Biochem Exam 5: Vitamin B12 And Tetrahydrofolate

Front 1

Which vitamins are water soluble? List them!

Back 1

B1 (Thiamin)
B2 (Riboflavin)
B3 (Niacin)
B5 (Pantothenic Acid)
B6 (Pyridoxine)
B9 (Folate or folic acid)
B12 (Cobalamin)
B8 (Biotin), and
C (Ascorbic Acid)

Front 2

Which vitamins are fat soluble? List them!

Back 2

D (cholecalciferol)
A (retinol, β-carotenes)
E (tocopherols)
K (phylloquinones; menaquinones)

Dexter Always Enjoys Killing!

Front 3

What 2 vitamins are involved in hematopoiesis?

Back 3

Folic acid (B9)
Vitamin B12 (cobalamin)

Front 4

What are some sources of folate?

What does folate deficiency result in?

Back 4

Yeast, liver, and leafy vegetables

anemia

Front 5

What are some sources of vitamin B12?

What does B12 deficiency result in?

Back 5

Liver, kidney, egg and cheese

pernicious anemia

Front 6

T/F

Cobalamin is a complicated molecule with different names based on what's attached to it.

Back 6

True!


*B12 has cobalt center

Front 7

For the production of RBCs and leukocytes in the bone marrow to take place, what 3 things are needed?

Back 7

Nucleotides
Amino acids
Iron

In the bone marrow, the body makes billions of RBCs and leukocytes per hour!

Front 8

What is essential in reactions involving one-carbon transfers?

Back 8

Folic acid

Front 9

What is the coenzyme form of folate?

Back 9

Tetrahydrofolate (FH4)

Front 10

a) How does FH4 participate in metabolic reactions (think o chem)?

b) What types of reactions is it involved with?

Back 10

a) By accepting and donating single-carbon groups

b) Amino acid interconversion and DNA synthesis (purines and pyrimidine thymine).

Front 11

What are these amino acids converted to using TH4?
a) Gly
b) His
c) Homocysteine

Back 11

Gly → Ser
His → Glu
**Homocysteine → Met

(**requires both TH4 & B12)

Front 12

a) Folate exists in 3 active forms, what is the main circulating form?

b) What form of folate is in 90% of food? How does the body convert it to the circulating form?

Back 12

a) Monoglutamate N5-FH4

b) Folate w/ 3 or more glutamate → polyglutamate. In the GI, conjugases remove glutamate to enhance folate absorption. Then, in the liver, monoglutamate is changed back to polyglutamate.

Front 13

*Methyl group (one-carbon units) donors for folate:

Back 13

serine
glycine
histidine
formaldehyde
formate

Front 14

In what form is folate present in purine synthesis?

In what form is folate present in pyrimidine synthesis?

Back 14

N10-formyl-FH4

5,10-Methylene-FH4

Front 15

T/F
Deficiency in any of the active forms of folate will lead too verall folate deficiency

Back 15

TRUE

inhibits folate recycling

Front 16

Because of its role in DNA synthesis, folate deficiency may be induced in therapy of what?

Back 16

Cancer

Front 17

a) Methotrexate is an analog of what?

Back 17

Folate

Front 18

Methotrexate is a a)___________ inhibitor of b)_______________, a key enzyme in pyrimidine biosynthesis.

Back 18

a) Competitive

b) Dihydrofolate reductase
(dihydrofolate--->tetrahydrofolate)

Front 19

a) What is 5,10-methylene-FH4's purpose in pyrimidine synthesis?

b) What is the enzyme at this step?

Back 19

a) It transfers a one-carbon unit to dUMP to form dTMP.

b) Thimidylate synthase
(5-Flouroacil can inhibit this enzyme)

Front 20

What diseases is methotrexate used to treat?

Back 20

Rheumatoid arthritis
Psoriasis
Asthma
Alcoholic cirrhosis
Inflammatory bowel disease
Cancer

(*via dihydrofolate reductase inhibition)

Front 21

a) What are side effects of methotrexate?

b) Can folate supplements be given along with methotrexate?

