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Block 2 - Week 1 > One-Carbon Metabolism > Flashcards

One-Carbon Metabolism Flashcards

1
Q

What cycles/pathways does one-carbon metabolsim include?

A
  • Folate cycle
  • Methionine cycle
  • Transsulfuration pathway
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2
Q

What are 3 reactions THF (tetrahydrofolate) is needed for?

A
  • Synthesis of dTMP (which is essential for DNA synthesis)
  • Synthesis of purine nucleotides
  • Vitamin B12-dependent re-methylation of homocysteine to form methionine
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3
Q
  • What are sources of natural folates?
  • What are sources of synthetic folic acids?
A

Natural folates:

  • Nuts
  • Chickpeas
  • Leafy greens

Synthetic folic acids:

  • Added to many grain products to prevent NTDs
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4
Q

THF is the ____ ____ form of folate and accepts one-carbon groups at positions ____, ____, or both, and transfers these groups to other compounds

A

THF is the active coenzyme form of folate and accepts one-carbon groups at positions N5, N10, or both, and transfers these groups to other compounds

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5
Q

Synthetic folic acids have a fully-oxidized pteridine ring and ____ glutamate residue

A

Synthetic folic acids have a fully-oxidized pteridine ring and single glutamate residue

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6
Q

Natural folates and those in humans contain a ____ ____ that aids in their cellular retention

A

Natural folates and those in humans contain a polyglutamate tail that aids in their cellular retention

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7
Q

The polyglutamate tail of natural folates must be removed by a ____ ____-____ ____ prior to intestinal absorption

A

The polyglutamate tail of natural folates must be removed by a jejunal brush-boarder peptidase prior to intestinal absorption

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8
Q
  • What is the transporter involved in folate absorption?
  • What does a defeciency in this lead to?
A
  • Proton-coupled folate transporter (PCFT)
  • Failure to thrive and megablastic anemia
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9
Q
  • What is the transporter involved in folate transport into the interstitial space?
  • Where is this transporter expressed?
A
  • Reduced folate carrier (RFC)
  • Ubiquitously expressed in cells/tissues (is the major folate transporter)
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10
Q

What are 3 conditions that affect folate absoption?

A
  • Excessive alcohol intake
  • Crohn’s disease
  • Celiac disease
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11
Q

What converts folate to dihydroflate (DHF) to tetrahydrofolate (THF)?

A

DHFR (dihydrofolate reductase)

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12
Q
  • What converts DHF to THF in the folate cycle?
  • What is required for this process?
A
  • DHFR (dihydrofolate reductase)
  • NADPH which gets converted to NADP+
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13
Q

THF reacts with ____ to form ____ which is essential in purine synthesis

The enzyme for this reaction is ____

A

THF reacts with formate to form N10-formyl-THF which is essential in purine synthesis

The enzyme for this reaction is formyl-THF synthase

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14
Q

What are 2 sources of formate?

A
  • Catabolism of tryptophan
  • Metabolism of methanol
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15
Q

____ is important in purine synthesis

____ is a required substrate in this process

A

N10-formyl-THF is important in purine synthesis

AICAR (S-aminoimidazole-4-carboxamide ribonucleotide) is a required substrate in this process

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16
Q

____ in urine is a diagnositc sign of folate deficiency if it occurs after a test dose of ingested histidine

A

FiGlu in urine is a diagnositc sign of folate deficiency if it occurs after a test dose of ingested histidine

(this is because low THF leads to the accumulation of FIGlu after histidine catabolism)

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17
Q

N10-formyl-THF can be reduced to form ____

Catabolism of ____ also produces this

A

N10-formyl-THF can be reduced to form N5,N10-methenyl-THF

Catabolism of histidine also produces N5,N10-methenyl-THF

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18
Q

N5,N10-methenyl-THF can be reduced to form ____

This reaction requires ____

A

N5,N10-methenyl-THF can be reduced to form N5,N10-methylene-THF

This reaction requires NADPH

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19
Q

Glycine can be reversibly converted Serine

In this reaction ____ is reversibly converted to ____

This requires vitamin ____ and enyzme ____

A

Glycine can be reversibly converted Serine

In this reaction N5,N10-methylene-THF is reversibly converted to THF

This requires vitamin B6 and enyzme SHMT

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20
Q

dTMP is essential for ____

This is created in the folate cycle by the conversion of ____ to ____

A

dTMP is essential for DNA synthesis

This is created in the folate cycle by the conversion of N5,N10-methylene-THF to DHF

Note: this is why THF is absolutely required for DNA synthesis

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21
Q

How does a folate deficiency impair cell division in rapidly growing cells?

