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IHO Block 3 > Folate, Vitamin B12 and Inhibitors > Flashcards

Folate, Vitamin B12 and Inhibitors Flashcards

1
Q

What are Folate and V12 required for?

A

DNA synthesis and maintenance of neurons and red blood cells.

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2
Q

Why is folate important molecularly?

A

It is a critical precursor in the neosynthesis of TH4. It is a carbon donor in thymidylate and purine synthesis, as well as amino acid metabolism and methionine synthesis.

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3
Q

Why is B12 important molecularly?

A

It is a critical cofactor in the generation of tetrahydrofolate from liver stores of tetrahydrofolate.

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4
Q

What is the main cause of primary resistance to low doses of folate inhibitors (like MTX)?

A

-Reduced expression or mutation of the reduced folate carrier (RFC)

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5
Q

What things can exhibit resistance to folate inhibitors?

A

Cancer cells and bacteria (esp. Pneumocystis jirovecii an AIDS-associated infection)

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6
Q

What is used to overcome the resistance to folate inhibitors?

A
  • High doses of MTX

- Addition of administration of Leucovorin

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7
Q

What does Leucovorin do?

A

-Allows normal cells with functional RFC to overcome the drug-induced inhibition of dihydrofolate reductase. ==> fundamental principle of RESCUE THERAPY

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8
Q

What happens in folic acid or vitamin B12 deficiency?

A
  • Bad effects on rapidly growing cells and neurons

- Most prominent and earliest clinical sign of deficiency is MEGALOBLASTIC ANEMIA

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9
Q

What is the mechanism of trimethoprim?

A

Folic acid inhibitor

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10
Q

What is the mechanism of sulfamethoxazole?

A

Blocks dihydropteroate synthetase

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11
Q

What two drugs act synergistically, selectively blocking successive steps in the folate synthesis pathway in bacteria?

A

Trimethoprim & Sulfamethoxazole

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12
Q

What are the two mechanisms by which tetrahydrofolate is synthesized?

A
  1. Folate is converted to dihydrofolate which is converted to tetrahydrofolate by dihydrofolate reductase (DHFR).
  2. Methyltetrahydrofolate from liver stores is converted to tetrahydrofolate, a reaction that requires Vitamin B12.
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13
Q

What two things use tetrahydrofolate?

A
  1. Two steps in the conversion of 5-phosphoribosylamine to IMP (purine synthesis) use tetrahydrofolate as a carbon donor.
  2. Tetrahydrofolate is also involved in the generation of dTMP from dUMP (pyrimidine synthesis) - this reaction is catalyzed by thymidylate synthase
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14
Q

What is the rate limiting step in DNA synthesis?

A

The conversion of UMP to TMP, which is catalyzed by thymidylate synthase.

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15
Q

What pathway is important in the development of resistance to 5-FU?

A

Conversion of UMP to UDP by pyrimidine monophosphate kinase

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16
Q

A deficiency in what enzyme leads to increased sensitivity to 5-FU?

A

Dihydropyrimidine dehydrogenase - catalyzes the degradation of thymidine nucleotides

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17
Q

How does purine synthesis start?

A

Conversation of ribose-5-phosphate to 5-phosphoribosyl-1 pyrophosphate (PRPP), which is catalyzed by PRPP synthetase (PRPS).

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18
Q

What is the first committed step (second step overall) in purine synthesis?

A

Formation of 5-phosphoribosylamine via glutamyl amidotransferase (GPAT)

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19
Q

How can IMP and GMP be created?

A

Via the “salvage pathway”. PRPP is combed with hypoxanthine or guanine bases (including 6MP and 6TG) by the actions of hypoxanthine-guanine phosphoribosyl transferases (HGPRT).

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20
Q

How do 6-MP and 6-TG work?

A

They inhibit guanylyl kinase, preventing conversion of GMP to GDP and causing “pseudo feedback inhibition” of HGPRT, PRPS, GPAT and the enzymes that produce XMP and adenylsuccinate from IMP.

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21
Q

What is a route for degradation of purine nucleotides (and 6-MP and 6-TG)?

A

It occurs via conversion of IMP to uric acid.
First, hypoxanthine is converted to xanthine, and xanthine to uric acid. These reactions are catalyzed by xanthine oxidase.

22
Q

What does allopurinol do?

A

Inhibits the xanthine oxidase enzyme!

23
Q

What enzyme catalyzes the conversion of ribonucleotides to deoxyribonucleotides and is acted on by hydroxyurea?

A

Ribonucleotide Reductase

24
Q

What two reactions is vitamin B12 an intermediate in?

A
  1. Reaction that converts methylTH4 (the primary stored from of TH4) to TH4
    - -In the process, homocysteine is converted to methionine (inc. homocystine levels are diagnostic for vitamin B12 deficiency)
  2. The conversion of methylmalonyl CoA to succinylCoA
25
Q

Increased levels of what are diagnostic of VB12 deficiency?

A

Homocystine!!

26
Q

What type of folate is used in supplements?

