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Ch 38 - Tetrahydrofolate, Vitamin B12, and S-Adenosylmethionine
Terms in this set (58)
CO2 can be transferred from one carbon group to another via what molecule?
One-carbon groups at lower oxidation than CO2 are transferred via what 3 molecules?
Lower than CO2: FH4 (Tetrahydrofolate), Vitamin B12, SAM (S-Adenosylmethionine)
What molecule is the major one-carbon carrier in the body?
what level of oxidation of a one-carbon group can no longer be reoxidized?
what does the term folate mean?
Water soluble B-complex vitamin that functions in transferring single-carbon groups at various stages of oxidation
What are the two reactions that vitamin B12 is involved in?
Rearranges methyl groups of L-Methylmalonyl coenzyme-A to form Succinyl-CoA
Transfers a methyl group from FH4 (tetrahydrofolate) to homocysteine forming methionine.
What are the 6 compounds that SAM (S-Adenosylmethionine) transfers a methyl group to?
Homocysteine is derived from which precursor?
What two methyl-group transferring agents are used in this process?
What other methyl-group transferring agent's concentration would be high if there was a deficiency in the intrinsic factor?
What is this process called?
Why: because intrinsic factor helps absorb B12
B12 is used in the process of converting homocysteine into methionine with methyl-FH4
Process: Methyl-Trap Hypothesis
what molecule can be seen in the lab tests for people with vitamin B12 deficiencies?
AKA Vitamin B12
What does the Schilling test determine?
What is the process of the Schilling Test?
The amount of B12 not absorbed through the digestive tract
Radioactive B12 is ingested then a urine sample is taken to determine the amount of B12 and the ingested vs. the excreted are compared.
If decreased amounts of intrinsic factor are released, what is a good factor to check that may determine what is causing the levels to be so low.
Autoantibodies towards intrinsic factor
Lisa drinks heavily almost every night because her boyfriend left her about 25 years ago. She has started to present with blood problems and the doctor finds that she has megaloblastic anemia. What are some reasons to why are her folate levels so low?
Inadequate dietary intake
Direct damage to intestinal cells and brush border enzymes
Defect in enterohepatic circulation
Liver damage resulting in decreased plasma proteins
Interference with kidney reabsorption
In megaloblastic anemia, why can there be low levels of RBC's in the blood, but high levels of precursor RBC's in the bone marrow?
Ineffective Erythropoiesis: Erythroid progenitors are created but destroyed before they reach the circulation.
Where on FH4 (tetrahydrofolate) is the one-carbon group attached?
Both (a bridge connecting both)
What are the three parts of TH4 (tetrahydrofolate)?
Folate's pteridine ring is the most oxidized/reduced form of the three members of the folate family?
What reduces folate to TH4?
Which is of the two molecules mentioned above is the most favored of the body?
DHFR (dihydrofolate reductase)
how does one treat a folate deficiency in an alcoholic patient?
Cessation of Alcohol
Diet rich in folate
How do sulfa drugs treat bacterial infections without harming human cells?
Interfere with synthesis of folate in bacteria.
Human's don't synthesize folate, so it doesn't effect us
Where are 5 good sources of folate?
Green Leafy Vegetables
how much is the daily allowance of folate per day?
How much is recommended for women who are pregnant?
How much is recommended for Savanna Murphy (case #10), who has previously had a child with neural tube defects?
Daily: 400 micrograms
Pregnant: 400 micrograms
Previous: 4000 micrograms
what products in the United States are now being supplemented with folate to reduce the risk of neural tube defects?
what organ stores half of the bodies folate?
what happens to a large portion of folate in the liver?
Excreted the bile and is reabsorbed
the collection of one-carbon groups attached to FH4 (tetrahydrofolate)
What is the most oxidized form of FH4?
Next most oxidized?
Next most oxidized after that?
N10-formyl-FH4 (now referred to as F for "F"ormyl)
N5,N10-methenyl-FH4 (bridge) (now referred to as I for "yl")
N5, N10-methylene-FH4 (bridge) (now referred to as E for "ene")
N5-Methyl-FH4 (Now referred to as M for "M"ethyl)
What are 5 sources of carbon for the one-carbon pool of FH4 (tetrahydrofolate)?
Serine (major contributor) (can be produced from glycolysis)
Glycine (comes from serine once it has donated a carbon group)
Formate (donates the most oxidized one-carbon group (N10-formyl-FH4))
how can glycolysis contribute to the carbon source for the one-carbon pool of FH4?
Serine can be synthesized from 3-phosphoglycerate which is an intermediate in glycolysis
what carbon source for the one-carbon pool of FH4 donates the most oxidized one-carbon group, N10-formyl-FH4)?
Mallory was born about 2 days ago and has been presenting with diarrhea, anemia and immunocompromization. Doctors found that she has adequate amounts of intrinsic factor in her digestive tract.
