Formation of folates by microorganisms: towards the biotechnological production of this vitamin.

PubMed ID: 30073396

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Revuelta JL, Serrano-Amatriain C, Ledesma-Amaro R, Jiménez A

Appl Microbiol Biotechnol. Aug 2018. doi: 10.1007/s00253-018-9266-0


In this review, Dr. Revuelta from the Metabolic Engineering Group, at University of Salamanca (Spain) and coworkers describe the current strategies aimed at overproducing folates in microorganisms, in view to implement an economic feasible process for the biotechnological production of the vitamin.

Folates are a group of water-soluble compounds that are part of the B vitamin family (B9). Folates are essential micronutrients which function as cofactors in one-carbon transfer reactions involved in the synthesis of nucleotides and amino acids. Folate deficiency is associated with important diseases such as cancer, anemia, cardiovascular diseases, or neural tube defects. Epidemiological data show that folate deficiency is still highly prevalent in many populations. Hence, food fortification with synthetic folic acid (i.e., folic acid supplementation) has become mandatory in many developed countries. However, folate biofortification of staple crops and dairy products as well as folate bioproduction using metabolically engineered microorganisms are promising alternatives to folic acid supplementation.

Unfortunately, all the vitamin B9 commercially available for food supplementation is chemically synthesized Folic Acid, and may present some drawbacks. Several studies seem to raise doubts regarding the safe use of chemically synthetized Folic Acid in foods, whereas natural folates do not cause such adverse health effects in individuals. Despite the remarkable improvements in folate production that have been achieved, the fermentation process is not competitive as yet with the chemical synthesis.

As the authors describe in their conclusion:

Future research should thus focus on the following points:

(i) understanding the complex regulatory mechanisms governing the enzymatic activities involved in the folate pathway;

(ii) flux metabolic analysis to uncover possible bottlenecks and to channeling pABA and pteridine substrates towards the folate biosynthetic pathway;

(iii) the blocking of chorismate-consuming pathways to enhance the synthesis of the limiting pABA substrate;

(iv) the characterization and engineering of folate eukaryotic transporters to facilitate the import of the pABA and pterin substrates into the mitochondria, where the synthesis of folates takes place; and

(v) the optimization of the fermentation conditions and further development of downstream processes for the recovery and purification of the product.



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