B33 CAN Chemistry

Question 1

How does Tetrahydrofolate (THF) synthesis purines and pyrmidines

Answer 1

The 2 nitrogens grab hold of 1 carbon unit used in the biosynthesis

Question 2

Dihydrofolate reducatase catalyses what reaction?

Answer 2

DHF —> Active THF by reducing a double bond

Question 3

DHFR inhibitor is what class of chemotherapy

Answer 3

Antimetabolite

Question 4

Methortrexate as a substrate

Answer 4

MTX is a potent competitive inhibitor of DHFR forming charged H-bonded assisted bonds (due to protonation of binding site) induce a change in conformation

Question 5

MTX Transport & resistance

Answer 5

MTX is imported into cells by the Reduced Folate Carrier (RFC)

MTX is also a substrate for Folyl Plyglutamyl synthase (FPGS) due to its glutamate tail.

Question 6

What does the Folyl polyglutamyl synthase (FPGS) do to MTX to increase retention within the cell

Answer 6

FPGS adds glutamic acids onto the glutamate chain exhibited on MTX, this INCREASES MTXs polarity leading it to not be readily efluxed

Question 7

Cancer Cell resistance to MTX

Answer 7

If a cancer cell exhibits a mutation in its levels of RFC
Or if a cancer cell exhibits a mutation with enzyme FPGS
-> leads to MTX increased levels of efflux and decreased levels of influx

Question 8

5-Fluorouracil (5FU) is what form of chemotherapy and what type of drug?

Answer 8

5FU is an antimetabolite and a prodrug (changed to 5F-dUMP)

Question 9

How does 5FU work?

Answer 9

5FU -> 5F-dUMP binds to the active site of Thymidilate synthase (TS) and activates the natural mechanism of dUMP to -> dTMP
but at some point during the mechanism instead of breaking apart the molecules become crosslinked to the TS.
This is due to F -> instead of H and F cannot be lost as an ion

—> TS and 5F-dUMP & folate cofactor all boiund together

Question 10

Antihormonal therapies (2 stratigeis)

Answer 10

Estrogen biosynthesis inhibtion (letrazole)

Estrogen receptor antagonists (tamoxifen -> and its metabolites)

Question 11

Breast tumours ER+ or ER-

Answer 11

ER+ breast tumours have their growth stimulated by circulationg levels of estrogen hormone

Er- Breast tumours have growth not dependent of estrogen levels

Question 12

Tamoxifen

Answer 12

(Prodrug)
Agonist of ER (Stronger affinity than natural products due to H-bonding and protonoation of binding site)
Tamoxifen binds to ER displacing helper proteins,
Helix-12 is displaced and blocks the site where ER recruitrs co activator leading to no trascription factors

Question 13

Fulvestrant (SERD)

Answer 13

Steroid, binds to ER
increases hydrophobicity (increase lipohilictity)
Leads to unstable misfoled ER and cell recognises it as degration target