Folic acid

from Wikipedia, the free encyclopedia
Structural formula
Structure of folic acid
Folic acid monoglutamate (n = 1), folic acid polyglutamate (n = 2, 3, ...), here the lactam form of the two possible lactam-lactime tautomers
General
Common name
  • Vitamin B 9
  • Vitamin B 11
  • Vitamin M
other names
  • Folic acid
  • Pteroyl-mono-glutamic acid
  • L -folic acid
  • (2 S ) -2 - [(4 - [(2-amino-4-oxo-1 H pteridin-6-yl) methylamino] benzoyl) amino] pentanedioic acid ( IUPAC , lactam form )
  • (2 S ) - N - (4 - [([2-Amino-4-hydroxypteridin-6-yl] methyl) amino] benzoyl) glutamic acid ( IUPAC , lactim form )
Molecular formula C 19 H 19 N 7 O 6
CAS number 59-30-3
PubChem 6037
ATC code

B03 BB01

Brief description orange-yellow, crystalline powder
Occurrence Wheat germ, beef liver, (soy) beans, chickpeas, yeast, whole grain bread, spinach, kale, Brussels sprouts, asparagus, nuts, fruit, fish and egg yolks
physiology
function Transfer of C 1 groups in biochemical reactions
Daily need 60-600 µg
Consequences in case of deficiency Cell division disorders (as a result: megaloblastic anemia ), neural tube defects during embryogenesis
Overdose 15 mg / day
properties
Molar mass 441.40 g · mol -1
Physical state firmly
Melting point

250 ° C (decomposition)

solubility poor in water (1.6 mg l −1 at 25 ° C)
safety instructions
Please note the restricted labeling requirements for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

The folic acid ( lat. Folium "leaf", due to the presence in green plant leaves), and Vitamin B 9 , Vitamin M , vitamin B 11 , is (uncommon) a 1941 discovered, heat- and light-sensitive vitamin from the B complex . It is chemically composed of a pteridine derivative, para -aminobenzoic acid and L - glutamic acid . While the name folic acid means the synthetic (industrially produced) form of the B vitamin with a glutamate residue (see picture with n  = 1), folate refers to the sum of the folate-effective compounds, i.e. both with one glutamate residue (monoglutamate) or several glutamate residues ( polyglutamates ) .

Occurrence

Lentils ( Lens culinaris )

Foods with particularly high levels of folic acid are yeasts with up to 2500  µg per 100 g and grain germs and bran (especially wheat germ ) with up to 600 µg per 100 g gross weight. Other natural sources of folic acid that contain significant amounts are legumes (especially lentils with 204 µg per 100 g raw), veal and poultry liver , dark green leafy vegetables, egg yolks , parsley , garden cress and sunflower seeds with around 100 µg per 100 g each.

Furthermore, poppy seeds , fresh green vegetables and kidneys have a folic acid content of 50 to 100 µg per 100 g, followed by cooked asparagus , boiled spinach leaves , tomatoes , blackberries , cauliflower , oranges , beef , veal and cereal flakes with 10 to 50 µg per 100 g .

Manufacturing

Folic acid is produced by the ton in the chemical industry. To this end, 6-hydroxy-2,4-diaminopyrimidine is first synthesized from guanidine and ethyl cyanoacetate , which is then converted with nitrous acid to form the nitro derivative and then reduced to 6-hydroxy-2,4,5-triaminopyrimidine. Tin (II) chloride , sodium dithionite or hydrogen in conjunction with a hydrogenation catalyst ( palladium on carbon) are used as reducing agents for this purpose .

Preparation of 6-hydroxy-2,4,5-triaminopyrimidine
Synthesis of 6-hydroxy-2,4,5-triaminopyrimidine, a starting material for industrial folic acid synthesis

In a three-component reaction , the 6-hydroxy-2,4,5-triaminopyrimidine is then converted into folic acid with 1,1,3-trichloroacetone and N - (4-aminobenzoyl) - L -glutamic acid under weakly acidic conditions and with the aid of sodium hydrogen sulfite implemented. Instead of the trichloroacetone, 2,3-dibromopropionaldehyde or methylglyoxal can also be used.

