Fitz- Folate, Vitamin B12 and Inhibitors

Question 1

What is the main enzyme that converts Foalte to tetrahydrofolate?

Answer 1

DHFR

Question 2

Methyltetrahydrofolate form liver stores is converted to tetrahydrofolate by a mechanism that requires what vitamin….

Answer 2

B12

Question 3

Thymidylate synthase catalyzes what reaction?

Answer 3

dUMP to dTMP

THF4 is also involved in this rxn

Question 4

What is the rate limiting step in DNA synthesis?

Answer 4

The conversion of UMP to TMP

thymidylate synthase

Question 5

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

Answer 5

Conversion of UMP to UDP (pyrimidine monophosphate)

Question 6

What enzyme deficiency leads to increased sensitivity to 5FU?

Answer 6

dihydropyrimidine dehydrogenase

Question 7

De novo purine syntehsis begins w/ the conversion of ribose 5 phosphate to…..

Answer 7

PRPP (catalyzed by PRPS)

Question 8

What is the first committed step in purine synthesis?

Answer 8

Formation of 5 phosphoribosylamine by GPAT

Question 9

Besides de novo synthesis of IMP and GMP what is the other pathway?

Answer 9

Salvage pathway

PRPP is combined w/ hypoxanthine or guanine bases

Question 10

What is xanthine oxidase?

Answer 10

Enzyme involved in the conversion of IMP to uric acid

Question 11

What enzyme is inhibited by allopurinol?

Answer 11

xanthine oxidase

Question 12

What is the main function of folate and B 12?

Answer 12

DNA synthesis

maintain neurons and RBC

Question 13

What is leucovorin?

Answer 13

Naturally occurring compound used to replace folate in rescue hterapy

bypasses DHFR

Question 14

Do we have a higher daily requirement for folate or B12?

Answer 14

Folate–there is a small amt stored in the liver

B12- 5 yr supply stored in the liver

Question 15

What are the 1 major folate transporters?

Answer 15

Reduced folate carrier- high capacity, low affinity in all cells
Folate receptor- high affinity, low capacity in all cells

Question 16

Put these in order by affinity to the folate carrier….

folate
LV
MTX

Answer 16

LV>folate> MTX

Question 17

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

Answer 17

Reduced expression or mutation of the RFC

Question 18

What is used to overcome resistance to drugs like MTX?

Answer 18

HIGH doses of MTX +
Leucovorin–> allows normal cells w/ functional RFCs to overcome the drug-induced inhibition of DHFR

**RESCUE THERAPY

Question 19

How does the over-expression of folate receptor relate to cancer?

Answer 19

It allows for differential sensitivity in some cancer cells

Question 20

What is polyglutamination and how does it relate to cancer?

Answer 20

Keep folate in cells and increase the affinity of TH4 for target enzymes.

Cancer cells are BETTER at polyglutamating than normal cells–> differential sensitivity.

Question 21

What is the earliest and most prominent sign of folate/B12 deficiency?

Answer 21

Megaloblastic anemia

diet, pregnancy, alcholism, inhibitors

Question 22

What is the most common cause of B12 def?

Answer 22

IF def (often in elderly

Question 23

How does B12 def relate to Folate def?

Answer 23

B12 def prevents access to stored TH4 leading to def in folate

Question 24

What enzyme does methotrexate affect in the folate pathway?

Answer 24

DHFR (competitive inhibitor)

Question 25

What are the therapeutic uses of methotrexate?

Answer 25

cancer
immunosuppression
antibiotic
abortificacient

Question 26

What enzyme does trimethoprim affect in the folate pathway?

Answer 26

competitive inhibitor of bacterial DHFR

Question 27

What drug is trimethoprim usually combined with and why?

Answer 27

Sulfamethoxazole

These drugs act synergistically, selectively blocking the steps in the folate synthesis pathway in bacteria.