MTHFR and Colon Cancer

Question 1

polymorphism

Answer 1

2+ phenotypes occur in nature b/c they have opposing/balancing evolutionary advantages

Question 2

what is the full name of the MTHFR enzyme?

Answer 2

5,10 Methylene tetrahydrofolate reductase

Question 3

how many amino acids does the MTHFR enzyme have?

Answer 3

656

Question 4

where is the MTHFR gene located? approximately how many bases is the DNA v. RNA for it?

Answer 4

located on the short p arm of the 1st chromosome
DNA=19K bases
RNA=2K bases

Question 5

where is the famous polymorphism for MTHFR? what is the variation?

Answer 5

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

Question 6

what is the wild type for MTHFR genotype?

Answer 6

CC

Question 7

t/f: different ethnicities have different prevalences of the MTHFR genotypes

Answer 7

true!

Question 8

which ethnicity has the highest prevalence of the TT genotype?

Answer 8

Hispanics

Question 9

why is MTHFR important in 1C transfer?

Answer 9

reduces 5,10 Methylene THF to 5 methyl THF, which is the C donor to methionine from Hcy

Question 10

without enough 5 methyl THF, methionine and _________, the universal C donor will be deficient. Why is this problematic?

Answer 10

SAM(s-adenosyl methionine) will be deficient–> needed to methylate proteins, DNA, and lipids(activate or prevent gene expression/DNA replication)

Question 11

what is the major circulating form of folate?

Answer 11

5 methyl THF

Question 12

what is the activity ranking of the MTHFR enzyme across genotypes?

Answer 12

cc>ct>tt

Question 13

how does TT MTHFR activity compare to CC?

Answer 13

only about 1/3

Question 14

why is it even with TT genotype, DNA synthesis is adequate?

Answer 14

b/c DNA synthesis comes from 5,10 methylene THF, which is the SUBSTRATE, not product, of MTHFR

Question 15

with the TT genotype both __________ and ___________ folate levels are lower

Answer 15

serum and erythrocyte

Question 16

do Americans typically take in the RDA of folate? What is the RDA for folate?

Answer 16

400 DFE=RDA, but N. Americans typically do NOT get this amount

Question 17

t/f: lowered folate status in TT individuals can be corrected with high folate diet/supplement

Answer 17

true, BUT will trend across genotypes will be maintained

Question 18

how is Hcy status affected in a TT individual with high intake of folate?

Answer 18

lowered, BUT not to the level seen in CC individuals, even CC ind. on low folate diets

Question 19

why is low folate and the TT genotype associated with colon cancer?

Answer 19

less folate=less SAM for DNA methylation–> more transcription and increased cell proliferation

Question 20

what is the general pathway for colorectal cancer progression?

Answer 20

polyps–> adenomas–> carcinoma

Question 21

what is the difference between an adenoma and carcinoma?

Answer 21

adenoma=mass of cells, but carcinoma is a tumor that can metastasize

Question 22

when folate intake is low how does this promote cancer? (2 ways)

Answer 22

1. DNA is not properly methylated due to 5 methyl THF leaking out of cells
2. nucleotides are insufficient due to deficiency of 5, 10 methylene THF–> mutation can occur during replication

Question 23

SAM is an allosteric inhibitor of what?

Answer 23

MTHFR… when sufficient amounts are being produced(enzyme running well) the process self-regulates rate through feedback inhibition

Question 24

why do TT individuals consuming a high folate diet have a lower risk of colon cancer?

Answer 24

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

Question 25

t/f: high folate intake reduces risk of colorectal cancer in all genotypes

Answer 25

true!

Question 26

what was the rational for increasing folate through fortification? how does this work?

Answer 26

decrease NTDs—> theory that high Hcy levels increase NTD