MTHFR and Colon Cancer Flashcards
polymorphism
2+ phenotypes occur in nature b/c they have opposing/balancing evolutionary advantages
what is the full name of the MTHFR enzyme?
5,10 Methylene tetrahydrofolate reductase
how many amino acids does the MTHFR enzyme have?
656
where is the MTHFR gene located? approximately how many bases is the DNA v. RNA for it?
located on the short p arm of the 1st chromosome
DNA=19K bases
RNA=2K bases
where is the famous polymorphism for MTHFR? what is the variation?
famous one= one on nucleotide 677 and cytosine is changed to thymine, which changes the AA when the protein is synthesized from alanine to valine
what is the wild type for MTHFR genotype?
CC
t/f: different ethnicities have different prevalences of the MTHFR genotypes
true!
which ethnicity has the highest prevalence of the TT genotype?
Hispanics
why is MTHFR important in 1C transfer?
reduces 5,10 Methylene THF to 5 methyl THF, which is the C donor to methionine from Hcy
without enough 5 methyl THF, methionine and _________, the universal C donor will be deficient. Why is this problematic?
SAM(s-adenosyl methionine) will be deficient–> needed to methylate proteins, DNA, and lipids(activate or prevent gene expression/DNA replication)
what is the major circulating form of folate?
5 methyl THF
what is the activity ranking of the MTHFR enzyme across genotypes?
cc>ct>tt
how does TT MTHFR activity compare to CC?
only about 1/3
why is it even with TT genotype, DNA synthesis is adequate?
b/c DNA synthesis comes from 5,10 methylene THF, which is the SUBSTRATE, not product, of MTHFR
with the TT genotype both __________ and ___________ folate levels are lower
serum and erythrocyte
do Americans typically take in the RDA of folate? What is the RDA for folate?
400 DFE=RDA, but N. Americans typically do NOT get this amount
t/f: lowered folate status in TT individuals can be corrected with high folate diet/supplement
true, BUT will trend across genotypes will be maintained
how is Hcy status affected in a TT individual with high intake of folate?
lowered, BUT not to the level seen in CC individuals, even CC ind. on low folate diets
why is low folate and the TT genotype associated with colon cancer?
less folate=less SAM for DNA methylation–> more transcription and increased cell proliferation
what is the general pathway for colorectal cancer progression?
polyps–> adenomas–> carcinoma
what is the difference between an adenoma and carcinoma?
adenoma=mass of cells, but carcinoma is a tumor that can metastasize
when folate intake is low how does this promote cancer? (2 ways)
- DNA is not properly methylated due to 5 methyl THF leaking out of cells
- nucleotides are insufficient due to deficiency of 5, 10 methylene THF–> mutation can occur during replication
SAM is an allosteric inhibitor of what?
MTHFR… when sufficient amounts are being produced(enzyme running well) the process self-regulates rate through feedback inhibition
why do TT individuals consuming a high folate diet have a lower risk of colon cancer?
have a good amount of DNA synthesis and just the right amt of SAM produced to have perfect level of MTHFR activity to produce the 5 MTHF to methylate DNA properly
t/f: high folate intake reduces risk of colorectal cancer in all genotypes
true!
what was the rational for increasing folate through fortification? how does this work?
decrease NTDs—> theory that high Hcy levels increase NTD
