Fitz- Folate, Vitamin B12 and Inhibitors Flashcards
What is the main enzyme that converts Foalte to tetrahydrofolate?
DHFR
Methyltetrahydrofolate form liver stores is converted to tetrahydrofolate by a mechanism that requires what vitamin….
B12
Thymidylate synthase catalyzes what reaction?
dUMP to dTMP
THF4 is also involved in this rxn
What is the rate limiting step in DNA synthesis?
The conversion of UMP to TMP
thymidylate synthase
What reaction is important in the development of resistance to 5 FU?
Conversion of UMP to UDP (pyrimidine monophosphate)
What enzyme deficiency leads to increased sensitivity to 5FU?
dihydropyrimidine dehydrogenase
De novo purine syntehsis begins w/ the conversion of ribose 5 phosphate to…..
PRPP (catalyzed by PRPS)
What is the first committed step in purine synthesis?
Formation of 5 phosphoribosylamine by GPAT
Besides de novo synthesis of IMP and GMP what is the other pathway?
Salvage pathway
PRPP is combined w/ hypoxanthine or guanine bases
What is xanthine oxidase?
Enzyme involved in the conversion of IMP to uric acid
What enzyme is inhibited by allopurinol?
xanthine oxidase
What is the main function of folate and B 12?
DNA synthesis
maintain neurons and RBC
What is leucovorin?
Naturally occurring compound used to replace folate in rescue hterapy
bypasses DHFR
Do we have a higher daily requirement for folate or B12?
Folate–there is a small amt stored in the liver
B12- 5 yr supply stored in the liver
What are the 1 major folate transporters?
Reduced folate carrier- high capacity, low affinity in all cells
Folate receptor- high affinity, low capacity in all cells
Put these in order by affinity to the folate carrier….
folate
LV
MTX
LV>folate> MTX
What is a cause of primary resistance to low doses of folate inhibitors (like MTX)?
Reduced expression or mutation of the RFC
What is used to overcome resistance to drugs like MTX?
HIGH doses of MTX +
Leucovorin–> allows normal cells w/ functional RFCs to overcome the drug-induced inhibition of DHFR
**RESCUE THERAPY
How does the over-expression of folate receptor relate to cancer?
It allows for differential sensitivity in some cancer cells
What is polyglutamination and how does it relate to cancer?
Keep folate in cells and increase the affinity of TH4 for target enzymes.
Cancer cells are BETTER at polyglutamating than normal cells–> differential sensitivity.
What is the earliest and most prominent sign of folate/B12 deficiency?
Megaloblastic anemia
diet, pregnancy, alcholism, inhibitors
What is the most common cause of B12 def?
IF def (often in elderly
How does B12 def relate to Folate def?
B12 def prevents access to stored TH4 leading to def in folate
What enzyme does methotrexate affect in the folate pathway?
DHFR (competitive inhibitor)
What are the therapeutic uses of methotrexate?
cancer
immunosuppression
antibiotic
abortificacient
What enzyme does trimethoprim affect in the folate pathway?
competitive inhibitor of bacterial DHFR
What drug is trimethoprim usually combined with and why?
Sulfamethoxazole
These drugs act synergistically, selectively blocking the steps in the folate synthesis pathway in bacteria.