Back 21

a) Gastrointestinal distress (diarrhea)
Severe folate deficiency (anemia)

b) Yes, folate supplement reduces drug toxicity, adequate supplements of folate do not reduce methotrexate’s efficiency.

Front 22

What are the best dietary sources of folate?

Back 22

Liver (*highest)
Fortified cereals
Legumes (garbanzo beans and lentils)
Vegetables (Leafy greens)


Less rich sources:
Eggs
Oranges

Liver:
Chicken, 1 ea 924
Chicken, 1 oz 655
Turkey, 1 ea 500
Beef 4, oz 249
Brewer’s yeast, 1 tbsp 280
Cooked asparagus, 1 cup 263
Cooked lentils, ½ cup 179
Romaine lettuce, 1 ½ cup 114
Orange juice, 8 oz 109
Cooked spinach, ½ cup 103
Cooked broccoli, 1 cup 76
Cooked beets, ½ cup

Front 23

T/F

Deficiency of folate first affects cells that are actively synthesizing DNA.

Back 23

True!

Front 24

Why do RBCs need a continuous supply of folate?

Back 24

Because they turn over every 120 days

Front 25

T/F

Folate is passively transported across the intestinal wall.

Back 25

False!

Hydrolyzed folate is actively transported across the intestinal wall.

Front 26

How are folate supplements absorbed in the intestine?

Back 26

Passive diffusion

Front 27

What drugs can inhibit folate absorption?

Back 27

Alcohol and anticonvulsants
(also smoking)

Front 28

What drug interferes with both absorption and storage of folate? (and what is it competing for?)

Back 28

Alcohol competes for transport proteins

Front 29

Is absorption of folate better with or without food?

Back 29

Without food, nearly 100% of the supplement is bioavailable.
With food, as in fortified cereals, its absorption is slightly reduced.

Front 30

How much folate is stored in the body?

Half of it is stored where?

Back 30

5 to 10 mg

Liver

Front 31

A daily intake of 400 μg (RDA) of folate is thought to be _______-preventive.

Back 31

Chemo

Front 32

What disorder can be caused by folate deficiency?

Back 32

Megaloblastic/macrocytic anemia

Front 33

What are 5 possible causes of folate deficiency?

Back 33

1. Low intake
2. Inadequate absorption (alcoholism and anticonvulsants)
3. Increased requirement (pregnancy)
4. Compromised utilization (Vit. B12 deficiency, folate def secondary to B12 def)
5. Excessive excretion (long-standing diarrhea)

Front 34

(Early/Late) stages of RBC synthesis in _____________ are the first affected by folate deficiency.

Back 34

Early, bone marrow

Front 35

T/F

RBC and WBC synthesis are both affected by folate deficiency.

Back 35

True!

Front 36

What can folate deficiency cause in the fetus?

Back 36

Neural tube defects

Maternal deficiency of folate:
Spina bifida
Anencephaly (no brain)

Front 37

T/F

With folate deficiency, you are not able to make DNA, so RBCs grow large, but cannot divide and mature.

Back 37

True!

Front 38

What leads to increased cell size in megaloblastic anemia?

What happens to the oxygen carrying capacity?

Back 38

Continuous hemoglobin synthesis and other cell components. (w/o being able to divide= one massive cell)

Without folate to make DNA, cells remain in a large immature form → megaloblasts
(Megaloblasts retain their nuclei)
With fewer mature RBCs released from bone marrow → oxygen carrying capacity decreases → anemia (megaloblastic anemia).

Front 39

What are some signs/symptoms of folate deficiency?

Back 39

Inflammation of the tongue and mouth (glossitis and stomatitis) (all B def)
Abnormal pigmentation of the skin (due to anemia)
Weakness
Tiredness
Diarrhea
Poor growth
Depression
Mental confusion

Front 40

Can megaloblasts carry O2?

Back 40

Nope!

Front 41

What mineral is contained in vitamin B12's complex structure?

