Figure 2
Metabolic interactions between folates and vitamins B 12 , B 6 , and B 2 . 677C → T thermolabile polymorphism with weakened interaction with B2 NAD cofactor disables MTHFR function by up to 70% in homozygotes. 15% of population is homozygous (2 inherited genes) 50% is heterozygous (one inherited gene). In the presence of this mutation (677C → T) when folate is plentiful this pathway provides adequate SAM for DNA methylation maintenance and shunts more 5,10 methylene THF to support DNA synthesis with less Uracil misincorporation into DNA with less 50% decreased incidence of colon cancer and acute lymphocytic leukaemia. However, in the presence of the mutation, if folate is low, then SAM DNA methylation may increase OR decrease and de novo DNA thymidine synthesis may decrease. There is disruption of normal intracellular methylated folate forms and all or some of these perturbations favour increased incidence of colon, breast, gastric, cervical and prostate cancer. Under most circumstances DNA synthesis through dTMP generation takes precedence over SAM DNA methlyation. Serine Hydroxymethyltransferase (SHMT) recently found to shift folate metabolism in the direction favoring de novo dTMP - DNA synthesis. B2 found to modulate (lessen) effects of MTHFR polymorphisms. Diet and all B vitamin levels modulate various folate pathways and therefore risks for malignancy!. Newly noted polymorphisms of DHFR (rs1677693 & rs1643659) have 30% decreased risk while MTR polymorphism (rs4659744) has 25% decreased risk of colon cancer only in the absence of FA supplements or FA supplemented diet. Changes in B vitamin concentrations and enzyme polymorphisms may produce unpredictable DNA methylation changes in part by varying DNA methyl transferase concentrations and SAM/SAH concentrations i.e. folate depletion may cause global DNA hypomethylation and specific CpG hypermethylations.