You can find information about some biochemical processes here.
- Citric acid cycle
- Choline metabolism
- Cobalamin metabolism
- Methylation cycle
- Neurotransmitter synthesis
- Parasympathetic and sympathetic nervous system
- Redox Cycles
Citric Acid Cycle
The body needs energy to activate processes like the fatty acid synthesis, the cholesterolsynthesis, the gluconeogenesis or the protein synthesis. In oder to receive this energy we eat food which is then broken down and metabolized into energy units like acetyl-CoA, NADH and ATP.
Main components of food, fats, amino acids and carbohydrates, are metabolized differently.
Carbohydrates are first broken down into glucose and then go through the glycolysis. The result is pyruvate,which gets transported into the mitochondria and converted to acetyl-CoA by the enzyme-complex pyruvate dehydrogenase. This is one of the most important enzymes in the mitochondria. It depends on the cofactors vitamin B1, B2 (FAD), B3 (NAD), B5 (coenzyme A/ CoA-SH) and alpha-lipoic acid
Fatty acids enter the mitochondria dependent on their length. Short-chained fatty acids can pass into the mitochondria directly, while long- and middle-chained fatty acids need to bind to carnitine to enter the mitochondria. In the fatty acid oxidation short units are broken down from the fatty acid and converted into acetyl-CoA.
Different amino acids can fuel the energy metbaolism from different points by being converted to pyruvate, acetyl-CoA or alpha ketoglutarate, etc.
Acetyl-CoA reacts with oxalacetate to form citrate (or citric acid), which enters the citric acid cycle. In the citric acid cycle NADH/H+ and FADH2 are formed from NAD+ und FAD. Electrons and protons are transferred from the citric acid cycle-metabolites to NAD+:
NAD+ +2H+ +2e- -> NADH H+
Electrons are negatively charged (e-) which makes them rich in energy. NADH/H+’s ability to contain these electrons and to transfer them to other substances/into other reactions makes it energetically very valuable.
The most important electron transfer by NADH/H+ and FADH2 is in the oxidative phosphorylation, a process in which ATP is produced from ADP. ATP is also in a very energy-rich state with a high-energy bond between the second and third phosphate. In reactions that require energy ATP is often used. In a reaction with water the ATP (adenosyltriphosphate) separates into ADP (adenosyldiphosphate) and inorganic phosphate or Pi (PO4(3-)), containing one phosphorus:
This reaction is exergonic, releasing energy to the sorroundings and thereby provides energy for other reactions to work.
This is the synthesis pathway of choline from the phospholipid phosphatidylcholine, as well as other choline forms.
Phosphatidylcholine is derived from the phospholipid- metabolism. Phosphatidylserine is converted to phosphatidylethanolamine and then methylated to phosphatidylcholine. Phospholipids form cell membranes in phospholipidlayers and can bind cytoslic calcium.
Influence of UV light and Calcium
During UV light exposure there is an increase in the release of choline and acetylcholine. The UV light stimulates phospholipase A2 (PLA2), leading to increased cleavage of phosphatidylcholine to glycerylphosphorylcholine and fatty acids.
Calcium stimulates the synthesis of phophatidylcholine by increased phosphorylcholine conversion to CDP-choline. Calcium is also a cofactor for the phospholipase A2. Phospholipase A2 is an enzyme that might increase inflammatory processes, because it releases the fatty acid arachidonic acid which can have inflammatory effects. Substances that inhibit this enzyme might have anti-inflammatory effects, like the Shiitake mushroom.
Methylation in the middle Pathway
This shows how choline is converted to betaine which methylates homocysteine to methionine in the methylation cycle.
This graphic explains the vitamin B12/cobalamin metabolism, in which hydroxocobalamin becomes adenosylcobalamin and methylcobalamin.
Methionine synthase reductase (MSR) converts cob(II)alamin to methylcobalamin. Its activity is reduced by enzyme mutations in the MTRR gene. Methionine synthase reductase belongs to the ferredoxine- NADPH-reductases, which contain iron-sulfur-clusters.
Methionine synthase regenerates methylcobalamin from cob(I)alamin and is encoded by the MTR gene.
Here’s a picture of the methylation cycle.
Methionine is an amino acid that contains a methyl group (CH3-> a compound with one carbon atom and three hydrogen atoms). Methyl groups are required in multiple processes in the body and methionine can donate its methyl group, enabling these reactions.
For methionine to transfer its methyl group it first needs to be converted to S-adenosylmethionine (SAM-e), with ATP and magnesium. When S-adenosyl methionine has donated its methyl group, it turns into homocysteine.