Back 41

Cobalt

Front 42

Vitamin B12 is synthesized exclusively by what 3 things?

Back 42

Bacteria
Fungi
Algae

(Plants do not synthesize Vit. B12)

Front 43

How can cows and sheep obtain B12?

Back 43

Bacterial synthesis in their multiple stomachs, or from soil they ingest while grazing.

Front 44

How is B12 in food released from proteins?

Back 44

HCl and gastric juices

Front 45

What does free B12 bind to when ingested?

Where is this synthesized?

Back 45

R-protein (Transcobalamin I/ haptocorrins)

**Synthesized by the salivary glands in the mouth.

Front 46

a) Where does the R-protein/ Vit. B12 complex travel to?

b) Then, what releases Vit. B12?

c) Then, _____________, a glycoprotein produced by parietal cells in stomach, binds to Vit. B12.

Back 46

a) Small intestine

b) Pancreatic proteases (e.g. trypsin)

c) Intrinsic factor (IF)

*thus stomach and/or pancreatic pathologies will decrease B12

Front 47

a) Where does the IF/Vit. B12 complex travel to?

b) At the ileum, the complex binds to a receptor for ___________.

c) In the _________, what does B12 attach to in order to enter the portal blood?

Back 47

a) Ileum

b) Absorption

c) Enterocytes, transcobalamin II (TCII)

Front 48

What parts of the body take up B12 from the portal blood?

Back 48

Liver
Bone marrow
RBCs

Delivery to tissues is done via receptor for the complex

Front 49

What are the ONLY 2 conversion reactions require B12, and what are their enzymes?

Back 49

Methylmalonyl CoA → succinyl CoA by methylmalonyl CoA mutase

Homocysteine → Met by methionine synthase/ homocysteine methyl transferase
(also requires folate*)

Front 50

Which B12-requiring conversion reaction is the assay (Schelling test) for B12 deficiency based on?

Back 50

Methylmalonyl CoA → succinyl CoA by methylmalonyl CoA mutase

Front 51

What is the methyl group donor in Met synthesis?

Back 51

Methyltetrahydrofolate (MTHF)

*This reaction frees THF to participate in DNA synthesis.
*lack of methionine leads to abnormal myelin

Front 52

What is the name of the B12 deficiency that causes death within 2 to 5 years?

Back 52

Pernicious anemia

Front 53

What is juvenile pernicious anemia characterized by?

Back 53

Defective production of intrinsic factor by gastric parietal cells

Front 54

T/F

Symptoms of folate-deficiency anemia are similar to B12 deficiency pernicious anemia.

Back 54

True!

Both have megaloblasts in the blood

Front 55

The cause of pernicious anemia is true Vit. B12 deficiency resulting from hampered absorption of the vitamin.
This is due to the lack of availability of what?

What are possible causes of B12 deficiency?

Back 55

Intrinsic factor

Causes of true Vit. B12 deficiency:
Absence of intrinsic factor (IF)
Absence or defective synthesis of pancreatic proteases
Bacterial overgrowth of the small intestine
Tapeworm infestation
Use of certain antiulcer medications (reduction of acid synthesis)
Chronic malabsorption syndromes (AIDS)
Chronic pancreatic disease
Absence or surgical removal of much or all of the ileum and stomach (Crohn’s disease (Crohn ileitis)

Front 56

What is the time to develop B12 deficiency from the following mechanisms?

a) Vegan diet
b) Intrinsic factor failure
c) Ileal dysfunction

Back 56

a) 10-12
b) 1-4
c) rapid

Front 57

What are the most nutrient-dense dietary sources of B12?

Back 57

Organ meats (liver, kidneys, and heart)
Seafood
Beef
Eggs
Hot dogs (contain organ meat scraps)
Ham
Milk and milk products

Front 58

What are the 3 possible treatment options for patients with defective B12 absorption?