Industrial synthesis of folic acid
Industrial synthesis of folic acid from 6-hydroxy-2,4,5-triaminopyrimidine, 1,1,3-trichloroacetone and N - (4-aminobenzoyl) - L -glutamic acid

Chemical and physical properties

Tautomeric forms of folic acid
Carboxylic acid ester
Lactam form
Phosphoric acid ester
Lactim form

Acidity

Folic acid is a three protonic acid . The corresponding negative decadic logarithm of acidity constants (pK S values) in water under normal conditions be 4.65; 6.75; 9.00.

Tautomerism

Lactam-lactime tautomerism occurs in the pterin partial structure of the molecule , the two molecules that can be formulated as boundary structures are systematically referred to as (2 S ) -2 - ({4 - [(2-amino-4-oxo-1 H -pteridine- 6-yl) methylamino] benzoyl} amino) pentanedioic acid (lactam form) and (2 S ) - N - {4 - [(2-Amino-4-hydroxypteridin-6-yl) methylamino] benzoyl} glutamic acid (lactim form ) designated.

stability

The vitamin is sensitive to light (especially UV radiation ), oxygen , heavy metals , elevated temperatures and (albeit very slightly) water. So too intensive watering and long storage and cooking times of food should be avoided. Intensive solar radiation that hits human skin also reduces folic acid in the body. In fair-skinned people, the effect is particularly strong.

biochemistry

Folic acid is the precursor of the coenzyme tetrahydrofolic acid (THF) . The reduction of folic acid to dihydrofolic acid is vitamin C dependent. Further reduction produces the active form, tetrahydrofolic acid, which is present as an anion tetrahydrofolate under physiological conditions . This has a central position in the C1 metabolism. THF acts particularly as a supplier of methyl (CH 3 -), methylene (CH 2 =) and formyl groups (HCO-) ​​and is involved in the synthesis of purine bases and deoxy-thymidine monophosphate (dTMP), which are responsible for the DNS replication are necessary. THF is also a coenzyme for the methylation of homocysteine to methionine . The C1 modules of the THF u. a. of the amino acids serine , glycine and histidine . In amino acid metabolism is as a cofactor pyridoxal phosphate needed. An exercise test with histidine is used to diagnose folic acid deficiency. Because it participates in the synthesis of DNA building blocks, folic acid plays a crucial role, particularly during pregnancy and in cells that are often dividing (e.g. bone marrow ).

Recording and storage

Folic acid is essential for the human organism and cannot be produced by it. Therefore, folic acid must be taken in with food. In order to get into the cell interior, starting with the intestinal mucosa cells, the folic acid molecule depends on the presence of the transport protein proton-coupled folate transporter , which is also responsible for its export into the bloodstream. THF and 5-derivatives of THF use the folate transporter 1 for import, also and especially in the intestine. Folate, dihydrofolic acid (DHF) and THF can switch into the mitochondria by means of the mitochondrial folate transporter .

Folate and its derivatives are stored in the cytosol and mitochondria of cells by binding to polyglutamate . Only in this way can many of the carbon-transferring reactions take place. The enzyme folyl polyglutamate synthetase is required for the binding of DHF and THF in particular .

In cell cultures, excess folate led to a significant decrease in the expression of all folate-transporting proteins ( PCFT , RFC , folate receptor ) in intestinal cells. In the human organism, excess folic acid can mask a vitamin B 12 deficiency. Due to the strong dependence on vitamin B 12 and folic acid metabolism, megaloblastic anemia develops if one of the two is deficient .

