Table of Contents<\/b><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”5780″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 1. Structure of Folic Acid (FA):<\/b> Folic acid (pteroylmonoglutamic acid<\/i><\/b>) is the synthetic and the most stable form of the vitamin. FA is fully oxidized and consists of a [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”introduction”][vc_column][vc_custom_heading text=”Introduction”][vc_column_text single_style=””]<\/p>\n Folates represent a large family of water-soluble B vitamins, which were first recognized and reported by Lucy Wills in 1933 as a hematopoietic factor<\/b> in yeast and liver extracts. In 1940, Snell and colleagues described a factor that is essential for the growth of Lactobacillus casei<\/i><\/b>. Subsequently, this factor was isolated, characterized, and named as \u2018folate<\/b>.\u2019 In 1941, Mitchell coined the term \u2018folic acid<\/b>\u2019 (Latin word \u2018folium\u2019<\/b> for \u2018leaf\u2019)<\/b>, who extracted the substance from 4 tons of spinach leaves<\/i><\/b> [1].<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-1″][vc_column][vc_custom_heading text=”Biochemistry and Function of Folates in Human Cells”][vc_column_text single_style=””]<\/p>\n By convention, \u2018folates<\/b>\u2019 is a generic term, referring to a large family of compounds consisting of a 2-amino-4-hydroxy-pteridine ring<\/b>, linked by a methylene (CH2<\/sub>) group to a p-aminobenzoyl moiety<\/b>, which is in turn linked through amide bond to the \u03b1-amino group of a monoglutamate or poly-\u03b3-glutamate<\/b>. One-carbon (1-C<\/b>) units can be attached to N-5, N-10, or both. On the other hand, the name \u2018folic acid\u2019<\/b> is reserved for the synthetic form<\/b> with the fully oxidized pteridine ring and no 1-C substitution (see Figure 1<\/b>) [2].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Naturally occurring folate forms consist of derivatives of 5,6,7,8-tetrahydropteroyl-\u03b3-glutamate (THF) that are fully reduced at 5,6,7, and 8 positions of the pyrazine ring<\/b>. The molecular structure of FA, THF, and the reduced folate forms are shown in Figure 2<\/b>. Natural folate forms are polyglutamates, with five to eight glutamate residues prevailing in the mammalian cell. Folates exhibit a one-carbon unit at the N-5 and\/or N-10 position, which can be transferred by means of certain enzymes.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Reduced folates function as acceptors and donors of \u2018one-carbon units\u2019<\/b> at three different oxidation levels<\/b> (see Figure 2<\/b>) [3], for example:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Over one hundred different vitamers (folate derivatives) has been detected in biological tissues<\/i><\/b>. Vitamers are the members of the same vitamin family; and are chemically related compounds having qualitatively comparable metabolic activities, i.e., similar vitamin activities.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In summary, folate forms differ in three aspects<\/b>, for instance:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n These chemical differences are strongly related to the bioavailability, cellular distribution, and functions of the different folate forms<\/u><\/i>.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”5782″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 2. Structure of Tetrahydrofolate (THF) and the Reduced Folate Forms.<\/b> Bonds at positions, 5,6,7, and 8 can be oxidized to 5,6-dihydrofolate<\/b> (DHF<\/b>). One carbon units can be accepted by tetrahydrofolate<\/b> (THF<\/b>) at N-5 and\/or N-10 positions of the pteridine ring.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Adequate folate intake is crucial for cell division and homeostasis. Folates act as essential co-enzymes<\/b> in many biological pathways (see Figure 3<\/b>), such as:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The folate metabolism intersects with the methionine cycle<\/i> and the choline pathway<\/i>.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Apart from DNA synthesis, important functions are the methylation of homocysteine<\/i><\/b> (Hcy) and the formation of S-adenosyl methionine<\/i><\/b> (SAM<\/b>), the most important methyl donor in the cell<\/u>. Most of the folate coenzymes exist in the liver (hepatic folate levels range from 10 \u2013 35 \u03bcmol\/L<\/i>).<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The dihydrofolate reductase<\/b> (DHFR<\/b>) reduces FA to DHF and DHF to the active form, THF. The cytosolic folate metabolism consists of three interrelated cycles<\/i><\/b> (see Figure 3<\/b>), viz.,<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n 5-Methyl-THF is the predominant folate form, comprising 82-93% of total folate in the human serum<\/i><\/b>. After cellular uptake, 5-methyl-THF is converted into THF. This reaction is carried out by the cobalamin (Cbl, vitamin B<\/b>12<\/sub><\/b>)-dependent methionine synthase<\/b>.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The methionine cycle is an important pathway for the conversion of Hcy (a non-proteinogenic amino acid<\/u><\/i>) to methionine (an essential proteinogenic amino acid<\/u><\/i>) and the formation of SAM. Elevated plasma-concentrations of total Hcy (tHcy) can be caused by deficiencies of B vitamins [such as vitamin B9<\/sub> (folate)<\/a>, <\/i><\/b>vitamin B<\/i><\/b>12<\/sub> <\/i><\/b>(Cbl), or vitamin B<\/i><\/b>6<\/sub> <\/i><\/b>(pyridoxal 5\u2019-phosphate)]<\/i><\/b> or genetic defects<\/i><\/b>. 5, 10-Methylene-THF is converted to [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”5783″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 3. Summary of Folate Pathway.