Back 58

Monthly injection

Use of a vitamin B12 nasal gel

Weekly ingestion of vitamin B12 supplement with megadoses (300 x RDA)
RDA for adult age 19 to 50: 2 μg/day
Over 51 years of age: 2.4 μg/day

Front 59

Why does the FDA recommend intake of both B12 and folate when treating a deficiency, then later rectifying after bloodwork?

Back 59

Because large doses of folate can mask the warning signs of Vit. B12 deficiency (potentially fatal)

Front 60

B12 deficiency causes nerve degeneration, producing what symptoms?

*neurlogical disease only when chronic

Back 60

Sensory disturbances in the legs (tingling and numbness)
Paresthesia (burning and prickling)
Loss of concentration and memory
Visual disturbances
Disorientation
Dementia
Sore tongue
In the worst cases, loss of bowel and bladder control

Front 61

SAM (S-adenosylmethionine) is an essential -CH3 donor for what 5 reactions?

Back 61

Norepinephrine → Epinephrine
Guanidinoacetate → Creatine (lack =tiredness)
Nucleotides → Methylated nucleotides
Phosphatidylethanolamine → Phosphatidylcholine
Acetylserotonin → Melatonin

Front 62

Wht is the methyl donor for SAM synthesis?

Back 62

Met

Front 63

What is Met produced from?

What is required in the synthesis of Met?

Back 63

Homocysteine

Vitamin B12

Front 64

The Methyl Trap Hypothesis:

a) In the absence of Vit. B12, THF is trapped in what form?

b) A shortage of the coenzyme form of folate leads to inhibition of DNA synthesis. Therefore, B12 deficiency causes what condition?

c) There will also be an accumulation of what?

Back 64

a) methyl-bound form N5-methyl-FH4 (MTHF)

b) Secondary folate deficiency (folate cannot be released from enzyme)

c) Homocysteine → homocystinuria

Front 65

Why does hyperhomocysteinemia occur?

Back 65

Homocysteine is derived from S-adenosylhomocysteine after SAM donates its methyl group.

Cystathionine → cysteine → accumulation of cysteine → inhibition of cystathionine synthesis → homocysteine accumulation → release in the bloodstream

Front 66

What product can come from homocysteine being:

a) methylated? (and what is required for this to occur?)
b) condensed with serine?

Back 66

a) Methylated to form methionine (MTHF and Vit. B12 necessary)

b) Condensed with serine to form cystathionine (pyridoxal phosphate/Vit. B6)

Front 67

a) What is high homocysteine linked to?

b) And how can this lead to atherosclerosis (hint: what does it inhibit)?

Back 67

a) Neurological and cardiovascular diseases

b) Inhibition of glutathione peroxidase → low glutathione → increased oxidized LDL → atherosclerosis

Front 68

What can be done clinically to determine the cause of megaloblastic anemia?

Back 68

Measure blood levels of folate and B12

Front 69

T/F

The deficiency of the coenzyme form of folate during pregnancy has been linked to a high risk of neural tube defects in the fetus.

Back 69

True!

Front 70

Intake of folate supplement at what time can decrease the risk of neural tube defects?

Back 70

Before conception, and at least 1 month after conception

Front 71

a) A mutation in N5,N10 methylene-FH4 reductase causes an elevation of _____________ secondary to (folate/B12) deficiency.

b) This mutation makes the enzyme ____________.

c) It causes inhibition of ____ synthesis.

d) N5-methyl-FH4 levels (decrease/increase).

Back 71

a) Homocysteine, folate

b) Thermolabile

c) DNA

d) Decrease

Front 72

Degradation products of what are involved in one-carbon metabolism?

Back 72

Choline

Front 73

Choline can be oxidized to _____________, and then to _____________.

Back 73

Betaine aldehyde, betaine

Front 74

What is a secondary route preventing accumulation of homocysteine?

Back 74

In the liver, betaine or trimethylglycine can donate a methyl group to homocysteine forming methionine

Front 75

If SAM accumulates, what can be methylated to form sarcosine?

Back 75

Glycine

N-methyl glycine = Sarcosine