Physiological need

The recommended daily dose according to the RDA is 200 µg. The reference values for nutrient intake (1st edition 2015 of the German Nutrition Society ) recommend a daily intake of 300 µg folic acid (women who want to have children around 550 µg at the time of possible fertilization). With a view to the additional prevention of atherosclerosis , 600 µg were previously recommended for healthy adults, 800 µg for pregnant women and nursing mothers. The intake of more than 1,000 µg folic acid daily has no additional health effect and only leads to a cycle of non-metabolic folic acid in the body. The reason for this is the extremely limited activity of the so-called dihydrofolate reductase (DHFR) and its associated rapid saturation. This in the liver occurring enzyme helps the supplied folic acid into a usable form for the human organism ( tetrahydrofolic acid to transform). After administration of large amounts of folic acid, most of these are excreted unchanged in the urine as pteroyl monoglutamate. The risks of an oversupply with folic acid are now viewed critically. For example, an excess of folic acid can mask a vitamin B12 deficiency, which can damage the nervous system.

Folic acid deficiency and malformations

A folic acid deficiency in the human body affects the blood count in that it can lead to megaloblastic or hyperchromic macrocytic anemia . Humans can store a maximum of 12 to 15 mg of folic acid; this corresponds to a supply for three to four months. Normally the blood serum contains 5 to 20 μg / L, the erythrocytes between 160 and 640 μg / L of the vitamin. If there is a deficiency, the serum level falls first, which is why this is usually determined using high-performance liquid chromatography (HPLC) or chemiluminescence . Folic acid deficiency very often occurs as a result of increased alcohol consumption, diseases of the small intestine or liver diseases. In women, the folic acid requirement is increased when taking contraceptives and during pregnancy.

In embryonic development , a folic acid deficiency favors the development of neural tube defects such as spina bifida or anencephaly . It should also have an impact on premature birth . Every year in Germany around 800 children are born with a neural tube defect, which means that around one in a thousand newborns is affected; Pregnancies terminated because of spina bifida must be added. An adequate supply of folic acid during pregnancy also seems to play an important role with regard to language development in the child. A prospective observational study from Norway also shows a connection between folic acid deficiency and autism , which is why folic acid should be taken when a pregnancy is desired.

Folic acid deficiency leads to megaloblastic anemia ( hyperchromic macrocytic anemia ). The joint responsibility of folic acid in cell maturation, differentiation and division, in particular that of red and white blood cells and mucous membrane cells, is currently being investigated in several universities and research laboratories. In the case of diseases of the cardiovascular system, for example arteriosclerosis , care should also be taken to ensure an adequate supply of folic acid. The value for the amino acid homocysteine in the blood is regarded as a cardiovascular risk factor. Homocysteine ​​is converted into methionine with the help of folic acid and vitamin B 12 . The positive effects of increased folic acid doses - which among other things lower the homocysteine ​​level - on the course of cardiovascular diseases have not been well documented.

Risks of Supplementation

Data from randomized controlled studies on folic acid supplementation indicate an increased risk of tumors when folic acid is taken in combination with vitamin B 12 in patients with coronary artery disease (CHD). Malignant lung tumors, which also contribute to the increased mortality of patients with folic acid vitamin B 12 supplementation, occur more frequently.

Legal Aspects

Since the turn of the millennium, folic acid has been added to staple foods in an increasing number of countries. This action now applies to 67 countries worldwide. However, no country in the European Union takes part in such an action.

Germany

Since two thirds of adults in Germany take in an average of less than 300 µg per day, some paediatricians and some health politicians are calling for flour (if it is not wholemeal flour) to be mixed with folic acid. In this way, malformations in neural tube formation, which occur in the first three weeks of pregnancy and thus at a point in time when the pregnancy is usually not yet known, should be prevented. Medical advocates of folic acid fortification argue that the number of pregnancies with neural tube defects in Germany is particularly high in an international comparison (12.36 per 10,000 births; internationally 7.88 per 10,000 births). Every year in Germany there are around 800 pregnancies with neural tube defects, the majority of which are terminated after a positive screening test. Herrmann / Obeid are of the opinion that a periconceptional administration of folic acid can reduce the frequency of neural tube defects by 20 to 60%.

From the point of view of the Ministry of Food, there is no requirement for admixtures in Germany. Nutrition experts from consumer advice centers u. a. of flour with folic acid that oppose mandatory enrichment, since consumers naturally with fruit , vegetables and whole grain bread can absorb enough folic acid, and he was free, moreover, food supplements or even sold in shops, folic acid fortified cereal bars , beverages, dairy products or saline to acquire .

