this chapter talked about folate, B12, and S-adenosyl methionine: three compounds that can either donate or accept single carbon groups and participate in a wide variety of essential reactions in the body. folate has three structural components: a bicyclic pteridine ring, para-amino benzoic acid (PABA), and a polyglutamate tail. folate can be obtained from the diet from animal products, leafy greens, legumes, fruits. after ingestion, folate is cleaved by brush border proteases to the monoglutamate form, reduced in intestinal epithelial cells and transported to the liver, where it is reconjugated into the polyglutamate form and stored.
folate can be reduced to dihydrofolate, and then to tetrahydrofolate, the form that is able to accept carbon groups. it can then accept carbons can attach to the N5 or N10 (on the pteridine ring and PABA, respectively), to form N10-formyl-FH4. this compound is converted to the bridge form N5,N10 methenyl FH4, which can be reduced to N5,N10 methylene FH4 and further reduced to folate's most stable form, N5 methyl FH4. this is the predominant form that folate is found in blood, and once formed, can not be re-oxidized to other forms of folate.
folate can accept carbons from a variety of different sources, including serine, formate, glycine, formaldehyde, histidine, choline, methionine. serine is the major carbon donor and forms glycine (recall from chapter 39 that this is the major pathway of glycine formation) and N5,N10-methylene FH4. the opposite reaction, donation of one carbon groups, is also possible: the formation of the nucleotide dTMP, which is required for DNA synthesis, involves transferring a carbon from N5,N10 methylene FH4 to dUMP to form dTMP and FH2, which is reduced back to FH4 by dihydrofolate reductase.
vitamin B12 is the second one carbon transfer compound: it is composed of a large corrin ring with a cobalt ion in the middle, which can form complexes with carbon molecules. vitamin B12 is synthesized by bacteria and as such needs to be ingested in the form of animal products. digestion depends on the form it is obtained in; it can come in a free form, or bound to dietary proteins. if ingested in the free form, it will be bound to haptocorrins in the mouth or stomach, then cleaved and bound to intrinsic factor in the duodenum. if bound to dietary proteins, folate will be cleaved in the stomach or intestine and also be bound to intrinsic factor. at this point it is absorbed and bound to transcobalamin II and transported to the liver.
vitamin B12 is involved in two important reactions: (see diagram) the conversion of homocysteine to methionine, and the conversion of methylmalonyl CoA to succinyl CoA (aiding in the conversion of propionyl CoA to succinyl CoA in fatty acid oxidation and amino acid synthesis). if vitamin B12 is deficient, then one of the two pathways for homocysteine conversion is blocked (see diagram), and homocysteine will begin to accumulate- a condition called hyperhomocysteinemia. this condition can also occur when the cystathione synthase enzyme is blocked, or if the enzyme that converts N5N10 methylene FH4 to N5 methyl FH4 is blocked.
one final carbon donor: SAM is s-adenosyl methionine, formed by methionine and ATP (see diagram). it can donate carbon groups to O or N, as opposed to folate, which donates to S or C. after donation, it forms s-adenosyl homocysteine, which can be converted to homocysteine.
questions
folate structure, sources, and digestion...
1. what are the structural components to folate?
2. what is the function of folate in chemical reactions?
3. where do the carbon groups attach to folate?
4. what does the reduction of folate yield?
5. most of the folate in the body is in the form of...
6. what are some sources of folate in the diet?
7. what is the difference between the folate in supplements vs. dietary sources?
8. what happens to dietary folate in the intestine?
9. what happens to folate in the liver?
one carbon pool...
10. what is the one carbon pool?
11. describe the reduction of the formyl group on FH4.
12. what is the major donor of the carbon group to folate in humans?
13. describe the interconversions of the one carbon units of FH4.
14. what does the reaction of serine and FH4 produce?
15. what is dTMP and how is it related to the one carbon pool?
16. what is DHFR?
vitamin B12...
17. what are the key structural characteristics of vitamin B12?
18. what are the two key reactions that B12 aids in?
19. how is vitamin B12 produced and what are some dietary sources?
20. what are the two forms that vitamin B12 will be present in dietary sources?
21. describe the digestion and absorption of vitamin B12.