A
  • decreased dTMP from dUMP –> decrease DNA synthesis
  • decreased purine synthesis
  • decreased repair of damaged DNA
  • increased dUMP –> dU incorporated into DNA –> increased DNA fragmentation
22
Q

Causes of megaloblastic anemia

A

Folate and/or vitamin B12 deficiency

23
Q

Megaloblastic anemia

A
  • Condition in which the bone marrow produces unusually large structurally abnormal, immature RBCs (megaloblasts)
  • Results from defective DNA synthesis and unbalanced cell growth from B12 and/or folate deficiency
  • Immature RBCs have increasedd MCV > 100 fl
    • Spleen normally removes megaloblasts when they reach peripheral circulation
24
Q

Folate deficiency causes ____ neutrophils

A

Folate deficiency causes hypersegmented neutrophils

25
Glossitis
* Condition where the tongue is swollen/inflamed/glossy * Results from defective replacement of damaged papila * Can be caused by: * Folate or iron deficiency * Allergies * Infections
26
Methotrexate is a ____ of \_\_\_\_ High doses of methotrexate inhibit rapid cell growth in certain cancers. Name 4 examples.
Methotrexate is a _competitive inhibitor_ of _DHFR_ High doses of methotrexate inhibit rapid cell growth and can be used to treat certain cancers such as: * Acute lympoblastic leukemia * Breast Cancer * Osteosarcoma * Advanced Non-Hodgkin's Lymphoma
27
Leucovorin Rescue
N5-Formyl-THF (AKA leucovorin) is a natural storage form of folate used as an antidote to the harmful effects of methotrexate on healthy cells by bypassing the need for activation by DHFR
28
Vitamin B12 connects ____ cycle to the ____ cycle Within this connection N5-methyl-THF is converted to THF in the folate cycle, and ___ is converted to ____ in the methionine cycle Note: This step is B12 dependent
Vitamin B12 connects _folate cycle_ to the _methionine cycle_ Within this connection N5-methyl-THF is converted to THF in the folate cycle, and _homocysteine_ is converted to _methionine_ in the methionine cycle Note: This step is B12 dependent
29
Lower doses of methotrexate are used to reduce ____ and treat symptoms of \_\_\_\_ Methotrexate promotes the intracellular accumulation of purine biosynthetic intermediate ____ which leads to the production of ____ which has potent anti-inflammatory effects
Lower doses of methotrexate are used to reduce _inflammation_ and treat symptoms of _rheumatoid arthritis_ Methotrexate promotes the intracellular accumulation of purine biosynthetic intermediate _AICAR_ which leads to the production of _adenosine_ which has potent anti-inflammatory effects
30
The methionine cycle produces ____ which acts as a methyl group donor 4 examples of methlation reactions are:
The methionine cycle produces _SAM (S-adenosylmethionine)_ which acts as a methyl group donor 4 examples of SAM methlation reactions are: * Hormone synthesis: Norepinpehrine --\> Epinephrine * Phospholipid synthesis: PE --\> PC * DNA methylation * Histone methylation
31
After SAM donates a methyl group it becomes ____ which is then converted into \_\_\_\_
After SAM donates a methyl group it becomes _SAH (S-adenosylhomocysteine)_ which is then converted into _homocysteine_
32
Homocysteine can be remethylated to ____ in the \_\_\_\_ This reaction requires ____ which comes from \_\_\_\_
Homocysteine can be remethylated to _methionine_ in the _liver_ This reaction requires _betaine_ which comes from _choline_
33
Homocysteine can be condensed with ____ to form ____ via the enzyme \_\_\_\_ \_\_\_\_ can then be converted into cysteine and a-ketobutyrate. Cysteine inhibits \_\_\_\_. This feedback inhibition keeps methionine from being used for cysteine synthesis unless needed. These reactions all require vitamin \_\_\_\_
Homocysteine can be condensed with _serine_ to form _cystathionine_ via the enzyme _cystathionine B-synthase_ _cystathioine_ can then be converted into cysteine and a-ketobutyrate. Cysteine inhibits _cystathionine B-synthase_. This feedback inhibition keeps methionine from being used for cysteine synthesis unless needed. These reactions all require vitamin _B6_
34
\_\_\_\_, the oxidized disulfide of homocysteine, is not efficiently reabsorbed by the kidneys, causing ____ when homocysteine metabolism is impaired
_Homocystine_, the oxidized disulfide of homocysteine, is not efficiently reabsorbed by the kidneys, causing _homocystinuria_ when homocysteine metabolism is impaired
35
Causes of homocystineuria (4 examples) Treatment of most common cause (3 examples)