A

Folic acid (synthetic, but more stable!)

27
Q

What is Leucovorin?

A

(5-formyl-TH4, folinic acid) - naturally occurring compound that is used to replace folate in rescue therapy!
-Doesn’t requrie DHFR for its conversion to TH4

28
Q

What are the natural forms of VB12?

A
  • Anything ending in -cobalamin

- Adenosylcobalamin, Methylcobalamin

29
Q

What is hydroxocobalamin used for?

A
  • Treatment of cyanide poisoning

- More plasma protein binding –> remains in circulation longer!

30
Q

Where is folate found?

A
  • Green, leafy vegetables, dried beans and peas, sunflower seeds and citrus fruits, as well as yeast, liver and kidney
  • Fortified cereal products (breads, flours, corn meals, pastas, rice)
31
Q

How is folate absorbed and stored?

A

Absorbed in small intestine. A relatively small quantity is stored in the liver, and there is a high daily requirement only ~ 1-6 month supply.

32
Q

Where is VB12 found?

A

-Original source is bacteria, but most is obtained from animal products or fortified foods in the diet where it is bound to proteins!

33
Q

How is VB12 absorbed and stored?

A
  • Absorption requires acidic pH and intrinsic factor! (made in stomach)
  • Occurs via specific transport system in small intestine
  • ~5 year supply is stored in the liver (so deficiency is rare except in the elderly)
34
Q

What are the two major folate transporters?

A
  1. Reduced folate carrier

2. Folate receptor

35
Q

What is important about the reduced folate carrier?

A

-It is found in all cells
-High capacity, low affinity transporter in all cells
-Important for: pharmacological concentrations
LV>Folate>MTX
-Some cancer cells have decreased expression of RFC

36
Q

What are some cells primary resistance to MTX? How can this resistance be overcome?

A
  • Decreased expression of RFC
  • Resistance can be overcome by giving really high doses of MTX –> which causes increased uptake of MTX by the FOLATE RECEPTOR
37
Q

How do you “rescue” normal cells?

A

Use LV (leucovorin) which binds and gains entry via the folate receptor. This supplies normal/non-cancer cells with the TH4 they need!

38
Q

What is important about the folate receptor?

A
  • High affinity, low capacity system
  • Transports via POTOCYTOSIS
  • Working at physiological concentrations
  • FOLATE&raquo_space; MTX
  • Overexpression of this receptor causes differential sensitivity in some cancer cells
39
Q

What is potocytosis?

A

When you internalize a receptor/folate and some membrane

40
Q

What is polyglutamination?

A

Adding glutamates onto folate to keep it inside the cell once it’s been transported inside. This is done by the enzyme folylpolyglutamate synthase.

41
Q

What does polyglutamination do?

A
  • Keeps folates in cells
  • Inc. affinity of TH4 for target enzymes
  • Cancer cells are better at polyglutaminating –> causes their differential sensitivity!
42
Q

What causes folate deficiency?

A
  • Insufficient dietary intake
  • High demand (pregnancy)
  • Alcoholism
  • Intestinal disease (sprue)
  • Inhibitors
43
Q

What does folate deficiency result in?

A
  • Megaloblastic anemia
  • Neural tube defects and other congenital abnormalities
  • No neurologic damage in adults
44
Q

What usually causes VB12 deficiency?

A

Malabsorption (from intrinsic factor deficiency - can’t treat with oral supplements)

45
Q

What does VB12 deficiency cause?

A
  1. Folate deficiency by preventing access to stored tetrahydrofolate
  2. Megaloblastic anemia (called pernicious anemia if due to impaired intrinsic factor production) and neurological damage (paresthesias and weakness that progress to spasticity, ataxia and other CNS disorders)
46
Q

What happens when you correct VB12 deficiency?

A

It can stop progression of neurological effects but cannot reverse them!

47
Q

What will folate supplements do in megaloblastic anemia?

A

It reverses the anemia, but will not reverse the nervous system damage. It’s important that VB12 status be determined before beginning folic acid supplementation
(ESP in elderly (over 50) - believe that 10% of senile dementia caused by B12 deficiency)

48
Q

What is the mechanism of MTX?

A

Competitive inhibitor of dihydrofolate reductase (DHFR)

49
Q

What are the therapeutic uses of MTX?

A
  • Cancer (1st solid tumour cure - choriocarcinoma)
  • Immunosuppressant: RA, psoriasis, inflammatory bowel disease/Crohn’s disease
  • Antibiotic
  • Abortifacient - in 1st trimester - typically combined with MISOPROSTOL (PGE1)
50
Q

What is the mechanism of trimethoprim?

A

Selective, competitive inhibitor of Bacterial dihydrofolate reductase (DHFR)

51
Q

What are other clinically important inhibitors related to MTX?

A

Premetrexed and Pralatrexate - like MTX

52
Q

What are other clinically important inhibitors related to Trimethoprim?

A

Pyrimethamine - antimalarial drug!!

IHO Block 3 (13 decks)

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