liveonearth (liveonearth) wrote,

Biochemistry: The One-Carbon Pool: Folate and B12 Metabolism

What are the carrier molecules for one-carbon groups?
biotin, tetrahydrofolate, s-adenosylmethionine (SAM)

What oxidation states of carbon does each carrier provide?
1) biotin carries CO2
2) tetrahydrofolate (THF or HF4) carried in all ox states but CO2
3) SAM is the main donor of active methyl groups

Which of these carriers are vitamin derivatives?
--Biotin is B7 aka Vitamin H
--tetrahydrofolate is made from folate twice reduced, and folate is water soluble B9
--SAM is not a vitamin, it's ATP plus methionine

--made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase EC
--Transmethylation, transsulfuration, and aminopropylation are the metabolic pathways that use SAM
--Although these anabolic reactions occur throughout the body, most SAM is produced and consumed in the liver

--is a coenzyme in many reactions, esp in the metabolism of amino acids and nucleic acids
--acts as a donor of a group with one carbon atom. It gets this carbon atom by sequestering formaldehyde produced in other processes.
--A shortage in THF can cause ANEMIA so we supplement folate
--Tetrahydrofolic acid is reduced by the drug methotrexate, which is used to impair nucleotide synthesis. This drug is a potent chemotherapy and anti rheumatic.

What transformations of dietary folate are required before it can be absorbed from the GI tract?
It must be deconjugated and reduced to be absorbed

What are the 2 rxns in the human body known to require vitamin B12?
(1) the mitochondrial methylmalonylcoenzyme A mutase conversion of methylmalonic acid (MMA) to succinate, which LINKS LIPID AND CARBOHYDRATE METABOLISM
(2) activation of methionine synthase, which is the RATE LIMITING STEP IN SYNTHESIS OF METHIONINE from homocysteine and tetrahydrofolate

What are the 2 roles played by the methyl cycle?
1) can donate methyl as SAM
2) generates FH4 (uses and regenerates)
--methyl group transfer to an acceptor molecule from SAM
--hydrolysis of SAM
--regeneration of MET from homocystiene
--enzyme: homocysteine methyltransferase
--cofactors: activated methyl and B12
--PRODUCTS OF THIS RXN (made via SAM): creatine, methylated nucleotides (PURINES), phosphatidylecholine, melatonin, dTMP, B12-CH3

B-12 and the FOLATE TRAP
Explain the "folate trap" (abberant methyl cycle) and its role in pernicious anemia.
--B-12 deficiency causes some folate to acidentally get converted to an inactive metabolite. The only way to convert the inactive product back to something useful requires B-12 as a cofactor, so it's stuck, you lose the folate, and you still have all the other symptoms of B-12 deficiency to deal with.
--B-12 Deficiency produces megaloblastic anemia due to its role in folate metabolism. During the many transformations of folate from one form to another, a proportion gets accidentally converted to N5-methyl-THF, an inactive metabolite. This is called the "folate trap," since there is no way for active N5,N10-THF to be regenerated except through a reaction for which a form of vitamin B12, methyl-B12, is a cofactor (see diagram, right). Deficiency of B12 then produces a situation where more and more folate is trapped in an inactive form with no biochemical means of escape. The end result is failure to synthesize adequate DNA.
--all that Dangerfield said in the notes: "the methyl-trap hypothesis explains why certain anemias respond to B12 or folate Tx"
--most B vits can be synthesized from folate so folate Tx works for nearly all B vits
--B-12 is important for the normal functioning of the brain and nervous system and for the formation of blood
--B-12 in metabolism of every cell, esp DNA syn/reg, also fatty acid syn & energy production
--many (though not all) of the effects of functions of B-12 can be replaced by sufficient quantities of folic acid (another B vitamin), since B-12 is used to regenerate folate in the body
--Most "B-12 deficient symptoms" are actually folate deficient symptoms, since they include all the effects of pernicious anemia and megaloblastosis, which are due to poor synthesis of DNA when the body does not have a proper supply of folic acid for the production of thymine
--When sufficient folic acid is available, all known B-12 related deficiency syndromes normalize, save those narrowly connected with the B-12 dependent enzymes Methylmalonyl Coenzyme A mutase (MUT), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase; and the buildup of their respective substrates (methylmalonic acid, MMA) and homocysteine.
----B12 deficiency also produces nervous system lesions not seen in folate deficiency. These lesions are manifest clinically as combined systems disease, a constellation of findings related to demyelination of axons in the spinal cord and cerebrum. These patients have decreased vibratory and proprioceptive senses in the extremities, spastic ataxia, disturbances of vision, taste, and smell, irritability, and somnolence. "Megaloblastic madness" is the term appended to the poorly documented cases of bizarre, sometimes psychotic behavior in B12-deficient patients. Clearly, there must be something that B12 is supposed to do about which folate has little or no concern. The best guess is that it has something to do with B12's role as a cofactor for methylmalonylCoA mutase.