* Vitamin B12 or folate deficiency * Methionine synthase deficiency * Severe vitamin B6 (pyridoxine) deficiency * _Most commone cause_: cystathionine B-synthase (CBS) deficiency) --\> termed classic homocystinuria Treatment of CBS deficiency: * Vitamin B6 (pyridoxine) supplements to increase resdiual enzyme activity in patients with B6 responsive variants * Reduce dietary methionine + give supplemental cysteine * Supplementation with betaine to increase utilization of hepatic pathway for homocysteine metabolism
36
Clinical characteristics of classic homocystinuria
37
Mutations in ____ can result in cystathioninuria which is pathologically benign and can be treated with ____ supplements
Mutations in _cystathionase_ can result in *cystathioninuria* which is pathologically benign and can be treated with _B6_ supplements
38
Folate deficiency in early pregnancy results in \_\_\_\_
Folate deficiency in early pregnancy results in _neural tube closure defects_
39
Increased risk of NTDs was first observed in women with a temperature sensitive varient of \_\_\_\_ In these women there was a decrease of ____ and an increase of \_\_\_\_
Increased risk of NTDs was first observed in women with a temperature sensitive varient of _methyl-THF reductase_ In these women there was a decrease of _N5-methyl-THF_ and an increase of _homocysteine_
40
It is recommended to pregnant women to consider taking ____ supplements to decrease the risk of \_\_\_\_
It is recommended to pregnant women to consider taking _folic acid_ supplements to decrease the risk of _NTDs_
41
Neural tube closure occurs ~\_\_\_\_ days post-conception
Neural tube closure occurs ~_23_ days post-conception
42
The most common severe congenital NTDs associated with folate deficiency in early pregnancy are ____ and \_\_\_\_
The most common severe congenital NTDs associated with folate deficiency in early pregnancy are _spina bifida_ and _anencephaly_
43
In addition to decreased DNA synthesis, folate deficiency may also alter what?
* Decreased levels of neurotransmitters * Decreased hypomethylation of DNA which leads to increased expression of certain micro RNAs
44
What are the irreversible reactions in the folate cycle? (have a general idea)
Irreversible reactions are shown by the red arrows in the picture Have a general idea of what they are
45
Vitamin B12 is only produced by \_\_\_\_ Major dietary sources of B12 include (3 examples) \_\_\_\_ and ____ are at risk for B12 deficiency
Vitamin B12 is only produced by _bacteria_ Major dietary sources of B12 include: * Meat * Eggs * Dairy products _Vegetarians/vegans_ and _some elderly patients_ are at risk for B12 deficiency
46
Enough B12 is stored in the ____ to last ____ years
Enough B12 is stored in the _liver_ to last _3-5 years_ years
47
Vitamin B12 and the methyl trap hypothesis
* The methlene-THF reductase reaction is irreversible * A vitamin B12 deficiency creates a functional (or secondary) folate deficiency by trapping folate as N5-methyl-THF * Results in megaloblastic anemia
48
Intestinal absorption of vitamin B12
1. Pepsin digests any bound dietary protein (vitamin B12 can be free or protein bound) 2. R-binders (transcobalamin I) bind free B12 3. R-binders are destroyed by pancreatic proteases 4. Intrinsic factor-B12 complex attaches to specific receptors (_without intrinsic factor B12 is exreted in stool_) 5. Complex is internalized, carried in blood by transcobalamin II to liver and other tissues
49
Vitamin B12 deficiency may also cause \_\_\_\_ 5 examples
Vitamin B12 deficiency may also cause _irreversible neurological symptoms_, including: * Symmetric numbness/tingling of feet * Diminishing vibratory and position sense * Progression to a spastic gait disturbance * Auditory and visual hallucinations (megaloblastic madness)
50
Severe vitamin B12 deficiency results in the accumultion of ____ causing \_\_\_\_
Severe vitamin B12 deficiency results in the accumultion of _L-methylmalonyl CoA_ causing _methylmalonic acidemia_ Note: If L-methylmalonyl CoA is used in place of Malonyl-CoA in FA synthesis --\> results in formation of methyl branched FAs which when incorporated into myelin sheath --\> causes destablization and neuron loss --\> *results in neurological symptoms*
51
Why is it important to assess vitamin B12 levels in patients with megaloblastic anemia and not simply treat with suupplemntal folate?
Because if the megaloblastic anemia is due to a vitamin B12 deficiency, this could lead to **permanent neurological symptoms!**
52
Potential dangers of excess folate
* Could hide a vitamin B12 deficiency by correcting the anemia caused by the B12 deficiency but won't prevent the permanent neurological damage * High doses of folic acid may accelerate the progression of preneoplastic lesions, increasing the risk of colorectal and possibly other cancers in specific individuals

Block 2 - Week 1 (9 decks)

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