"Molecular & Cellular Princ Med Heme Synthesis Mark Schmitt" GABY

Question 1

What is a porphyrin ring constructed from?

Answer 1

4 pyrrole rings (tetra pyrrole)

Question 2

All heme proteins contain a porphyrin ring structure with ___ as the chelated metal

Answer 2

iron

Question 3

Protoporphyrins contain 8 side chains that are modified with different groups:

Answer 3

4 methyl (M)
2 vinyl (V)
2 propionate (P)

Question 4

How many isomeric forms do protoporphyrins have?

Answer 4

15

Question 5

The protoporphyrin isomer in heme is ___

Answer 5

protoporphyrin IX

Question 6

Heme is ___

Answer 6

Protoporphyrin IX chelated with iron (Fe 2+)

Question 7

What are the differences among heme a, b and c?

Answer 7

Heme a –> modification of the number 2 vinyl group

Heme b –> no modifications

Heme c –> covalently bound to cysteine residues through the 2 vinyl groups

Question 8

Is heme the prosthetic group for hemoglobin and myoglobin only?

Answer 8

NO (see handout for list; 9 more proteins and enzymes are listed)

Question 9

What are the two simple precursors of heme?

Answer 9

glycine and succinyl CoA

Question 10

Fill in the product, enzyme that catalyzes the reaction below, and reaction location:

glycine + succinyl CoA

Answer 10

product: ALA
enzyme: ALA synthase
location: mitochondria

Question 11

Fill in the product and enzyme that catalyzes the reaction below, and reaction location:

ALA + ALA

Answer 11

product: PBG
enzyme: PBG synthase (ALA dehydrase)
location: cytosol

Question 12

Fill in the product and enzyme that catalyzes the reaction below, and reaction location:

4 x PBG

Answer 12

product: URO I
enzyme: URO synthase (PBG deaminase)
location: cytosol

Question 13

Fill in the product and enzyme that catalyzes the reaction below, and reaction location:

URO I … (hint: isomerization)

Answer 13

product: URO III
enzyme: URO III co-synthase
location: cytosol

Question 14

Fill in the product and enzyme that catalyzes the reaction below, and reaction location:

URO III … (hint: decarboxylation)

Answer 14

product: COPRO III
enzyme: URO decarboxylase
location: cytosol

Question 15

Fill in the product and enzyme that catalyzes the reaction below, and reaction location:

COPRO III … (hint: oxidation)

Answer 15

product: PROTO IX
enzyme: COPRO oxidase
location: mitochondrial matrix

Question 16

Fill in the product and enzyme that catalyzes the reaction below, and reaction location:

PROTO IX … (hint: oxidation)

Answer 16

product: protoporphyrin IX
enzyme: PROTO oxidase
location: mitochondrial matrix

Question 17

Fill in the product and enzyme that catalyzes the reaction below, and reaction location:

protoporphyrin IX + Fe 2+

Answer 17

product: protoheme IX (heme)
enzyme: ferrochelatase
location: mitochondria

Question 18

Where does lead inhibition occur in the heme synthesis pathway?

Answer 18

2nd step: (ALA + ALA = PBG)

Last step: (protoporphyrin IX + Fe 2 = heme)

Question 19

What 2 molecules would be found in the serum as the result of lead inhibition in the heme synthesis pathway?

Answer 19

ALA and COPRO III

Question 20

What are the two sites of heme synthesis regulation?

Answer 20

liver and erythroid cells

Question 21

Is heme regulated the same way in the liver and erythroid cells?

Answer 21

NO (see p. 49)

Question 22

Define porphyria

Answer 22

Genetic deficiency in heme metabolism

Question 23

List 4 types of porphyrias

Answer 23

1. erythropoietic
   a. congenital
   b. protoporphyria
2. hepatic
   a. acute intermittent
   b. cutanea tarda

Question 24

Describe the molecular and clinical consequences of the 2 erythropoietic porphyrias

Answer 24

a. congenital (autosomal recessive; deficiency in URO III co-synthase)
- accumulation of URO I and COPRO I
- anemia
- skin ulcers
- red urine
- reddish-brown fluorescent teeth
- increased body hair growth

b. protoporphyria ( autosomal dominant; deficiency in ferrochelatase)
- similar symptoms as congenital, but milder

Question 25

Describe the molecular and clinical consequences of the 2 hepatic porphyrias

Answer 25

a. acute intermittent (most common; autosomal dominant; deficiency in PBG)
- accumulation of ALA and PBG
- asymptomatic until eruption from exposure to chemicals such as estrogens, barbiturates, steroids and alcohol
- obscure symptoms (red urine, neurologic dysfunction, diarrhea, abd pains and vomiting)

b. cutanea tarda (sporadic or autosomal dominant; deficiency in URO decarboxylase)
- asymptomatic until liver disorder (ex from alcohol or contraceptive pills
- photosensitivity
- depletion of iron leads to remission

