Activity 2- Folate metabolism

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HUN-6249

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Feb 20, 2024

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Folate metabolism (10 points) Answer the following questions based on the article by Scaglione F and Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica, 2014; 44(5): 480-8. 1. Draw a diagram to represent the conversion of folic acid to its metabolically active form, tetrahydrofolate (THF). (1 pt) 2. What is the predominant form of folate found in plasma? (1 pt) L-5-methyl-THF "5,10-methylene-THF is in turn converted into L-5-methyl-THF [the predominant folate form found in plasma (Blom & Smulders, 2011)]" 3. Why is folic acid supplementation not effective in patients taking methotrexate? What would be a good alternative to folic acid and why? (1 pt) Methotrexate, along with other drugs like aminopterine, pyrimethamine, and trimethoprim, inhibits the enzyme dihydrofolate reductase (DHFR). DHFR is responsible for converting dihydrofolate (DHF) to tetrahydrofolate (THF), which is a crucial step in the metabolic activation of folic acid. Folic acid itself isn't active as a coenzyme. It has to undergo several metabolic steps, including the aforementioned conversion involving DHFR, to be metabolically active in the form of THF. The conversion of folic acid by DHFR in humans, especially in the liver, is significantly slower than in other organisms, like rats. High doses of folic acid will saturate DHFR, limiting its effectiveness, especially in individuals with lower-than-average DHFR activity. Supplementation with high doses of folic acid might lead to transients of plasma unmetabolized folic acid, especially when the daily intake is more than the recommended dietary allowance. 5-Methyltetrahydrofolate ([6S]-5-MTHF or 5-MTHF): This is the naturally occurring, active form of folate in the body. Several studies indicate that 5-MTHF has superior bioavailability compared to folic acid, regardless of the individual's genetic makeup. It does not require conversion by DHFR, bypassing the step inhibited by methotrexate. Increases in red blood cell (RBC) and plasma folate concentrations were significantly higher with 5-MTHF supplementation than with folic acid in various study groups. Unlike folic acid, 5-MTHF doesn't mask vitamin B12 deficiency, reducing the associated risks. Folinic Acid: Mentioned as an alternative especially when treatment with drugs like methotrexate, which inhibit DHFR, is in place.

4. 5-methyltetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism. a. What is the function of MTHFR? (2 pt) MTHFR is associated with folate metabolism and is a key enzyme in the conversion of homocysteine to methionine. b. Which vitamin cofactor is important for MTHFR activity? (1 pt) However, based on what I know, vitamin B12 is a crucial cofactor for enzymes involved in homocysteine metabolism, including the MTHFR pathway. c. What is the consequence of a mutation in the MTHFR gene leading to a substitution of an alanine for a valine? The mutation in the MTHFR gene resulting in an amino acid change from alanine to valine (A222V) affects the binding activity of the enzyme with flavin adenine dinucleotide (FAD) and its stability. Such a mutation is the most established genetic risk factor for neural tube defects (NTD) and leads to elevated plasma levels of homocysteine. The in vitro enzyme activity in the TT genotype (homozygous for this mutation) is reduced by about 75% compared to the wild-type enzyme. d. Would folate supplementation be recommended for individuals with polymorphisms in the MTHFR gene? What type of supplement would be ideal? (2 pt) Yes, supplementation with folate is recommended for individuals with the TT homozygosis (a type of polymorphism in the MTHFR gene), as it has been shown to reduce the risk of NTD and help in re-establishing correct levels of homocysteine in these individuals. As for the type of supplement that would be ideal, the text suggests that naturally occurring 5-MTHF (5- methyltetrahydrofolate) might present advantages over synthetic folic acid. This is because 5- MTHF displays higher bioavailability compared to folic acid, irrespective of the patient's genotype. It is suggested that 5-MTHF, or [6S]-5-MTHF specifically, should be considered a valid alternative to folic acid for supplementation or in the fortification of food products.