What is the function of intrinsic factor and where is it made?
--made in parietal cells in stomach
--function is absorbtion of B-12
--B-12 is first bound by another carrier in stomach (R-binder from gastric mucosa) but switches carriers when the pancreatic proteases enter the gut stream and destroy the R-binders
--Upon entry into the stomach, vitamin B12 becomes bound to one of two B12 binding proteins present in gastric juice. In the less acidic environment of the small intestine, these proteins dissociate from the vitamin, enabling it to bind to intrinsic factor and enter the portal circulation through a receptor in the ileal mucosa specific for the B12-intrinsic factor complex.

Where is B12 absorbed from the intestines?
--in the ileum to the blood
--via a specific receptor that recognizes the B-12--IF complex
--bound to transcobalamin II in blood
--to liver where it is stored
--transcobalamins are carrier proteins which bind cyanocobalamin (B12)

--Folic acid and folate (the anion form) are forms of the water-soluble Vitamin B9
--occur naturally in food and can also be taken as supplements
--folate has a pterin ring, we can't make those
--Folate gets its name from the Latin word folium ("leaf").
--found in foods: leafy vegetables: turnip greens, lettuces, also in dried beans and peas, fortified cereal products, sunflower seeds and other fruits and vegetables
--dietary folate must be deconjugated (from its chain of glutamates) and reduced to be absorbed
--after absorbtion we put the glutamates back on
--necessary for the production and maintenance of new cells.
--esp important during infancy and pregnancy
--needed to replicate DNA
--affecting most clinically the bone marrow, a site of rapid cell turnover
--RNA and protein synthesis are not hindered by folate deficiency, large red blood cells called megaloblasts are produced, resulting in megaloblastic anemia.
--everybody needs folate to make normal red blood cells and prevent anemia
--folate derivatives are substrates in a number of single-carbon-transfer reactions
--also are involved in the synthesis of dTMP (2'-deoxythymidine-5'-phosphate) from dUMP (2'-deoxyuridine-5'-phosphate)
--helps convert vitamin B12 to one of its coenzyme forms
--FOLATE (F) --reduced-> DIHYDROFOLATE (FH2) --reduced-again-> TETRAHYDROFOLATE (FH4)
--enzyme for both steps: DIHYDROFOLATE REDUCTASE
--the last reaction forming FH4 requires both B12 and folic acid and is not reversible
--uses NADPH and FADH2 to make FH4
--CARBON DONORS: serine is the main one, glycine, histidine, formaldehyde, formate
--F → FH2 → FH4 → CH2=FH4 → 1-carbon chemistry
--DRUGS INTERFERE WITH BIOSYNTHESIS OF FOLIC ACID AND FH4: dihydrofolate reductase inhibitors (such as trimethoprim and pyrimethamine), the sulfonamides (competitive inhibitors of para-aminobenzoic acid in the reactions of dihydropteroate synthetase), and the anticancer drug methotrexate (inhibits both folate reductase and dihydrofolate reductase)

Vitamin B1 (thiamine)
Vitamin B2 (riboflavin)
Vitamin B3,(niacin, includes nicotinic acid and nicotinamide)
Vitamin B5 (pantothenic acid)
Vitamin B6 (pyridoxine)
Vitamin B7, also called vitamin H (biotin)
Vitamin B9, also vitamin M and vitamin B-c (folic acid)
Vitamin B12 (cobalamin)


--"vitamin B-12" is the name for a whole class of chemicals with B-12 activity, and "cyanocobalamin" is only one of these.
--an especially common "vitamer" (that is, member of a family of vitamins, all of which have some particular nutritional activity in preventing some vitamin deficiency disease) of the B-12 vitamin family
--most famous vitamer of the family
--chemically the most air-stable
--easiest to crystallize
--easiest to purify after it is produced by bacterial fermentation
--cyanide is added to the molecule by activated charcoal columns in purification
--the use of this form of B-12 is the most wide-spread.
--does not occur in nature
--transcobalamins are carrier proteins which bind cyanocobalamin (B12)
--cyanocobalamin is not one of the forms of this vitamin which is directly used in the human body (or that of any other animal)
--animals and humans can convert it to active (cofactor) forms such as methylcobalamin.

--used in peripheral neuropathy, diabetic neuropathy etc
--has been studied in conjunction with sleep-wake rhythm disorders, where it appears to yield benefits, but at a low or inconsistent level
--used in vitamin B12 deficiency (pernicious anemia) treatment

--a natural analog of vitamin B-12
--intense red color
--mostly interconvertible forms
--Together with folic acid, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring—most notably the bone marrow and myeloid cells.
--As a cofactor, cobalamins are essential for two cellular reactions: (1) the mitochondrial methylmalonylcoenzyme A mutase conversion of methylmalonic acid (MMA) to succinate, which links lipid and carbohydrate metabolism, and (2) activation of methionine synthase, which is the rate limiting step in the synthesis of methionine from homocysteine and tetrahydrofolate (Katzung, 1989).
Tags: biochemistry, blood, diet, digestion, liver, pharmaceuticals, vit b, vitamins

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