Question 26

Acute intermittent porphyria is caused by a deficiency in:

a. URO synthase (PBG deaminase)
b. PBG synthase (ALA dehydrase)
c. ornithine transcarbamoylase
d. arginase
e. hypoxanthine-guanine phosphoribosyl transferase

Answer 26

a. URO synthase (PBG deaminase)

Question 27

Heme:

a. has side chains in the order MPMPMVVM
b. take 7 ATPs to synthesize
c. is recycled about 85%
d. is synthesized from 8 succinyl-CoAs and 8 glycines
e. is a tetrapyrrole with a Co2+ in the middle

Answer 27

d. is synthesized from 8 succinyl-CoAs and 8 glycines

Question 28

Heme biosynthesis is regulated at the level of:

a. ALA synthase
b. a-ketoglutarate dehydrogenase
c. ferrochelatase
d. COPRO oxidase
e. ubiquinol-cytochrome c oxidoreductase

Answer 28

a. ALA synthase

Question 29

Heme is a prosthetic group in all of the following except:

a. catalase
b. ferrochelatase
c. hemoglobin
d. nitric oxide synthase
e. neutrophil NADPH oxidase

Answer 29

b. ferrochelatase

Question 30

In heme synthesis

A. the last step is the insertion of cobalt
B. all the reactions occur in the mitochondria, the main site of heme use
C. there are 15 different isomeric forms that could be made, but the body makes protoporphyrin VIII
D. the body wastes lots of energy since it can absorb heme from the diet
E. the rate limiting step is the enzyme delta-aminolevulinate synthase

Answer 30

E. the rate limiting step is the enzyme delta-aminolevulinate synthase (ALA)

Question 31

Lead poisoning is a major problem among children in the US. Many of the effects of lead poisoning are caused by

A. inhibition of the urea cycle
B. inhibition of nucleotide synthesis which is extremely important in children
C. inhibition of the degradation of heme leading to jaundice
D. inhibition of heme synthesis leading to a induced porphyria
E. inhibition of branched chain keto acid dehydrogenase

Answer 31

D. inhibition of heme synthesis leading to a induced porphyria

Question 32

The enzyme PBGD (porphobilinogen deaminase or uropophyrinogen synthase)

A. is deficient in the disease acute intermittent porphyria
B. is located in the mitochondria
C. is the direct cause of most cases of jaundice
D. condenses five pyrrole rings to make uroporphrinogen
E. is deficient in the disease protoporphyria

Answer 32

A. is deficient in the disease acute intermittent porphyria

Question 33

The order of side groups from one to eight on protoporphyrin IX are

A. Methyl, Vinyl, Methyl, Vinyl, Methyl, Propionate, Propionate, Methyl
B. Methyl, Methyl, Vinyl, Methyl, Vinyl, Methyl, Propionate, Propionate
C. Methyl, Methyl, Vinyl, Vinyl, Methyl, Propionate, Propionate, Methyl
D. Methyl, Vinyl, Methyl, Vinyl, Methyl, Propionate, Propionate
E. Methyl, Propionate, Propionate, Methyl, Vinyl, Methyl, Vinyl, Methyl

Answer 33

A. Methyl, Vinyl, Methyl, Vinyl, Methyl, Propionate, Propionate, Methyl

Question 34

The structure of heme (protoporphyrin IX) contains

A. four pyrrole rings
B. three methyl, three vinyl and two propionate groups
C. An Fe2+ in the center of the porphyrin ring
D. A and C
E. All of the above

Answer 34

D. A and C

Question 35

Which of the following is false:

A. The synthesis of heme requires two simple precursors, glycine and succinyl coenzyme A
B. Heme is the prosthetic group for hemoglobin, myoglobin, catalase, and nitric oxide synthase
C. In liver cells the main target of control for heme biosynthesis is porphobilinogen synthase (ALA dehydrase)
D. Uroporphyrinogen synthase and Uroporphyrinogen III cosynthase are located in the cytosol
E. With out uroporphyrinogen III cosynthase only uroporphyrinogen I is formed

Answer 35

C. In liver cells the main target of control for heme biosynthesis is porphobilinogen synthase (ALA dehydrase)

Question 36

You were watching ER last night on TV and a patient came in complaining of abdominal A pains and vomiting, and doesn’t know his name. The patient mentions that he has been drinking. Dr. Susan Lewis says that he has just drank too much alcohol and orders a urine and blood test to see how much alcohol he drank, but Carter notices that his urine is red and exclaims that the patient has a porphyria. The urine test reveals high levels of ALA and PBG. This patient most probably has:

A. Acute intermediate porphyria, a deficiency of PBG deaminase (uroporphyrinogen synthase)
B. Alcohol poisoning, not a porphyria
C. Protoporphyria, a deficiency of ferrochelatase
D. Protoporphyria, a deficiency of uroporphyrinogen III synthase
E. Porphyria cutanea tarda, a deficiency of uroporphyrinogen decarboxylase

Answer 36

A. Acute intermediate porphyria, a deficiency of PBG deaminase (uroporphyrinogen synthase)