Homocysteine can be regenarated back to methionine by taking up another methyl group. There are two regeneration pathways for methionine. Also, instead of being recycled, homocysteine can be converted to cysteine and used for glutathione synthesis.
In the “middle pathway” choline acts as a methylgroup-donor. It contanis three methyl groups. First choline is converted to betaine (trimethylgylcine) and then methylates homocysteine back to methionine with zinc as a cofactor.
The body can synthesize choline from the phospholipide phosphatidylserine, using three methyl-groups but the body may depend on sufficient food intake of choline as well.
The “outer pathway” uses methylfolate and methylcobalamin as cofactors. Methylcobalamin transfers its methyl group to homocysteine and produces methionine and cob(I)alamin. Methylfolate then regenerates cob(I)alamin resulting in methylcobalamin and tetrahydrofolate.
A folate cycle recycles the folate when it has donated its methyl group. An important pace-setting enzyme for this recycling-process is the MTHFR (Methylenetetrahydrofolatereductase) enzyme. After 5,10-Methylene- Tetrahydrofolate has taken up a methylgroup from the amino acid serine, MTHFR converts it to 5-MTHF (5-Methyltetrahydrofolate).
MTHFR function is dependent on the cofactors FAD and NADPH.
Functions of S-Adenosyl Methionine
The methylation cycle plays an important role in the mitochondrial energy metabolism because SAM-e is required to synthesize apha-lipoic acid, carnitine and coenzyme Q10.
In neurotransmitter metabolism methylgroups are needed to break down dopamine, noradrenaline and adrenaline and to synthesize phosphatidylcholine a precursor of acetylcholine.
Some other functions of SAM-e are the methylation of DNA and the degradation of histamine.
Dysfunction of the Methylation Cycle
The methylation cycle is dependent on several vitamin and mineral cofactors. Deficiencies of these cofactors result in less production of SAM-e.
Also, gene mutations have been discovered, where the mutated genes reduce the activity of enzymes in the methylation cycle. The most prominent one is the MTHFR gene mutation, reducing MTHFR activity and leading to lower levels of 5-MTHF.
The methylation cycle has gathered some attention, especially in the treatment of diseases like ME/CFS and Autism, because of the important functions of methylgroups in the body and because of the possibility that mutated enzymes could impact its function.
More on gene mutations in: Theories- Cofactors in mutated enzymes
This shows the synthesis of the neurotransmitters dopamine, noradrenaline, adrenaline from the amino acid L-tyrosine.
Here the serotonin synthesis from L-tryptophan:
Dopamine and serotonin production depend on tetrahydrobiopterin (BH4), which requires GTP for synthesis and vitamin C or folate and NADPH for regeneration.
The enzymes COMT (cofactor: SAM-e) and MAO (cofactor: FAD) are needed for the breakdown of dopamine, noradrenaline and adrenaline. The first step in serotonin breakdown is the monoamine-oxidase/ MAO (cofactor: FAD).
Parasympathetic and Sympathetic Nervous System
The parasympathetic and sympathetic nervous system are part of the autonomic nervous system. The autonomic nervous system is called autonomic because the body controls its functions like heart rate, digestion or breathing mostly without any conscious actions. You can influence some functions to a certain degree though, like breathing or heart rate (through relexation techniques etc).
The parasympethetic nervous system is mainly activated in a state of relaxation. It is also described as the ‘rest-and-digest-mode’. Activation of the parasympathetic nervous system lowers the heart rate and blood pressure, increases digestion and urination and has other effects like constricting the pupils in the eye.
Serotonin and acetylcholine are neurotransmitters that are active in the parasympethetic nervous system. The parasympethetic nervous system is even said to be mostly cholinergic.
The sympathetic nervous system reacts to stress situations and brings the body into a ‘fight-and-flight’ mode. It increases the heart rate, reduces digestive function, dilates the pupils and increases blood flow to the skeletal muscles and the lung,..
This gives the body the energy it would need to react to a dangerous situation while reducing the digestive function etc. Neurotransmitters that act in the sympathetic nervous system are adrenaline, noradrenaline or acetylcholine.
In ME/CFS, the parasympathetic and sympathetic system are possibly dysregulated. Often people experience symptoms like increased heart rate or slow digestive function that could be associated with a problem in activating the parasympathetic nervous system. Dysregulation in the autonomic nervous system could be related to problems like imbalanced neurotransmitters, low energy levels and adrenal dysfunction.
This shows a simplified image of how antioxidants can regenerate each other.
The oxidized form of alpha lipoic acid, dihydrolipoic acid (DHLA), can recycle vitamin C, E, glutathione and coenzyme Q10.
Reduced glutathione can recycle vitamin C, vitamin E and coenzyme Q10.