Dihydrofolate reductase inhibitors Flashcards

1
Q

Examples of DHFR-I

A
Pyrimethamine = anti malarial 
Trimethoprim = antibacterial
Methotrexate = anti cancer / anti arthritic
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2
Q

MoA of DHFR-inhibitors

A

Folate antagonists
Inhibits the processing of folic acid
Competitively inhibits the bacterial enzyme dihydrofolate reductase required for the conversion of dihydrofolic acid to tetrahydrofolic acid

Inhibiting DHFR = inhibits synthesis of thymidine and DNA synthesis

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3
Q

Why is DHFR a good target?

A

There is significant structural variation of DHFR between species (man and bacteria) = selective to bacterial cells = reduced s/e

Structural differences = size, shapes and charge distribution of enzyme active site

The only source of thymidine required for DNA synthesis is the folate mediated addition of methyl group to dUMP = inhibit the mechanism inhibits thymidine synthesis

Bacteria needs large amount of nucleic acid to replicate = reduction in thymidine = can’t replicate

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4
Q

How can you reduce toxicity of DHFR methotrexate?

A

Leucovorin recovers the damage caused by methotrexate as it is metabolised to methylene tetrahydrofolate therefore there’s no need for the tetrahydrofolate produces by DHFR to synthesise thymidine

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5
Q

How is thymidine monophosphate synthesised?

A

Dihydrofolate reductase reduces dihydrofolate to tetrahydrofolate

Thimydylate synthase takes a methyl group from tetrahydrofolate and places it on dUMP leading to the synthesis of dTMP

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6
Q

Why is thymidine monophosphate important?

A

It is an essential nucleotide for DNA synthesis

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