Synthesis Of Heme

Question 1

Porphyrins

Answer 1

. Cyclic compounds
. Bind to metal ions (ferrous or ferric ions)
. Formed by linkage of 4 pyrrole rings through methenyl bridges
. Pigmented

Question 2

Ferrous

Answer 2

Fe2+

Question 3

Ferric

Answer 3

Fe3+

Question 4

How many types of porphyrins are there and what ones are important to humans?

Answer 4

4 types, type III important because it contains asymmetric substitution of ring D
. Type I may be synthesized in disease process

Question 5

Porphyringogens

Answer 5

. Porphyrin precursor
. Colorless
. Intermediates heme biosynthesis
. Exists in chemically reduced forms

Question 6

Heme

Answer 6

. Final product of porphyrin synthetic pathway

Question 7

What protoporphyrin is important to humans and why?

Answer 7

Type IV because one Fe2+ in center is what heme is

Question 8

Heme biosynthesis sites

Answer 8

Liver and erythrocyte- producing cells of bone marrow

Question 9

Where do reaction steps of heme biosynthesis occur?

Answer 9

. Initial and last steps of porphyrin formation are in mitochondria
. Intermediate steps in cytosol

Question 10

Hemin

Answer 10

. End product inhibitor
. Inhibits formation of aminolevulinic acid (ALA) by decreasing ALA synthase enzyme synthesis
.Overall heme synthesis inhibited because not enough ALA synthase to make ALA for synthesis
. Result of oxidation of Fe2+ to Fe3+ when excess heme accumulates

Question 11

Drugs that increase ALA synthase activity

Answer 11

Drugs that affect Heme-containing microsomes cytochrome P-450 mono-oxygenase system (barbiturates, sedatives, estrogens)

Question 12

How do drugs using microsomal cytochrome P450 mono-oxygenase system increase ALA synthase activity?

Answer 12

. Through de-repression
. Major pathway for hydroxylation and detoxification of aromatic/aliphatic compounds
. Drugs need to be metabolized via this pathway so more cytochrome P450 is needed and contains heme
. P450 synthesis inc., more heme consumed in lever, less free heme available, inc. ALA synthase activity and dec. hemin

Question 13

What does lead inhibit and how?

Answer 13

. Formation of porphobilinogen and formation of heme
. Inhibits ALA dehydratase elevating ALA and anemia
. Inhibits ferrochelatase

Question 14

ALA dehydratase

Answer 14

Enzyme that catalyze formation of porphobilinogen

. Inhibited by lead

Question 15

Ferrochelatase

Answer 15

Enzyme that enhances the incorporation of Fe2+ into protoporphyrin IX

Question 16

Porphyria

Answer 16

. Autosomal dominant (exp. congenital one that’s recessive) Disorders of specific enzymes in heme biosynthesis
. Often autosomal dominant disorders
. Nonspecific
. Decreased heme synthesis
. Increased ALA synthase and heme intermediate production prior to the mutated enzyme

Question 17

How are porphyria classified?

Answer 17

Hepatic or erythopoietic depending on whether enzyme deficiency occurs in RBC precursors in bone marrow or liver

Question 18

ALA and porphobilinogen accumulation symptoms

Answer 18

Abdominal pain and neuropsychiatric disturbances

Acute intermittent porphyria has these

Question 19

Photosensitivty cause

Answer 19

. Enzyme defects that lead to accumulation of tetrapyrrole intermediates
. Porphyrin-mediated formation of superoxide radicals (ROS) from oxygen
. ROS damages membranes and releases lysosomes

Question 20

Photosensitivity symptoms

Answer 20

. Skin itches and burns when exposed to visible light

Question 21

Porphyria treatments

Answer 21

. IV hemin injection (inhibits ALA synthase eventually dec. intermediates that built up)
. Avoidance of sunlight
. Ingestion of beta-carotene (free radical scavenger) help when experiencing photosensitivity

Question 22

Porphyrin accumulation cutaneous symptoms

Answer 22

. Skin or urine that is red to brown in natural light but pink to red in fluorescent light

Question 23

Lead poisoning

Answer 23

. Elevated ALA in urine
. Can cause anemia is lead level >40 mg/dL
. Affect IO, attention span, and academic achievement in kids that can’t be corrected
. Inc. protopoyphyrin IX in blood bc Fe 2+ can’t be put on to form full heme

Question 24

Lead level cutoff for ages 1-5

Answer 24

5 micrograms/dL

Question 25

Signs and symptoms of lead poisoning

Answer 25

. Stomach aches, cramping, constipation and diarrhea . Nausea. Vomiting . Persistent unexplained fatigue . Headache . Muscle weakness . Long-lasting effects, coma, and death is leve >80 mcg/dL

Question 26

T/F patients w/ chronic low levels of lead exposure have no obvious symptoms

Answer 26

T

Question 27

What therapy is used in attempt to remove lead?

Answer 27

Chelation therapy

Question 28

Porphyria cutanea tarda

Answer 28

. Chronic, uroporphyrinogen decarboxylase deficiency (UROD) . Uroporphyrin accumulates in urine . Most common, usually acquired . Those w/ UROD genetic deficiency (familial PCT) won’t have symptoms unless large amts porphyrins build in liver then disease becomes active . Photosensitive . Onset: 4-5th decade of life

Question 29

Acute intermittent porphyria

Answer 29

. Acute, porphobilinogen deaminase deficiency . Porphobilinogen and ALA accumulates in urine . Urine darkens on exposure to light or air . NOT photosensitive . 2nd most common, autosomal dominant, 5-10 of every 10,000 have it

Question 30

Rate limiting step in heme synthesis

Answer 30

. Glycine + succinyl CoA form ALA via ALA synthase

Question 31

ALA

Answer 31

Gamma aminolevulinic acid

Question 32

Heme pathway

Answer 32

1. Gly + succinyl CoA -> ALA via ALA synthase 2. ALA x2 -> porphobilinogen via dehydration rxn 3. Porphobilinogen x4 -> uroporphyrinogen III via condensing rxn 4. Uroporphyrinogen II -> protoporphyrin IX 5. Fe 2+ introduced to make heme via ferrochelatase

Question 33

How to test for porphyria

Answer 33

. Quantifying different metabolites | . Screening at genetic level

Question 34

Porphyria symptoms

Answer 34

. Abdominal pain, neuropsychiatric disturbances (anxiety to delirium) . Photosensitivity

Question 35

Porphyria cutanea tarda clinical expression influenced by __

Answer 35

``` . Fe . Sunlight . alcohol . Estrogen . Hep B/C, HIV . Smoking ```

Question 36

What can predispose people to PCT

Answer 36

Hemochromatosis (Fe overload disorder)

Question 37

PCT symptoms

Answer 37

. Chronic recurring blisters on sun exposed areas . Skin sensitive to minor injury . Hair growt on face and other sun exposed areas increases . Mild liver function abnormalities . Cirrhosis or liver cancer may develop

Question 38

Acquired PCT treatments

Answer 38

. Avoiding alcohol | . Phlebotomy

Question 39

Acute hepatic porphyrias

Answer 39

``` . ALA dehydratase deficiency porphyria . Acute intermittent porphyria . Hereditary coproporphyria . Variegate porphyria . GI symptoms, neuropsychiatric, motor, photosensitivity ```

Question 40

AIP treatment

Answer 40

. Medical support . Glucose . Injection of hemin to dec. ALA synthase synthesis . Avoid barbiturates, alcohol

Question 41

Erthyropoietic porphyrias

Answer 41

. Congenital erythropoietic porphyria . Causes skin rashes and blisters . May be at risk for hepatobiliary disease