Amy C. Liu 2012
BGD A EOC Revision Tutorial- Part B
Folate Metabolism
What is folate?
Folate is a vitamin. Vitamins are organic compounds we require in minute amounts for metabolism
and cannot synthesise ourselves, so must be supplied in the diet. There are two main classes of
vitamins- fat soluble and water soluble.
Does anyone know which vitamins are fat soluble? ADEK
Does anyone know which vitamins are water soluble? BC
Folate is also known as vitamin B9 and some rich sources include green leafy vegetables, legumes,
egg yolks, grains, cereals, liver and kidney although it is easily destroyed by cooking. One of the
important differences to understand about fat and water soluble vitamins is that water soluble ones
are readily excreted into the urine and so require regular intake as they are not stored. However, fat
soluble vitamins are stored in the body and so can accumulate and cause hypervitaminosis which is
when vitamins accumulate to toxic levels.
The structure of folate has three main parts:
1. Pteridine ring
2. Para-aminobenzoic acid
3. Glutamate- this is an amino acid. If there is only one, it makes a monoglutamyl folate while a
chain of 2-7 gives us the polyglutamyl form.
Clinical relevance- why is it important?
The main conditions that folate deficiency can cause are:
1. Anaemia- macrocytic, megaloblastic type. Haematopoetic tissue is among the most rapidly
reproducing cells in the entire body and folic acid (and vitamin B12) is essential for DNA
synthesis. Deficiency causes maturation failure of the erythropoetic cells.
2. Neural tube defects (e.g. spina bifida, anencephaly)- one of the most common birth defects(
~1 in 1000 live births). The crucial period is periconceptual when the neural tube is closing
which occurs early in pregnancy.
A normal diet usually comfortably exceeds the recommended dietary intake (RDI) of folate
(0.4mg/day). However there are some at risk groups we should be aware of:
- Pregnant women- requirements increase
- Alcoholics- poor diet
- Malabsorption diseases- poor absorption
- Elderly- poor diet
- Medications- e.g. anticonvulsants and oral contraceptives which interfere with absorption and
metabolism, also antibiotics and chemotherapy.
Biosynthesis
The folic acid biosynthesis pathway occurs in higher plants and many microorganisms such as
bacteria, but not in humans. Therefore it can be exploited in antibiotics such as sulphonamides. It
involves the piecing together of the PABA with a pteridine derivative and then the additions of
glutamates to make polyglutamyl dihydrofolic acid.
Forms in the body
Amy C. Liu 2012
As we saw in the biosynthesis pathway, plants and microorganisms produce folate in the form of
polyglutamyl dihydrofolic acid. This is the main dietary form of folate that we eat. Note that on this
diagram, the right side are all polyglutamyl forms, while the forms on the left only have one glutamate.
After we eat polyglutamyl dihyrofolic acid, it is oxidised and this polyglutamyl chain is removed by
intestinal enzymes to give monogluyamyl folic acid which we can then absorb through the gut.
Within the hepatocytes of the liver, folic acid is reduced to dihydrofolate and then immediately to
tetrahydrofolate, the fully reduced and active form of folate. Both reductions are carried out by
dihydrofolate reductase and the second reaction occurs quickly so that there are no significant
concentrations of dihydrofolate.
Tetrahydrofolate is converted to polyglutamyl tetrahydrofolate and then to derivatives which are the
functional form for utilisation and storage in cells. These derivatives are transported in the blood as
monoglutamyl tetrahydrofolate derivatives, mainly 5-methyl-FH4.
Folate and I-C metabolism:
Polyglutamyl-FH4 derivatives and vitamin B12 act as coenzymes supplying chemical groups
containing single carbon atoms for biosynthetic reactions requiring these 1-C groups. The one carbon
metabolism pathway is centered around folate and is needed for the synthesis of important
substances such as purines and pyrimidines for DNA and RNA as well as choline. Defects in 1-C
metabolism affect rapidly dividing cells most rapidly because of impaired DNA/RNA synthesis, hence
why haematopoietic tissue is greatly affected.
A range of 1-C fragments can be donated by amino acids and transferred onto nitrogen 5, 10 or the
bridge between the two on tetrahydrofolate. Once a carbon fragment is loaded, the tetrahydrofolate
derivative can be used for 1-C metabolism.
Most of the 1-C fragments are interchangable and reversible on tetrahydrofolate derivatives EXCEPT
for the methyl group.The formation of 5-methyl-tetrahydrofolate is irreversible, which is why it is the
dominant derivative both in the serum and tissues.
There is only one reaction by which it can be utilised- the methyl group is donated onto homocystine
and then methionine synthase converts it into methionine which then acts as the methyl donor in
many biosynthetic reactions.
Adrenergic and Cholinergic Mechanisms
Divisions of the nervous system:
The nervous system can be separated into parts based on structure and function.
Structurally:

Central nervous system- brain and spinal cord

Peripheral nervous system- nerves and ganglia outside the CNS that connect it to the body.
Functionally:

Somatic nervous system- innervates voluntary muscle (myotomes) and skin (dermatomes).
Mainly involved with detecting and responding to information from the external environment.

Autonomic/visceral nervous system- innervates organ systems in the body and other
visceral elements such as cardiac muscle, smooth muscle and glands. Mainly involved with
detecting and responding to information from the internal environment. Further divided into
sympathetic and parasympathetic components.
Amy C. Liu 2012
The autonomic nervous system
The autonomic nervous system can be further subdivided into sympathetic and parasympathetic
components. There is also an enteric division that innervates the wall of the GIT and consists of two
interconnected myenteric and submucosal plexuses.
- Parasympathetic system- originates in the craniosacral region (cranial nerves III, VII, IX, X
and S2-S4), associated with vegetative (homeostatic) function, innervates viscera only.
- Sympathetic system- originates in the thoracolumbar region (T1-L3), associated with
emergency (fight or flight) function, innervates viscera and peripheral regions of the body.
Neurotransmitters of the autonomic nervous system
The two main neurotransmitters of the ANS are acetylcholine (ACh) and noradrenaline.
Cholinergic neurons are found in both the sympathetic and parasympathetic nervous system and
release acetylcholine (ACh) as their neurotransmitter to act on cholinergic receptors (nicotinic or
muscarinic).
Adrenergic neurons are only found in the sympathetic nervous system and release noradrenaline as
their neurotransmitter to act on adrenergic receptors (α or β).
-
All motor nerve fibres leaving the CNS (ganglionic transmission) release ACh which acts
nicotinic receptors.
All postganglionic parasympathetic fibres release ACh which acts on muscarinic receptors.
All postganglionic sympathetic fibres release noradrenaline which acts on α or β
adrenoceptors with the major exception of sweat glands where ACh acts on muscarinic
receptors.
Amy C. Liu 2012
Action of receptors in the autonomic nervous system: