Folate Flashcards
How many modes of action does folate have
One
It only acts as a coenzyme in one-carbon transfer reaction
What reaction have we lost that prevents us from synthesizing folate
linking p-aminobenzoic acid to the pteridine ring
How many forms of folate are there? Which two positions are important
six different one-carbon conjugated forms of folate
N5 and N10
What are the two modification require to activate folate
- Fully reduced in order to have carbon units attached
- Active form of folate is conjugated with up to six glutamates
How is folate fully reduced? How many steps and what enzymes
2 sequential steps
both using Dihydrofolate reductase
Folate –> 7,8 dihydrofolate –> 5,6,7,8 tetrahydrofolate
what is the predominant form of folate in cells
pentaglutamate
What level of glutamylation is needed to be taken into cell? Retained?
First glutamate is added to pABA, it can then be taken into cells, and glutamated further
Converted to diglutamate in order to be retained in cells
The rate of glutamylation slows as the glutamate tail gets longer
What is the major form of folate that is taken into tissues
methyl-THF, once in the cell it is demethylated then glutamated
Most dietary folate is bound to _____
albumin
What are the three classes of folate-binding proteins
High affinity binding proteins: Can be membrane associated or soluble
other membrane associated proteins: Lower affinity then previous group
Enzyme: cytosolic enzymes that require folate (lower affinity)
How is folate excreted
very little excreted in urine
most of the folate bound to proteins is reabsorbed by the kidneys
Describe the catabolism of folate
Folate polyglutamate that is not enzyme-bound can be degraded by having the polyglutamate tail cleaved off followed by a cleavage in the molecule
the latter cleavage is catalyzed by ferritin
Iron dependent because ferritin is the storage form of iron
Why are folate requirements higher during pregnancy
Ferritin levels rise during pregnancy and ferritin is involved in the catabolism of folate
Biochemical function of folate
participate in catabolic or biosynthetic reactions as a coenzyme
What is the primary source of the one carbon unit?
Side-chain carbon of serine
Serine becomes glycine
What are the five major one-carbon transfer reactions
Serine to glycine
catabolism of histidine
synthesis of thymidylate
methionine, and purines
What is the most important step of the one-carbon interconversions of folate
The most important step is the conversion from THF to N5N10 methylene-THF because all one-carbon conjugate forms can be obtained from N5N10methylene THF
Catalyzed by serine hydroxymethyltransferase which is a PLP enzyme
This step uses the methylene group donated from the conversion of serine to glycine
What is the single carbon-folate that cannot be interconverted to any of the other forms
5-methyl-THF
What are the three interconvertible one-carbon conjugate forms? why are they freely interconvertible
methenyl THF, methylene THF, N10-formyl THF
Are freely interconvertible due to the three enzymes involved forming a trifunctional enzyme
Why is the conversion of methylene-THF to methyl-THF important? What process is it involved in? What vitamin is that process dependent on
Decreases levels of homocysteine which are a CV risk factor
Replenishes free THF that can be re-conjugated with one carbon units
It is irreversible and methyl-THF is involved in methionine synthesis which is dependent on vitamin B12
What is the methyl-folate trap in B12 deficiency?
In b12 deficiency, methyl-THF is not consumed and thus traps THF in an unusable form
There is another mechanism for freeing up THF, by oxidation of N10-formyl-THF which releases THF, however it is inhibited by low methionine which occurs when there is a B12 deficiency exacerbating the usable folate deficiency
What are the three metabolic processes where folate acts as a coenzyme
purine biosynthesis
Pyrimidine biosynthesis
Methionine biosynthesis
Which steps in purine biosynthesis use folate? Which form of folate?
N10-formyl-THF is used in steps 3 and steps 9
Which step in pyrimidine biosynthesis is folate used as a coenzyme? What form?
N5N10-methylene THF
Converts dUMP to dTMP using thymidylate synthetase
Makes thiamine containing nucleotides important for DNA
What needs to happen to Dihydrofolate to salvage it
Needs to be reduced to THF using DHFR
Why is DHFR a common anti-cancer target
By inhibiting DHFR we cannot get the active form of folate slowing down purine and pyrimidine synthesis
What are the two enzymes that can synthesize methionine? Describe them
MetH and MetE
MetH is B12 dependent and is also much more active than MetE
How do folate deficiencies result in neural tube defects
Rapid cell division and differentiation requires DNA which requires folate fast
Folate requirement
RDI 200 ug (double during pregnancy)
Hard to achieve toxicity need above 5000
What are the problems with excessive folate supplementation
Interferes with anticonvulsants
Can mask the development of anemia
