Folate (7 questions)

Question 1

What are the CoE. forms of FOLATE?

Answer 1

DHF
THF
5-Formyl THF
10-Formyl THF
5,10-Methenyl THF
5,10-Methylene THF
5-Methyl THF

(7 total)

Question 2

How are RDAs for folate expressed?

Answer 2

DFEs

Question 3

DFE

Answer 3

Dietary Folate Equivalents

Question 4

What is the DFE for FOLATE?

Answer 4

1 mcg DFE = 1 mcg from food FOLATE

Question 5

What is the DFE for FOLIC ACID?

Answer 5

1 mcg DFE = 0.6 mcg FOLIC ACID

Question 6

What is the DFE for FOLIC ACID from dietary supplements taken on an empty stomach?

Answer 6

1 mcg DFE = 0.5 mcg FOLIC ACID (very high bioavailability)

Question 7

What is the difference between FOLATE and FOLIC ACID?

Answer 7

FOLATE = the form from natural food sources (green leafy vegetables); reduced form

FOLIC ACID = form from fortified foods (flours, breakfast cereals) or supplements; oxidized form

Question 8

Why is FOLATE more difficult to digest?

Answer 8

2 reasons why folate absorption is impeded:

1. FOLATE has very long tails of GLUTAMIC ACIDS
2. Reduced form

Question 9

What is the bioavailability of FOLATE?

Answer 9

50% naturally present form

Question 10

What is the bioavailability of FOLIC ACID?

Answer 10

~85% when taken with food

Question 11

What are the best food sources of folate?

Answer 11

1. Beef liver
2. Spinach, boiled
3. Black-eyed peas
4. Breakfast cereals
5. Green vegetables (asparagus, Brussels, lettuce, etc)

Also, fortified grains

Question 12

(T/F) There is a federal fortification of folate.

Answer 12

TRUE, since 1998.

140 micrograms folic acid per 100g product
FOLIC ACID MONOGLUTAMATE is the fortified form (it’s oxidized, so very easily absorbed)

Question 13

What is the formula for calculating DFEs?

Answer 13

mcg DFE = mcg naturally occurring folate + (1.7 x mcg folic acid)

Question 14

Example 1: Calculating DFEs

A serving (85g) of frozen spinach contains 120 mcg of folate. What is the DFE?

Answer 14

Folate (mcg DFE) = 120 mcg x 1
120 mcg DFE

Question 15

Example 2: Calculating DFEs

A serving (40g) of ready-to-eat breakfast cereals contains 200 mcg folic acid. What is the DFE?

Answer 15

Folate (mcg DFE) = 200 mcg x 1.7
340 mcg DFE

Question 16

Example 3: Calculating DFEs

A serving (30g) of enriched wheat flour contains a combination of naturally occurring folate (5 mcg) and folic acid (50 mcg). What is the DFE?

Answer 16

Folate (mcg DFE) = (5 x 1) + (1.7 x 50)
90 mcg DFE

Question 17

(T/F) Folic acid from supplements and fortification do not need to undergo digestion and are readily absorped.

Answer 17

TRUE

Question 18

FILL IN THE BLANK

Folate naturally found in food is in XXXXXXXXXX form and must be digested to XXXXXXXXXX form.

Answer 18

POLYGLUTAMATE FORM

MONOGLUTAMATE FORM

Question 19

What 2 enzymes are needed for folate absorption?

Answer 19

CARBOXYPEPTIDASES are needed to hydrolyze (“remove”) the polyglutamate tail from folate to allow for absorption:

1. Soluble carboxypeptidase
2. Enzyme bound to brush border membrane

Question 20

Soluble carboxypeptidase

Answer 20

From pancreatic juices and bile secreted into the jejunum

Needed to hydrolyze polyglutamate tail from folate for absorption

Question 21

Enzyme bound to brush-border membrane

Answer 21

Contributes to digestion/absorption more than soluble form

—It is zinc-dependent and requires a HIGHER pH (more basic) in the duodenum (thanks to bicarbonate from the pancreas)
—It is inhibited by ETOH ingestion and certain foods (legumes, lentils, cabbage, and oranges)

Question 22

(T/F) Dietary supplements of folate are inhibited by the ingestion of ETOH due to the enzyme bound to brush-border membrane.

Answer 22

FALSE

Only natural forms of folate require the two carboxypeptidases enzymes to hydrolyze the polyglutamate tail from folate to allow for absorption

The enzyme bound to brush-border membrane is inhibited by ETOH and certain foods (lentils, legumes, oranges, and cabbage)

Question 23

Proton-coupled folate transporter

Answer 23

A high affinity folate carrier expressed in proximal jejunum and duodenum

Facilitates the transport of folic acid and folate into the enterocytes

Question 24

What happens once folate and folic acid are in the enterocyte?