What could be her diagnosis?
What causes this problem?
How is it treated?
Hereditary Folate Malabsorption
Mutation in the PCFT (Proton-coupled folate transporter protein)
High-dose oral folate: because if given in high concentrations it can absorb sufficient folate
What is in high concentrations when there is a folate deficiency?
FIGLU is produced by deterioration of histidine when folate is in low supply.
What are three major tests to test for concentration of folate?
FIGLU test (high concentrations of FIGLU mean low folate)
Microbiological test (growing bacteria in the serum of those with low folate)
Protein binding of folate (to see measure quantity of folate)
how does folate deficiency block the synthesis of DNA?
FH4 is required for the synthesis of dTMP (deoxythymindine monophosphate) and the purine bases for DNA replication
What one-carbon group is used in the transformation of dUMP to dTMP (to produce nucleotides)?
What happens to FH4 after that?
How is this fixed?
N5, N10-Methylene-FH4 (E)
FH4 goes to FH2
DHFR regenerates FH2 to FH4 through NADPH
where does N5-Methyl-FH4 (M) go to since it can't be oxidized?
how does 5-FU (5-fluorouracil) a good treatment for cancer?
It is converted in the cells to FdUMP nucleotide which blocks the thymidylate synthase reaction (the conversion of dUMP to dTMP (creation of regular nucleotides))
how is methotrexate a good treatment for cancer?
Methotrexate has the same structure as folate except for a methyl group of N10. This inhibits DHFR which prevents the conversion of FH2 to FH4
Why is it difficult to be deficient in B12
B12 is stored in high content and is only given off is small amounts taking years to become deficient. Plus the intake of B12 is around 5-30 micrograms daily, and the body takes in around 1-5 micrograms of that.
What are a few major sources of B12?
What protein do free B12 bind to in humans?
Where is this protein located?
How does it get released in the stomach and small intestines?
Salivary Glands/Gastric Mucosa
released by proteases
how is bound B12 (bound to proteins) enter the plasma?
Proteins are degraded in the small intestines by proteases
B12 binds to intrinsic factors
This complex binds to the receptors (cubilin) on the wall of the ileum which is internalized into the gut tube cells.
B12 binds to transcobalamin II which then causes this complex to be released from the cells into the plasma
What is the name of the receptor for B12-intrinsic factor complex?
What are 5 conditions that can lead to pernicious anemia?
Deficiency in intrinsic factor
High intestinal pH
Mutation in Cubilin (B12-intrinsic factor receptor)
Mutation in Amnionless (protein used for internalization of B12-intrinsic factor-cubilin complex)
What two structures does B12 form?
Methionine (from transferring N5-Methyl-FH4 (M) to homocysteine)
Succinyl-CoA (from rearrangement of L-methylmalonyl-CoA)
What are two ways that pernicious anemia can be treated?
Injections of B12
SAM (S-adenosylmethionine) can transfer methyl groups to what?
Oxygen or Nitrogen atoms
How is the one-carbon group from Serine, Glycine, Histidine or other one-carbon group donators then transferred to a nitrogen or oxygen?
the one-carbon group is donated to folate which reduces it to N5-Methyl-FH4. N5-Methyl-FH4 donates a methyl group to vitamin B12 which donates that to homocysteine which converts it into Methionine. Methionine is then activated into SAM and SAM transfers methyl groups to oxygen and nitrogen.
What are two disorders that can occur from B12 deficiency?
What are a few symptoms of the neurological B12 deficiency?
Numbness and tingling in hands and feet
Diminishing vibratory and position sense
spastic gate disturbances
Extremely Irritable (megaloblastic madness)
Gustatory (taste) desensitization
What is the methyl-trap hypothesis?
Inability of the N5-methyl-FH4 (M) of folate to be removed (trapped) because of B12 deficiency
certain neurotrasmitters require methylation by SAM. So an increase in SAM (sold by health food stores as SAMe which is a stabilized form of SAM), would alleviate what condition?
How does B12 deficiencies affect the Homocysteine levels?
How does it affect the levels of Cysteine?
Increases Homocysteine: Homocysteine is converted to Methionine by B12. If B12 is deficient, then there is an increase in Homocysteine.
Increases Cysteine: Homocysteine can be converted to cystathionine which eventually gets converted to cysteine. If Homocysteine is increased, cysteine levels are increased
Do it now!
Women who give birth to children with neural tube defects and had a folate deficiency also had a link to this disorder.
what is usually deficient if there is a folate deficiency?
(these are precursors for DNA synthesis and DNA repair)
memorize this too!
SAM gives its methyl group to DNA methyltransferase during DNA synthesis. There are still some SAM's around to give the methyl group away, but what is blocking the pathway?
SAH has a higher affinity for DNA Methyltransferase enzymes than SAM thus altering the ability for SAM to give off its methyl group
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