22. what happens to vitamin B12 after it is absorbed into the ileum?
s-adenosylmethionine (SAM)...
23. what does SAM do?
24. how is SAM synthesized?
25. what does SAM form after it donates its methyl group?
methyl trap hypothesis...
26. what is the most stable form of folate in the folate cycle?
27. what is the only reaction that can extract the methyl from N5 methyl FH4?
28. what is the methyl trap hypothesis?
29. how is homocysteine synthesized?
30. how can a vitamin B12 deficiency lead to an hyperhomocysteinemia?
31. what are two other ways in which homocysteine can accumulate?
32. what is the connection between neural tube defects and folate?
answers
1. bicyclic pteridine ring, para-amino benzoic acid (PABA), and a polyglutamate tail.
2. it accepts a one carbon group.
3. N5 or N10.
4. dihydrofolate and tetrahydrofolate.
5. FH4.
6. green leafy vegetables, fruits, legumes. also synthesized by bacteria.
7. dietary sources have the reduced form whereas supplements have the oxidized form.
8. brush border conjugases convert it into the monoglutamate form, which is absorbed into the intestine, where it is converted into tetrahydrofolate. FH4 is then transported to the liver.
9. it is reconjugated and mostly secreted in the bile to be reabsorbed.
10. a term which refers to the single carbons that are attached to N5 or N10 of folate.
11. the formyl group is formed by the addition of the carbon to N10; this carbon can form a ring structure with a double bond which connects to N5. the double bond can be reduced, and the ring can also be reduced, moving the carbon group to N5.
12. serine.
13. N10-formyl-FH4 forms N5,N10 methenyl FH4, which is reduced to N5,N10 methylene FH4, which is reduced to N5 methyl FH4.
14. serine donates its hydroxymethyl group to FH4, forming glycine and N5,N10 methylene FH4.
15. dTMP is a nucleotide required for the synthesis of DNA, that is formed from addition of dUMP and a carbon from N5,N10 methylene FH4. this forms dTMP as well as FH2.
16. dihydrofolate reductase, the enzyme that aids in the reduction of FH2 back to FH4, after reactions such as the dTMP reaction, which forms FH2.
17. the overall structure is a "corrin" ring with 4 pyrrole rings, out of which 2 are joined directly and 2 are joined by a methylene bridge. in the center of the ring is cobalt, which can bind to carbon.
18. donation of a carbon group from N5 methyl FH4 to homocysteine to form methionine. also, rearrangement of methylmalonyl CoA to form succinyl CoA.
19. it is only synthesized by bacteria and is consumed in the diet in the form of meat, eggs, diary, fish, poultry, seafood.
20. either bound to dietary proteins or in the free form.
21. the free form is bound to the haptocorrin protein, which is secreted in the mouth and stomach. the bound form is cleaved from its proteins by proteases in the stomach and small intestine, and then bound to haptocorrin. in the intestine, both forms have their haptocorrins removed by intestinal proteases, and then are bound to intrinsic factor, which facilitates their absorption into ileum enterocytes.
22. in the enterocyte cells, B12 complexes with transcobalamin II, and then is transported to the liver and other tissues (about 50% to the liver).
23. it is involved in the donation of a methyl group to oxygen or nitrogen- it is involved in at least 35 important reactions.
24. methionine and ATP.
25. homocysteine and adenosine.
26. N5 methyl FH4.
27. the methionine synthase reaction with the aid of vitamin B12.
28. a lack of vitamin B12 causes an accumulation of the N5 methyl F4 form of folate, causing a folate deficiency.
29. from s-adenosyl homocysteine, which is formed when s-adenosyl methionine donates a carbon group.
30. vitamin B12 is required for the conversion of homocysteine back to methionine. if this pathway is blocked, homocysteine will be used for the synthesis of cysteine. when cysteine accumulates, this pathway will also be blocked, leading to an accumulation of homocysteine.
31. malfunctioning of the enzyme that converts N5N10 methylene FH4 into N5 methyl FH4 can prevent homocysteine conversion to methionine and cause homocysteine accumulation. also, a defect in the cystathionine synthase enzyme will prevent homocysteine from being converted into cystathione and will cause it to accumulate.
32. folate deficiency during pregnancy has been shown to lead to neural tube defects in the developing fetus.
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