ALAS-E aka ALAS-2 (only in erythrocytes) 2. ALAS-N aka ALAS-1 (nonspecific)

Question 6

What 3 enzymatic steps of heme biosynthesis occur in mitochondria?

Answer 6

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

Question 7

Heme ring system

Answer 7

Derived from 8 residues each of glycine (from cytosol) and succinyl CoA (from Kreb’s cycle). Iron atom also from cytosol.

Question 8

delta-Aminolevulinic Acid Synthase (ALAS)

Answer 8

Rate-limiting and regulated enzyme in heme synthesis pathway

Question 9

Synthesis od ALA synthase (4 steps)

Answer 9

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

Question 10

How is ALAS-E regulated?

Answer 10

By the availability of iron

Question 11

Heme feedback loop

Answer 11

Heme is a feedback inhibitor, repressing transcription of gene and inhibits its own activity in most cells

Question 12

Sideroblastic anemia

Answer 12

X-linked disorder caused by deficiency in ALAS-E

Question 13

What are porphyrias?

Answer 13

Enzyme deficits in synthetic pathway. Caused by breakdown of heme biosynthetic control mechanisms. Classified by cause and symptoms.

Question 14

2 acquired porphyria examples

Answer 14

1. Lead poisoning: Inhibits several enzymes 2. Iron deficiency: protoporphyrin IX excreted in feces (water insoluble)

Question 15

Acute intermittent porphyria

Answer 15

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.

Question 16

Cutaneous porphyrias

Answer 16

Photosensitivity

Question 17

Mixed porphyrias

Answer 17

Both neurologic and skin issues

Question 18

3 steps to catabolize heme-containing proteins

Answer 18

1. Degrade globin 2. Process hydrophobic products or porphyrin ring cleavage 3. Retain/reuse iron

Question 19

3 potential dangers of eliminating heme proteins

Answer 19

1. Free heme is pro-oxidant (inflammatory) 2. Free iron is pro-oxidant 3. Protoporphyrin degredation products pro-oxidants

Question 20

Products of heme catabolism

Answer 20

bilirubin + Fe3+

Question 21

3 reticuloendothelial system steps

Answer 21

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

Question 22

4 stages of bilirubin metabolism

Answer 22

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

Question 23

Unconjugated bilirubin

Answer 23

Non-covalently bound to albumin. High affinity for membrane lipids leading to impairment of cell membrane function, especially in nervous system.

Question 24

Conjugated bilirubin

Answer 24

Very little should be in blood. Excreted by feces and urine.

Question 25

Hepatocellular disease

Answer 25

Makes a 3rd kind of bilirubin which covalently binds to serum albumin

Question 26

Jaundice

Answer 26

Deposition of conjugated and unconjugated bilirubin in skin and sclera. Looks yellow-green color

Question 27

Hyperbilirubinemia

Answer 27

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.

Question 28

Unconjugated hyperbilirubinemia

Answer 28

May be caused by increased production of bilirubin or decreased clearance of bilirubin. All are mutations of glucuronyl transferase gene.

Question 29

Crigler-Najjar syndrome

Answer 29

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.

Question 30

Kernicterus

Answer 30

Bilirubin-induced brain damage

Question 31

Gilbert’s syndrome

Answer 31

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.

Question 32

2 main reasons for anemia

Answer 32

1. Under-production of mature RBCs 2. Loss of RBCs

Question 33

5 causes of underproduction of RBCs

Answer 33

1. Bone marrow disease 2. Deficiency in folic acid and/or vitamin B12 3. Underproduction of Hb 4. Underproduction of heme 5. Iron deficiency

Question 34

Idiopathic aplastic anemia

Answer 34

Bone marrow fails to properly make RBCs. Fanconi’s syndrome and Aase syndrome are 2 known reasons for this.

Question 35

Fanconi’s syndrome

Answer 35

Abnormal gene that damages cells and keeps them from repairing DNA resulting in idiopathic aplastic anemia

Question 36

Aase syndrome

Answer 36

Poor development of bone marrow resulting in idiopathic aplastic anemia

Question 37

Megaloblastic anemia

Answer 37

Type of vitamin deficiency anemia due to deficiency in folic acid or B12

Question 38

Pernicious (megaloblastic) anemia

Answer 38

Type of vitamin deficiency anemia due to malabsorbtion of vitamin B12 in GI tract

Question 39

Hypochromic anemia

Answer 39

Less Hb deposited in cells

Question 40

Iron-deficiency anemia

Answer 40

Most common form from blood loss, poor absorbtion, diet, lead poisoning (lead replaces iron ions in proteins).

Question 41

Hemolytic anemia

Answer 41

Premature destruction of RBCs. Could be for intrinsic (genetic) reasons or extrinsic.

Question 42

Thallasemias

Answer 42

Hypochromic and microcytic anemias

Question 43

Immune hemolytic anemia

Answer 43

RBCs destroyed by immune system (could happen with Rh factor difference between mother and fetus)