2. What is the predominant form of folate found in plasma? ChatGPT The predominant form of folate found in plasma is L-5-methyl-THF (as mentioned in the passage: "5,10-methylene-THF is in turn converted into L-5-methyl-THF [the predominant folate form found in plasma (Blom & Smulders, 2011)]"). based off that article, Why is folic acid supplementation not effective in patients taking methotrexate? What would be a good alternative to folic acid and why? (1 pt) ChatGPT Based on the provided article excerpts, there isn't a direct statement that says folic acid supplementation is not effective in patients taking methotrexate. However, the article does mention some potential issues with folic acid, such as the low activity of DHFR in the human liver causing exposure to high transients of plasma unmetabolized folic acid at doses greater than the RDA. A good alternative to folic acid, as mentioned in the article, is naturally occurring 5-MTHF (L-5- methyltetrahydrofolate). It is suggested that 5-MTHF may be more or at least as effective as folic acid in improving folate status. 5-MTHF may present important advantages over synthetic folic acid, making it a potential valid alternative to folic acid supplementation. Why is folic acid supplementation not effective in patients taking methotrexate? 1. Methotrexate, along with other drugs like aminopterine, pyrimethamine, and trimethoprim, inhibits the enzyme dihydrofolate reductase (DHFR). DHFR is responsible for converting dihydrofolate (DHF) to tetrahydrofolate (THF), which is a crucial step in the metabolic activation of folic acid. 2. Folic acid itself isn't active as a coenzyme. It has to undergo several metabolic steps, including the aforementioned conversion involving DHFR, to be metabolically active in the form of THF. 3. The conversion of folic acid by DHFR in humans, especially in the liver, is significantly slower than in other organisms, like rats. High doses of folic acid will saturate DHFR, limiting its effectiveness, especially in individuals with lower than average DHFR activity. 4. Supplementation with high doses of folic acid might lead to transients of plasma unmetabolized folic acid, especially when the daily intake is more than the recommended dietary allowance (RDA). What would be a good alternative to folic acid and why? 1. 5-Methyltetrahydrofolate ([6S]-5-MTHF or 5-MTHF): This is the naturally occurring, active form of folate in the body.  Several studies indicate that 5-MTHF has superior bioavailability compared to folic acid, regardless of the individual's genetic makeup.  It does not require conversion by DHFR, bypassing the step inhibited by methotrexate.

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 Increases in red blood cell (RBC) and plasma folate concentrations were significantly higher with 5-MTHF supplementation than with folic acid in various study groups.  Unlike folic acid, 5-MTHF doesn't mask vitamin B12 deficiency, reducing the associated risks. 2. Folinic Acid: Mentioned as an alternative especially when treatment with drugs like methotrexate, which inhibit DHFR, is in place. In Summary: Folic acid supplementation is not effective in patients taking methotrexate because methotrexate inhibits DHFR, the enzyme responsible for converting folic acid into its active form. A better alternative would be 5-MTHF or folinic acid because they bypass the metabolic step that methotrexate inhibits and offer other benefits, such as higher bioavailability and not masking vitamin B12 deficiency. based off the provided article, a. What is the function of MTHFR? b. Which vitamin cofactor is important for MTHFR activity? c. What is the consequence of a mutation in the MTHFR gene leading to a substitution of an alanine for a valine? d. Would folate supplementation be recommended for individuals with polymorphisms in the MTHFR gene? What type of supplement would be ideal? ChatGPT Based on the information you provided: a. What is the function of MTHFR? The exact function of MTHFR isn't specified in the given text. However, based on the context, MTHFR is associated with folate metabolism and is a key enzyme in the conversion of homocysteine to methionine. b. Which vitamin cofactor is important for MTHFR activity? The text does not specify a particular vitamin as a cofactor for MTHFR. However, based on what I know, vitamin B12 is a crucial cofactor for enzymes involved in homocysteine metabolism, including the MTHFR pathway. c. What is the consequence of a mutation in the MTHFR gene leading to a substitution of an alanine for a valine? The mutation in the MTHFR gene resulting in an amino acid change from alanine to valine (A222V) affects the binding activity of the enzyme with flavin adenine dinucleotide (FAD) and its stability. Such a mutation is the most established genetic risk factor for neural tube defects (NTD) and leads to elevated plasma levels of homocysteine. The in vitro enzyme activity in the TT genotype (homozygous for this mutation) is reduced by about 75% compared to the wild-type enzyme. d. Would folate supplementation be recommended for individuals with polymorphisms in the MTHFR gene? What type of supplement would be ideal? Yes, supplementation with folate is recommended for individuals with the TT homozygosis (a type of polymorphism in the MTHFR gene), as it has been shown to reduce the risk of NTD and help in re-establishing correct levels of homocysteine in these individuals. As for the type of supplement that would be ideal, the text suggests that naturally occurring 5-MTHF (5-methyltetrahydrofolate) might present advantages over synthetic folic acid. This is because 5-MTHF displays higher bioavailability

compared to folic acid, irrespective of the patient's genotype. It is suggested that 5- MTHF, or [6S]-5-MTHF specifically, should be considered a valid alternative to folic acid for supplementation or in the fortification of food products.

Activity 2- Folate metabolism

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