Quatrefolic® represents an innovative dietary ingredient designed to act as a nutrient in all areas where folic acid and folate supplementation has been recommended and allowed. The terms folic acid and folate are often used interchangeably for the water-soluble B-complex vitamin, essential for the maintenance of cellular functions and health. Folate deficiency is one of the most common vitamin deficiencies and eating folate-rich foods may not provide the recommended daily dosage; thus, the need for supplementation. Quatrefolic® is the glucosamine salt of(6S)-5-methyltetrahydrofolate and is structurally analogous to the reduced and active form of folic acid. Developed by Gnosis S.p.A, it represents the fourth-generation folate providing greater stability, higher water solubility and multiple ingredients formulation flexibility compared to 5-methyltetrahydrofolatecalcium salt guaranteeing an improved bio availability.
Choosing Quatrefolic® as a source of folate presents several advantages both for manufacturer of food and feed ingredients and for the consumer of supplements and food products:
• Provides the active form of folate, 5-methyltetrahydrofolate, naturally present in the body and available for its biological action.
• Has been recognized GRAS. Gnosis has undertaken several in-vitro and in-vivo preclinical and clinical studies to characterize and guarantee the safety profile of the product.
• Is a Gnosis proprietary product with patents and trademark applications guaranteeing a wide range of use and covering all areas of folate application.
• Is produced according to cGMP, guaranteeing a reproducible quality profile.
• Glucosamine, as a salt of (6S)-5-methyltetrahydrofolate, does not come from animal sources and the product is suitable for vegetarian consumption.
• Higher bio availability and improved water solubility showed by Quatrefolic® respect to calcium salt, open new perspectives and uses for combinations and formulations with vitamins and minerals, both for dietary supplements and Food &Beverage industry.
The terms "Folate" and "folic acid", also known as vitamin B9, are often used interchangeably to indicate a group of water-soluble B-vitamins. Actually, there are differences in the forms:
1st generation - Food folate: Refers to the various tetrahydrofolate derivatives naturally present in foods.
2nd generation - Folic acid: Got its name from folium, the Latin word for leaf, when it was isolated from spinach in 1941. It is a synthetic oxidized molecule, that does not occur in nature but can be utilized by the human body as a precursor to form natural folates that are biologically active. Folic acid lacks coenzyme activity and must be reduced to the metabolically active form within the cell, through a series of biochemical steps before it can be used by the body's cells in vital metabolic path ways such as DNA production, cell reproduction and homocysteine metabolism.
3rd generation - (6S)-5-methyltetrahydrofolate calcium salt: In 1989 Bio research S.p.A. was the first company to evaluate the real importance of 5-methyltetrahydrofolate and filed the use of stable pharmaceutical composition of 5-methyltetrahydrofolate. The calcium salt of 5-methyltetrahydrofolate is available commercially and represents the third generation of folate. Until now, 5-methyltetrahydrofolate calcium salt was the only folic acid derivative available on the market, and able to penetrate the body cells without the need of further metabolism process.
The 4th generation: Quatrefolic®: The goal for Gnosis' R&D was to develop an innovative folate salt form able to overcome the existing calcium salt form limitations related to stability and poor solubility. In February 2008, Gnosis patented a new generation of folate derivative, brand named Quatrefolic®, (6S)-5-methyltetrahydrofolate glucosamine salt. Quatrefolic®represents the fourth-generation folate endowed with long lasting stability as well as a peculiarly high water solubility, improved bio availability and well established safety.
In concert withvitamin B12, folate coenzymes allow the conversion of the amino acidhomocysteine into methionine. The lack of this conversion has been associated with various pathologies and diseases.
Conversion of tetrahydrofolic acid into 5-methyltetrahydrofolate is mediated by the action of the enzyme methylentetrahydrofolate reductase. In individuals with a genetic defect of the methylentetrahydrofolate reductase (MTHFR) this enzyme conversion is limited, consequently it will predispose these individuals to an increased risk for certain disease conditions.
Supplementation with 5-methyltetrahydrofolate is preferable to the one with folic acid, as it is immediately bio available to react with homocysteine to avoid the possibility to incur in hyperhomocysteinemia.
1-Main Components of the Folate Biochemical Cycle. Abbreviations:
DHFR = dihydrofolate reductase; MTHFR =methylenetetrahydrofolate reductase. Reactions:
Pathway 1 - Biosynthesis of nucleotides for incorporation into DNA and RNA;
Pathway 2 - Remethylation of homocysteine to formmethionine (vitamin B12 serves as a coenzyme in this reaction);
3 - Methylation of substrates, including DNA, RNA,phospholipids, and proteins;
4 - MTHFR, which catalyzes the formation of 5-methylfolate needed for methylation reactions;5 - Dihydrofolate reductase enzyme.
5 - Dihydrofolate reductase enzyme.
2-Quatrefolic® supplementation allows 5-methyltetrahydrofolate to be immediately bio available for its biological action without being metabolized in the body. Quatrefolic® is unlikely to mask vitamin B12 resulting in tangible advantages and more safe profile of the product respect to folic acid.
Once formed, 5-methyltetrahydrofolate reacts with homocysteine by a single enzyme regulated by vitamin B12, leading to are cycling production of tetrahydrofolic acid. If vitamin B12 is deficient, the folate present in cells becomes "metabolically trapped" and 5-methyltetrahydrofolate is piled up in the cells, resulting in a persistent impairment of purine and pyrimidine biosynthesis (pathway 1) and in a methylation cycle block (pathway2), leading to megaloblastic anemia and neurological damage progress. Vitamin B12 deficiency is common in old age and may not be easy to recognise. Folic acid intake by supplementation may mask first symptoms of vitamin B12 deficiency, such as anemia, while 5-methyltetrahydrofolate supplementation does not. Actually folic acid supplementation may activate synthesis of purine and pyrimidine through pathway 1 correcting anemia, although vitamin B12 is absent; on the contrary the pathway 2 remains blocked leading to a nerve and cognitive deterioration that may continue unchecked.
3-Methylenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes in human physiology, deficiencies in production or function of this enzyme have been associated with increased risk of different diseases
4-Quatrefolic® is the glucosamine salt of (6S)-5-methyltetrahydrofolateand is structurally analogous to the reduced and active form of folic acid so Quatrefolic® completely bypasses the "damaged" MTHFR conversion step and delivers a "finished" folate the body can immediately use without any kind of metabolization.
5-The threshold of ingestion of folic acid that leads to the direct appearance of UMFA in the plasma, results to be highest than 200-300 μg/daily intake. The consumption of highest dosage of synthetic folic acid results in absorption of unreduced folic acid, which may interfere with folate metabolism for a period of years.
