150 Bfcp2A Biochemistry One Carbon Metabolism

Front 1

Why is the methylation cycle important?

Back 1

It produces adenosyl methionine which allows for epigenetic regulation via DNA regulation and capping mechanisms for mRNAs. There are hundreds of other methylation reactions.

Front 2

What B vitamins are especially important for the 1 carbon metabolic pathway?

Back 2

riboflavin (B2), pyridoxal phosphate (B6), tetrahydrofolate (B9), cobalamin (B12)

Front 3

What is a central compound of the methylation cycle?

Back 3

homocysteine

Front 4

What critical reaction provides a link between the folate and methylation cycles?

Back 4

homocysteine remethylation to methionine via methionine synthase (MTR) (requires B12)

Front 5

Which enzyme associates with MTR in the homocystein e to methionine reaction for the purpose of reducing cobalamin (B12)?

Back 5

MTR reductase (MTRR)

Front 6

Which alternative enzyme can generate methionine from homocysteine in the liver and kindey utilizing betaine?

Back 6

betaine-homocysteine methyltransferase (BHMT)

Front 7

How is S-adenyosylmethionine generated in the methylation cycle?

Back 7

methionine gets adenosylated to S-adenosylmethionine (AdoMet) by methionine adenosyltransferase (MAT)

Front 8

What is the active methyl donor of AdoMet?

Back 8

a sulfonium group +S-CH3 is 1000x more active than S-CH3 as a methyl donor.

Front 9

How does methylation of other substrates by AdoMet occur?

Back 9

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.)

Front 10

How is homocysteine regenerated in the methyl cycle?

Back 10

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.

Front 11

How are homocysteine and methionine levels regulated with during the FED and FASTED state?

Back 11

During the FED state homocysteine (and, consequently, the precursor pool for methionine) is irreversibly degraded to cysteine and α-ketobutyrate following the transsulfuration pathway.

Front 12

How does AdoMet affect the transulfuration pathway?

Back 12

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.

Front 13

What's the first step in homocysteine degradation?

Back 13

Condensation of homocysteine with serine to form cystathione by cystathionine β-synthase.

Front 14

What's the second step of the transulfuration pathway that results in the formation of cysteine?

Back 14

Hydrolysis of cystathione to cysteine and α-ketobutyrate by cystathioine γ-lyase (CTH).

Front 15

What's the major form of circulatin folate in the plasma?

Back 15

5-methyl THF.

Front 16

How does 5-methyl THF get into the cell?

Back 16

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.

Front 17

What is the major source of 1 carbon unit for 1 carbon metabolism?

Back 17

Serine

Front 18

Where does a C1 unit enter the folate cycle via serine?

Back 18

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.

Front 19

How can glycine donate C1 units for metabolism and what is the clinical significance?

Back 19

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.

Front 20

What is the significance of alternative metabolism of THF?

Back 20

It produces derivatives that are important for nucleotide metabolism.

Front 21

What is the active enzyme of the alternative metabolims pathway of THF and what does it produce?

Back 21

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).

Front 22

What are some other possible uses for 5,10-methylene THF?

Back 22

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.

Front 23

Which THF alternative metabolism pathway intermediate is the methyl donor for two reactions in purine de novo synthesis?

Back 23

10-formyl THF

Front 24

How is 5-methyl THF produced from 5,10-methylene THF?

Back 24

The reaction is catalyzed by methylenetetrahydrofolate reductase (MTHFR) along with the cofactor riboflavin (B2).

Front 25

What is 5,10-methylene THF converted to in the process of generating thymidine?

Back 25

dihydrofolate (DHF)

Front 26

How is DHF reconverted to THF?

Back 26

Via dihydrofolate reductase (DHFR)

Front 27

What genetic deficiency is the most common form of genetic hyperhomocysteinemia?

Back 27

MTHFR deficiency (results in homocystinemia, homocystinuria; some response to betaine treatement)

Front 28

What genetic deficiency results in homocystinuria and 5-methyl THF accumulation and is somewhat responsive to cobalamin (B12) treatment?

Back 28

methionine synthase deficiency (MTR); this disease may also be a result of MTRR deficiency (B12 reducing enzyme)

Front 29

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?

Back 29

cystathione β-synthase (CBS) deficiency

Front 30

What accounts for about 2/3 of all cases of elevated homocysteine levels?

Back 30

folic acid, vitamin B6, and vitain B12 deficiencies

Front 31

What is the most common anemia caused by a vitamin deficiency?

Back 31

Folate-deficient anemia

Front 32

What is the likely cause of methyl trapping?

Back 32

low cobalamin levels resulting in the accumulation of 5-methyl THF

Front 33

Why is there a debate about supplementing with folic acid, vitamin B6, and vitamin B12 to combat cardiovascular and periphral arterial disease?

Back 33

These are cofactors that are important for one carbon metabolis and prevent the accumulation of homocysteine which is a risk factor for these illnesses.

Front 34

Why is folate supplementation important for pregnant women?

Back 34

It effectively reduces neural tube defects.

Front 35

What treatment is used to try to prevent abberant demethylation due to AdoMet?

Back 35

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.