"Molecular & Cellular Princ Med Heme Synthesis Mark Schmitt" GABY Flashcards by B -

Q

What is a porphyrin ring constructed from?

A

4 pyrrole rings (tetra pyrrole)

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Q

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

A

iron

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Q

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

A

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

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Q

How many isomeric forms do protoporphyrins have?

A

15

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Q

The protoporphyrin isomer in heme is ___

A

protoporphyrin IX

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Q

Heme is ___

A

Protoporphyrin IX chelated with iron (Fe 2+)

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Q

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

A

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

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Q

Is heme the prosthetic group for hemoglobin and myoglobin only?

A

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

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Q

What are the two simple precursors of heme?

A

glycine and succinyl CoA

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Q

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

glycine + succinyl CoA

A

product: ALA
enzyme: ALA synthase
location: mitochondria

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Q

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

ALA + ALA

A

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

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Q

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

4 x PBG

A

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

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Q

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

URO I … (hint: isomerization)

A

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

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Q

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

URO III … (hint: decarboxylation)

A

product: COPRO III
enzyme: URO decarboxylase
location: cytosol

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Q

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

COPRO III … (hint: oxidation)

A

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

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Q

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

PROTO IX … (hint: oxidation)

A

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

Q

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

protoporphyrin IX + Fe 2+

A

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

Q

Where does lead inhibition occur in the heme synthesis pathway?

A

2nd step: (ALA + ALA = PBG)

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

Q

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

A

ALA and COPRO III

Q

What are the two sites of heme synthesis regulation?

A

liver and erythroid cells

Q

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

A

NO (see p. 49)

Q

Define porphyria

A

Genetic deficiency in heme metabolism

Q

List 4 types of porphyrias

A

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

Q

Describe the molecular and clinical consequences of the 2 erythropoietic porphyrias

A

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

Describe the molecular and clinical consequences of the 2 hepatic porphyrias

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

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

a. URO synthase (PBG deaminase)

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

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

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

a. ALA synthase

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

b. ferrochelatase

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

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

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

D. inhibition of heme synthesis leading to a induced porphyria

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

A. is deficient in the disease acute intermittent porphyria

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

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

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

D. A and C

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

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

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

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