Answer 24

Once folate enters the CYTOPLASM of the cell, it is going to be reduced by dihydrofolate reductase to DHF, then THF with NADPH and reductase enzyme

Question 25

How does folate leave the enterocyte?

Answer 25

THF will bind with a folate binding protein and be transported outside of the enterocyte, VIA MRP3

Question 26

MRP3

Answer 26

An active-carrier dependent Multi-drug Resistant Protein 3, that binds THF to transport folate outside the enterocyte

Question 27

What CoE. form will folate be in portal circulation?

Answer 27

5-methyl THF, OR DHF, OR the formulated forms as well. It will be monoglutamated

Question 28

RFC

Answer 28

Reduced Folate Carriers; ubiquitously expressed Facilitates carrier-mediated uptake into the liver (majority) and other tissues

Question 29

FOLR1

Answer 29

Folate Receptor Alpha; expressed in brain Note defects in gene are associated with neurological disorders

Question 30

What are the forms of folate in hepatocytes and other cells? What is the breakdown?

Answer 30

~33% THF ~33% 5-methylTHF ~33% 5- or 10- formyl THF

Question 31

How is folate trapped in cells?

Answer 31

Once in the cell, it will be converted to the polyglutamate form, trapping it into the cell

Question 32

Polyglutamate synthetase

Answer 32

Enzyme that catalyzes the addition of 4-8 glutamate / glutamic acids Requires ATP Traps folate within the cell

Question 33

Gamma-glutamyl hydrolase

Answer 33

Enzyme that removes glutamate residues prior to folate exiting the cell

Question 34

FILL IN THE BLANK In systemic circulation, folate is in XXXXXXXXXX form.

Answer 34

Monoglutamate form ---~1/3 free ---~2/3 bound to protein (albumin, alpha 2 macroglobulin, and high-affinity folate binding protein) In THF, 5-methylTNF or 10-formylTHF

Question 35

How much folate is stored in the body? Where?

Answer 35

7 to 30 mg stored 50% in the liver, in THF and 5-methyl THF polyglutamate forms

Question 36

(T/F) When folate is trapped inside the cell, it's typically also bound to some type of folate-binding protein. This will keep it anchored into the cell, as well as the polyglutamate tail.

Answer 36

TRUE

Question 37

Folate CoE. forms function in which 2 types of reactions?

Answer 37

1. Nucleotide biosynthesis 2. Methylation of AA

Question 38

How does THF form THF derivatives?

Answer 38

THF accepts one-carbon groups THF derivatives then serve as donors of one carbon units in a variety of biosynthetic reactions

Question 39

Folate is critical for.....

Answer 39

pyrimidine synthesis of DNA

Question 40

What are the 3 pyrimidines?

Answer 40

1) Cytosine 2) Uracil 3) Thymine

Question 41

Pyrimidine

Answer 41

The base Will be converted to CYTOSINE (which is used for RNA and DNA biosynthesis)

Question 42

(T/F) The base uracil can be converted to thymine.

Answer 42

TRUE, when the body needs to make DNA

Question 43

Uracil

Answer 43

ONLY used in RNA

Question 44

Thymine

Answer 44

ONLY used in DNA

Question 45

dUMP

Answer 45

DeoxyURIDINE monophosphate; used in RNA synthesis Can be converted to dTMP

Question 46

dTMP

Answer 46

DeoxyTHYMINE monophosphate; used in DNA synthesis

Question 47

Thymidylate synthetase

Answer 47

An enzyme that requires folate (as N5, N10-methylene THF)*** So in this reaction, a methyl group is going to be added, when uracil -----> thymine

Question 48

(T/F) The dUMP ---> dTMP reaction can take place without folate.

Answer 48

FALSE If there is a deficiency of folate, this reaction cannot take place.

Question 49

What is the consequence of utilizing uracil for DNA synthesis?

Answer 49

When there is a deficiency of the CoE form (5-, 10-methyleneTHF), the body will use URACIL into the DNA instead of using thymine, which causes all kinds of problems. This is considered an AP site (pre-mutagenic apyrimidinic site), which can lead to: ---DNA strand breaks ---DNA fragmentation ---or, the cell can recognize this as an anomaly, can the cell will go through APOPTOSIS (cell suicide) This accumulation of DNA damage could result in pre-cancerous changes.

Question 50

What CoE. form is required for the biosynthesis of purines? ***

Answer 50

10-formyl THF form

Question 51

What are the 2 purines?

