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35 Cards in this Set

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Why is the methylation cycle important?
It produces adenosyl methionine which allows for epigenetic regulation via DNA regulation and capping mechanisms for mRNAs. There are hundreds of other methylation reactions.
What B vitamins are especially important for the 1 carbon metabolic pathway?
riboflavin (B2), pyridoxal phosphate (B6), tetrahydrofolate (B9), cobalamin (B12)
What is a central compound of the methylation cycle?
homocysteine
What critical reaction provides a link between the folate and methylation cycles?
homocysteine remethylation to methionine via methionine synthase (MTR) (requires B12)
Which enzyme associates with MTR in the homocystein e to methionine reaction for the purpose of reducing cobalamin (B12)?
MTR reductase (MTRR)
Which alternative enzyme can generate methionine from homocysteine in the liver and kindey utilizing betaine?
betaine-homocysteine methyltransferase (BHMT)
How is S-adenyosylmethionine generated in the methylation cycle?
methionine gets adenosylated to S-adenosylmethionine (AdoMet) by methionine adenosyltransferase (MAT)
What is the active methyl donor of AdoMet?
a sulfonium group +S-CH3 is 1000x more active than S-CH3 as a methyl donor.
How does methylation of other substrates by AdoMet occur?
Methylation is catalyzed by methyltransferases, resulting in the production of S-adenosylhomocysteine (AdoHcy) which is itself a potent feedback inhibitor of most methyltransferases. (Methylation is highly regulated.)
How is homocysteine regenerated in the methyl cycle?
S-adenosylhomocysteine is hydrolyzed by AdoHcy hydrolase (SAHH). It produces adenosine and homocysteine which is important because the cycle as a whole is not reversible. These products are then transported out of the cell to prevent methyltransferase inhibition by reformation of AdoHcy.
How are homocysteine and methionine levels regulated with during the FED and FASTED state?
During the FED state homocysteine (and, consequently, the precursor pool for methionine) is irreversibly degraded to cysteine and α-ketobutyrate following the transsulfuration pathway.
How does AdoMet affect the transulfuration pathway?
When AdoMet levels increase due to methionine availability, AdoMet activates the first enzyme in homocysteine degradation (CBS) and inhibits the enzyme from the folate cycle (methylenetetrahydrofolate reductase--MTHFR) that provides a methylation agent (5-methyl THF) for the conversion of homocysteine to methionine.
What's the first step in homocysteine degradation?
Condensation of homocysteine with serine to form cystathione by cystathionine β-synthase.
What's the second step of the transulfuration pathway that results in the formation of cysteine?
Hydrolysis of cystathione to cysteine and α-ketobutyrate by cystathioine γ-lyase (CTH).
What's the major form of circulatin folate in the plasma?
5-methyl THF.
How does 5-methyl THF get into the cell?
By the folate receptor α (FR-α)--high affinity & reduced folate carrier (RFC). FR-α is expressed in select epithelia cells including the proximal tubules of the kidney, the choroid plexus, and the placenta.
What is the major source of 1 carbon unit for 1 carbon metabolism?
Serine
Where does a C1 unit enter the folate cycle via serine?
THF is converted to 5,10-methylene THF via the enzyme serine hydroxymethyltransferase (SHMT). PLP (B6) is a cofactor and there are cytosolic and mitochondrial forms of this enzyme.
How can glycine donate C1 units for metabolism and what is the clinical significance?
Glycine can contribute C1 units via the glycine cleavage enzyme; a deficiency in this enzyme can lead to nonketotic hyperglycinemia which can cause glycine encephalopathy.
What is the significance of alternative metabolism of THF?
It produces derivatives that are important for nucleotide metabolism.
What is the active enzyme of the alternative metabolims pathway of THF and what does it produce?
The alternative pathway produces 10-formyl THF, 5, 10 methenyl THF, and 5,10-methyleneTHF which can then be converted back to 5-methyl THF for use in the methylation cycle. The first three intermediates are produced by MTHFD (methylenetetrathydrofolatedehydrogenase).
What are some other possible uses for 5,10-methylene THF?
In addition to being the methyl donor substrate for the methylation cycle, it can be used as a methyl donor cofactor for thymidylate synthase (TYMS) in which dUMP is converted to dTMP.
Which THF alternative metabolism pathway intermediate is the methyl donor for two reactions in purine de novo synthesis?
10-formyl THF
How is 5-methyl THF produced from 5,10-methylene THF?
The reaction is catalyzed by methylenetetrahydrofolate reductase (MTHFR) along with the cofactor riboflavin (B2).
What is 5,10-methylene THF converted to in the process of generating thymidine?
dihydrofolate (DHF)
How is DHF reconverted to THF?
Via dihydrofolate reductase (DHFR)
What genetic deficiency is the most common form of genetic hyperhomocysteinemia?
MTHFR deficiency (results in homocystinemia, homocystinuria; some response to betaine treatement)
What genetic deficiency results in homocystinuria and 5-methyl THF accumulation and is somewhat responsive to cobalamin (B12) treatment?
methionine synthase deficiency (MTR); this disease may also be a result of MTRR deficiency (B12 reducing enzyme)
What genetic deficiency is characterized by homocycstinemia, homocystinuria, methioninemia, low plasma cysteine & other intermediates and can resonsed to supplementation of cysteine and pyridoxine (B6) and restriction of methionine?
cystathione β-synthase (CBS) deficiency
What accounts for about 2/3 of all cases of elevated homocysteine levels?
folic acid, vitamin B6, and vitain B12 deficiencies
What is the most common anemia caused by a vitamin deficiency?
Folate-deficient anemia
What is the likely cause of methyl trapping?
low cobalamin levels resulting in the accumulation of 5-methyl THF
Why is there a debate about supplementing with folic acid, vitamin B6, and vitamin B12 to combat cardiovascular and periphral arterial disease?
These are cofactors that are important for one carbon metabolis and prevent the accumulation of homocysteine which is a risk factor for these illnesses.
Why is folate supplementation important for pregnant women?
It effectively reduces neural tube defects.
What treatment is used to try to prevent abberant demethylation due to AdoMet?
Antimetabolite cancer chemotherapty; specifically, dihydrofolate reductase inhibitors such as methotrexate that trap folates in an oxidized form so that they cannot be used for further one-carbon transfers.