Transgenesis-Guided Folate Biofortification.

Folate deficiency is a global health problem that results in a huge burden of preventable birth defects and anemia, and heightened risks of vascular disease and cancer. This deficiency is commonest in poorer countries. Current solutions are to add chemically synthesized folic acid to staple foods or to administer folic acid supplements, but neither fix is feasible in poorer countries, where biofortification may be a more viable option. Although transgenic approaches to folate biofortification are commercially unacceptable in many countries, such approaches – used as experimental tools in model organisms – can provide valuable guidance to conventional breeding programs. Specifically, metabolic engineering using transgenes can show (i) how folate content is regulated, (ii) how far folate content can be raised, and (iii) whether raising folate content affects performance. Thus, transgenic experiments in plants and bacteria indicate that both the pterin branch and the p-aminobenzoate branch of the folate pathway must be upregulated to achieve large increases in folate, that these increases can be as much as 25- to 100-fold, and that such increases do not affect performance. In contrast, natural genotypic variation in folate content in most crops analyzed is only two- to four-fold. One insight from plant metabolic engineering that may be valuable for breeding is that crossing lines having high-level expression of the pterin branch with those having high-level expression of the p-aminobenzoate branch is likely to give rise to transgressive segregation, i.e. to progeny whose folate contents exceed those of either parent. A second insight, from comparative genomics-guided metabolic engineering in bacteria, is that folate content may be partly determined by competition between a folate-cleaving side-reaction of a coenzyme A biosynthesis enzyme and enzymes that recycle the cleavage products back to folate.