<\/b> Reduced folates<\/b> (shown in blue fonts) act as coenzymes, which serve as 1-C acceptor or donor units in a variety of reactions, viz., one carbon metabolism<\/b>. For example, (1)<\/b> methionine synthesis, (2) <\/b>histidine catabolism, (3)<\/b> purine ring synthesis, (4)<\/b> serine-glycine interconversion, and (5) <\/b>thymidylate synthesis. [MTHFR, methylenetetrahydrofolate reductase; MeCbl, methylcobalamin; MTR, methionine synthase; MTRR, methionine synthase reductase; THF, tetrahydrofolate]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-2″][vc_column][vc_custom_heading text=”The Methyl-Folate Trap”][vc_column_text single_style=””]<\/p>\n Cbl deficiency causes a functional folate deficiency<\/b>. The methionine synthase<\/i><\/b> (MS\/MTR<\/b>) is inactive in Cbl deficiency or after exposure to nitrous oxide. Because of the irreversible reaction of the enzyme MTHFR folate is \u2018trapped\u2019 as 5-methyl-THF<\/u><\/i> and cannot be converted to THF via MS (see Figure 3<\/b>) [4]. 5-methyl-THF is a poor substrate for the folylpoly-\u03b3-glutamate synthase<\/i><\/b> (FPGS<\/b>), which is responsible for the addition of glutamate moieties to folates. The polyglutamate synthesis ceases, which limits the pool of intracellular polyglutamates. The de novo<\/i> synthesis of purines and thymidylates grinds to a halt!<\/u><\/i><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-3″][vc_column][vc_custom_heading text=”Take Home Messages”][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_class=”blog-text-35795″ el_id=”conclusion”][vc_column][vc_custom_heading text=”Summary and Conclusions” el_class=”blog-text-35795″][vc_column_text single_style=””]<\/p>\n In this blog, we have presented a brief overview about the structure and relationship of folic acid and its derivatives. As well as the five major metabolic functions of folate pertaining to human cells.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In summary, vitamin B9<\/sub>, folate, and folic acid are generic terms for a family of related compounds (vitamers) that function as coenzymes in the processing of one-carbon (1-C) units. They are derived from pteroic acid, to which one or more molecules of glutamic acid are attached. Pteroic acid is composed of a pteridine ring (2-NH2<\/sub>-4-OH pteridine) joined to a p<\/i>-aminobenzoic acid residue.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n When pteroic acid is conjugated with one molecule of L<\/i>-glutamic acid, pteroylglutamic acid is formed; this can be reduced to DHF with hydrogens in positions 7 and 8, or to THF with hydrogens in positions 5, 6, 7, and 8. Only the reduced forms are biologically active. Other folate derivatives have multiple glutamic acid residues ranging from 1 to 7.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In a nutshell, folate is converted by specific enzymes to DHF, which is converted to THF and is in turn converted to methylene-THF and finally to 5-methyl-THF.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text single_style=”” el_class=”blog-banner-section”]<\/p>\n Folate (vitamin B9) is very important for your child\u2019s brain development!<\/p>\n During pregnancy, it helps prevent neural tube defects and plays a big role in forming a normal and healthy baby\u2019s brain and spinal cord. Folate also helps cells divide and assists in both DNA and RNA synthesis.<\/p>\n Emerging research suggests that the presence of FRAAs negatively impacts folate transport into the brain.<\/p>\n Yes, there is a test – The Folate Receptor Antibody Test (FRAT\u00ae<\/sup>) has emerged as a diagnostic tool for detecting the presence of FRAAs.<\/p>\n It is important to screen at an early age or as soon as possible as there may be corrective measures available. Please consult your physician for further information.<\/p>\n To request a test kit, click on the button below.<\/p>\n Request Now<\/a><\/p>\n<\/div>\n<\/div>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”text-gray-23″]For information on autism monitoring, screening and testing please read our blog<\/a>.[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-references” el_class=”blog-text-35795″][vc_column][vc_custom_heading text=”References” use_theme_fonts=”yes”][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row]<\/p>\n","protected":false},"excerpt":{"rendered":" Explore the biochemistry and functions of folates in health and disease. Learn more about the importance of folate intake and its role in essential biological pathways.<\/p>\n","protected":false},"author":3,"featured_media":5781,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[80,64],"tags":[],"yoast_head":"\n\n
\n<\/a><\/li>\n
\n2-amino-4-hydroxy-pteridine ring<\/i><\/b> (blue), linked at the C-6 position to a p<\/i><\/b>-aminobenzoic acid<\/b> (p<\/i><\/b>ABA<\/b>) (fuchsia), and L<\/i><\/b>-glutamic acid<\/b> (green). FA is the preferred form that is used in dietary supplements and fortified foods<\/b>, because of its stability and taste and odorless characteristics<\/b>.<\/p>\n\n
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\n5-methyl-THF by the flavoprotein 5,10-methylene-tetrahydrofolate reductase<\/b> (MTHFR<\/b>) in an irreversible<\/u><\/i><\/b> and flavin adenine dinucleotide (FADH<\/b>) and nicotinamide adenine dinucleotide phosphate (NADPH<\/b>)-dependent reaction.<\/p>\n\n
Did You Know? Folate Receptor Autoantibodies (FRAAs) may impede proper folate transport.<\/h4>\n
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Is there a test for identifying Folate Receptor Autoantibodies (FRAAs)?<\/h4>\n
![\"FRAT](\"https:\/\/autism.fratnow.com\/blog\/wp-content\/uploads\/2023\/12\/frat-mascot-image.webp\")
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\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/3067148\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/30587505\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/27641100\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/30693532\/
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