Austria

As in Germany, the folic acid supply in Austria is viewed as insufficient. From the Nutrition Report 2000 of the German Nutrition Society, due to similar eating habits, “the recommended folate intake is not achieved by a large part of the population in Austria with today's usual diet.” According to the Austrian Nutrition Report 2017, the average intake of folate is in both sexes and all age groups below the recommended intake of 300 μg per day. Only 27% of women and 42% of men are in the range of the recommended intake. The topic is not dealt with on the website of the Austrian Ministry of Social Affairs , there are no legal obligations to add folic acid to food, but it is discussed in specialist circles.

Switzerland

In January 2000, the Swiss Folic Acid Offensive Foundation started a national prevention campaign with the aim of closing the folic acid gap according to the 4th Swiss Nutrition Report 98 of the Federal Office of Public Health. Since then, over three hundred products have been fortified with folic acid, which are labeled with the folic acid vitamin logo . Thanks to this campaign, awareness of folic acid prevention increased from 38% to 76% between 2000 and 2010.

USA and Canada

In the USA and Canada , the addition of folic acid to wheat flour has been a legal requirement since 1998. Since then, only about half as many children have been born with spina bifida in Canada . Anencephaly fell by 38% and encephalocele by 31%. In the USA, a decrease of between 1 and 34 percent (average about 20%) was observed for spina bifida, depending on the population group, and similar results are available for anencephaly.

Web links

Wikibooks: Biochemistry and Pathobiochemistry: Folate Metabolism  - Learning and Teaching Materials

Individual evidence

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  2. ^ German Nutrition Society: Reference values ​​for nutrient intake. Folate . 1st edition, 3rd corrected reprint 2008.
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  4. ↑ a b Entry on folic acid in the ChemIDplus database of the United States National Library of Medicine (NLM) .
  5. ↑ NDL / FNIC: Food Composition Database Home Page ( Memento from March 3, 2015 in the Internet Archive ): Leavening agents, yeast, baker's, active dry.
  6. ↑ NDL / FNIC: Food Composition Database Home Page ( Memento of March 3, 2015 in the Internet Archive ): Food groups: cereal grains and pasta; legumes and legume products.
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  21. ↑ Mariel Croon: Getting pregnant. Find the right time . 2005, p. 67
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  23. ↑ Steven W. Bailey and June E. Ayling: The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake . In: Proc Natl Acad Sci USA . 2009, S. Epub. PMID 19706381 . (PDF; 297 kB).
  24. ^ Max Rubner Institute : Press release of March 13, 2012.
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  28. ↑ Folic acid is also good against speech delay. News from the Ärzte Zeitung from October 15, 2011.
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  30. ↑ Prenatal Folic Acid Supplementation Associated With Lower Risk of Autism .
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  37. ↑ Thorsten Denkler: Bread should be given vitamins by law . taz of October 16, 2006.
  38. ↑ folic acid. Main Association of Austrian Social Insurance Institutions, accessed on March 23, 2019 .
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  40. ↑ SBH information booklet No. 4/10 ( Memento from June 7, 2014 in the Internet Archive ), p. 20 (PDF; 2.6 MB).
  41. ↑ Decline in the Prevalence of Spina Bifida and Anencephaly by Race / Ethnicity: 1995-2002 . Pediatrics 2005; 116: 580-586.
  42. ↑ Philippe de Wals, Fassiatou Tairou, Margot I. van Allen, Soo-Hong Uh, R. Brian Lowry, Barbara Sibbald, Jane A. Evans, Michiel C. van den Hof, Pamela Zimmer, Marian Crowley, Bridget Fernandez, Nora S. . Lee and Theophile Niyonsenga: Reduction in neural-tube defects after folic acid fortification in Canada . N Engl J Med . 2007 Jul 12; 357 (2): 135-42, PMID 17625125 full text .

See also