Answer 51

1) Adenine 2) Guanine Both used in DNA and RNA

Question 52

Explain the process for dUMP -----> dTMP when there is not a folate deficiency present.

Answer 52

5-,10-methylene THF is going to be used for the dUMP ----> dTMP reaction. With thymidylate synthetase being required. The 5,10-methylene THF is going to donate the methyl groups, and then be converted back to DHF

Question 53

What is the base, that will be converted to adenine and guanine? **

Answer 53

INOSINE MONOPHOSPHATE (IMP) ** The biosynthesis of IMP is extremely important because it REQUIRES FOLATE; specifically, the 10-formyl THF form

Question 54

(T/F) The body must biosynthesis purines every time it needs to make RNA and DNA.

Answer 54

FALSE. There are salvage pathways, so when the body breaks down old DNA and RNA, it can reuse these purines.

Question 55

De Novo Synthesis

Answer 55

Meaning "FROM THE NEW" In reference to the biosynthesis of purines An example would be a child who is rapidly growing, or during a growth spurt, they are going to need de novo purine biosynthesis, and it is VERY critical. It is not a concern for older adults

Question 56

What CoE. form is required to convert glycine <-----> serine?

Answer 56

5, 10-methylene THF (also used in dUMP to dTMP)

Question 57

Serine hydroxymethyltransferase

Answer 57

PLP-dependent enzyme (B6 COENZYME**) that converts 5, 10-methylene THF <---->THF in the reaction: Glycine <-------> Serine Note: this is a reversible reaction

Question 58

Explain folate's role in homocysteine metabolism.

Answer 58

5-methyl THF is going to be picked up by the enzyme METHIONINE SYNTHASE, and is going to take that methyl group, and add it to COBALAMIN, so now we have METHYLCOBALAMIN. This converts 5-methyl THF ---> THF, allowing THF to go through the glycine <----> serine reaction, via SERINE HYDROXYMETHYLTRANSFERASE.

Question 59

Explain how SAM plays a role in the methylation of DNA.

Answer 59

SAM donates a methyl group to CYTOSINE, creating 5-methylcytosine.

Question 60

DNA methyl-transferase

Answer 60

Enzyme in the reaction of converting cytosine ---> 5-methylcytosine

Question 61

Where is the methyl group on 5-methylcytosine, originally come from? ***

Answer 61

Initially this methyl group came from 5-methyl THF, then given to B12, creating methylcobalamin, then given to methionine, and then converted to SAM, and now it's going to be provided here to make DNA. **AKA: IT STARTED OUT AS PART OF FOLATE

Question 62

How does methylation play an important role in gene expression?

Answer 62

The importance of the methyl groups getting added to cytosine is seen here. If the DNA is wrapped around histones (DNA spools), and the brown spots are methylated cytosines, it keeps the DNA tight and wrapped up. So the DNA cannot be accessed and transcription of DNA cannot occur. When methylation is removed, the spooling becomes much looser and DNA can now be accessed by other enzymes that CAN go through gene transcription. So gene expression is going to be increased It is all involved with 5-methyl THF bc that's where the methyl group originated from.

Question 63

Folate Deficiency

Answer 63

Megaloblastic macrocytic anemia (very common) ---fewer than normal RBCs, that are large and immature, oval-shaped

Question 64

What types of cells are likely to be affected by folate deficiency?

Answer 64

Rapidly-dividing cells, such as 1) enterocytes, and 2) blood cells

Question 65

How does folate deficiency present, clinically?

Answer 65

MCV increases and hypersegmentation of WBCs occur, due to: Impaired DNA synthesis, negatively effecting GI cells and snowballing into impaired nutrient absorption of other vitamins and minerals. -Glossitis and bright red tongue, swelling (in severe deficiencies) -Spina bifida and neural tube defects

Question 66

What is the upper tolerable intake for folate, in adults? Why?

Answer 66

1 mg for folic acid supplementation of fortified foods, because folic acid supplements can mask potential B12 deficiency associated with megaloblastic anemia but not neurological damage

Question 67

FILL IN THE BLANK Intakes of folate higher than XXXXXX times recommendations may be associated with increased cancer risk and cancer mortality (especially in those with pre-cancerous tumors). Why?

Answer 67

2.5x higher Because of folate's ability to be utilized in the synthesis of DNA. So, in those with cancers that are rapidly growing tissues, we do not want that to happen, and so increased intake of folate can actually drive cancer growth in that way.

Question 68

How is folate assessed?

Answer 68

Plasma folate concentrations (3 to 20 mcg/L). Below 3 = deficiency. This indicates the short-term status of folate RBCs folate <140 mcg/L considered deficient. This indicates the long-term status of folate because RBCs live for 120 days.