16: One-Carbon Metabolism Flashcards
How are catechols (dopamine, norepinephrine, and epinephrine) made and what is their function?
See red paper for synthesis
Release of the hormones epinephrine and norepinephrine from the adrenal medulla of the adrenal glands is part of the fight-or-flight response.
In the brain, dopamine functions as a neurotransmitter—a chemical released by nerve cells to send signals to other nerve cells. Parkinson’s is caused by a death in the dopamine producing cells in the brain. Patients are given DOPA since it will cross the blood brain barrier and hopefully increase the production of dopamine. More substrate means more product.
What is GABA and histamine?
GABA is the chief inhibitory neurotransmitter in the mammalian central nervous system.
Histamine is a potent vasodilator and may be a neural transmitter. It is released during allergic reactions. Antihistamine drugs are compounds that bear a structural similarity to histamine and can prevent the physiologic changes that it normally produces.
What is a 1-carbon group?
The transfer of one-carbon groups occurs frequently in metabolism. These one-carbon fragments can be thought of as existing in a readily available pool with interchange between different oxidation states of carbon.
What are 1-carbon group carriers?
Different carriers are employed for one-carbon groups of different oxidation states.
Biotin
Tetrahydrofolate
What is folic acid and THF?
Humans cannot synthesize the pterin ring, and the formation of tetrahydrofolate is dependent upon the dietary intake of a precursor, folate (pteroylglutamate, folic acid). Folate is an essential B9 vitamin, that is often destroyed in prepared foods. Rapidly dividing cells use a lot of folate. FOLATE DEFICIENCY: Since you need folate to make nucleotides it tends to affect rapidly dividing tissues. Indeed the first symptoms are an anemia. Folic acid is a major carrier of 1 carbon groups–we get folic acid from vegetables (foliage). Folate is needed for nucleotide synthesis. Folate deficiency gives neural tube defects.
Tetrahydrofolate carries one-carbon groups of all oxidation states except carbon dioxide. THF can serve as an acceptor of one-carbon fragments in degradative reactions and as a donor of one carbon fragments in biosynthetic reactions.
What is SAM and B12?
S-Adenosylmethionine is an important donor of methyl groups to a wide variety of biomolecules.
Vitamin B12 (cobalamin) is a coenzyme. The central core of the molecule is a tetrapyrrole with a central cobalt atom bonded to 4 pyrrole nitrogens. The fifth bond is to a 5’-deoxyadenosine unit (above the plane of the molecule) and the sixth bond is to dimethylbenzimidazole.
There are several forms of cobalamin in humans. They vary by the group attached to the fifth bond above the plain of the ring. The adenosyl version is found in the MMAM reaction, while the hydroxy version is used in the HMT reaction where it carries the methyl group in that position during the reaction. Most vitamin supplements have a CN group in that position. B12 is abundant in many foods but requires a specific factor called intrinsic factor for absorption. This factor is made in the stomach and is absorbed in the lower gut. Elderly people tend to make less intrinsic factor and some people develop an autoimmune disease that specifically destroys the intrinsic factor producing cells in the stomach. Hence B12 supplementation is often given by injection. Though less common there are also patients that are deficient in a specific protein that transports B12 around the body. This protein is called transcobalamine.
Why are 1-carbon groups important?
This one-carbon metabolism pathway is centered around folate. Folate has two key carbon-carbon double bonds. Saturating one of them yields dihydrofolate (DHF) and adding an additional molecule of hydrogen across the second yields tetrahydrofolate (THF). Folates serve as donors of single carbons in any one of three oxidation states: 5-methyl-THF (CH3THF; reduced), 5,10 methylene-THF (CH2THF; intermediate) and 10-formyl-THF (CHOTHF; oxidized). The single carbon donor CH3THF is used to convert homocysteine into methionine which can then be used to methylate DNA, the donor CH2THF is used (along with a molecule of hydrogen at the site of one of the double bonds) to convert dUMP (deoxyuridylate) into dTMP (thymidylate) and the donor CHOTHF is used to set up ring closure reactions in de novo purine synthesis. CH3THF is the primary methyl-group donor for processes such as DNA methylation reactions. Purines are used both in RNA synthesis and in DNA synthesis and dTMP is synthesized srtictly for DNA synthesis, be it for DNA repair or DNA replication.
The folate pathway is central to any study related to DNA methylation, dTMP synthesis or purine synthesis.
Differential methylation (e.g. hypermethylation of tumor suppressors) as well as disturbances in nucleotide synthesis and repair, are associated with several forms of cancer. There are also indications that hypermethylation is involved in the progression of adenomas to cancer. The pathway is also illustrative of the role of a number of B vitamins, including vitamin B12 (cobalamine) which is important for the sythesis of folate (vitamin B9) and of methionine.
What is an antifolate and what does it have to do with cancer?
Antifolates like birth control pills exacerbate the effects of folate deficiency & give issues like spina bifida. Encourage female patients to take folate supplements.
Antifolates are molecules similar to folate & cause folate deficiency.
What are the different flavors of folate and how are they made?
Formation of the N5-methyl form is non reversible in humans. It is only consumed by one reaction in the formation of methionine. More than 12% of the population is partially deficient in the enzyme that makes this form. These patients have a higher risk of heart disease and a lower risk of colon cancer (less nucleotide synthesis).
intestinal mucosal cells also reduce the folic acid to tetrahydrofolic acid in two steps by dihydrofolic acid reductase.
What is the source of 1-carbon groups?
S-Adenosylmethionine is an important donor of methyl groups to a wide variety of biomolecules.
What is the methyl cycle?
It is the 1-carbon cycle. It makes SAM (S-adenosyl methionine) & regenerate methionine.
What is the folate trap?
In a B12 deficiency you get a folate deficiency because you need B12 to run the homocysteine methyltransferase rxn to make methionine. In no B12, no RXN so you accumulate folate in the N,5 methyl form.–it becomes trapped & you become folate deficient & you cannot make nucleotides. The first symptom of folate deficiency is anemia. Elderly folks have less B12 & you can give them B12 injections.
The folate trap occurs when B12 is deficient, and causes a folate deficiency by trapping the folate in the N5 methyl form. This is then manifested as an anemia. However, if folate is supplemented folate never becomes deficient and the B12 deficiency will cause neurological problems without the anemia. Because of the dangers of folate supplementation it began with grains only about 10 years ago.
B12 is absorbed in ileum. It gets there via by binding to intrinsic factor in the stomach (made in stomach).
B12 is abundant in many foods but requires a specific factor called intrinsic factor for absorption. This factor is made in the stomach and is absorbed in the lower gut. Elderly people tend to make less intrinsic factor and some people develop an autoimmune disease that specifically destroys the intrinsic factor producing cells in the stomach. Hence B12 supplementation is often given by injection. Though less common there are also patients that are deficient in a specific protein that transports B12 around the body. This protein is called transcobalamine.
What is pernicious anemia?
Pernicious anemia is one of many types of the larger family of megaloblastic anemias. One way pernicious anemia can develop is by loss of gastric parietal cells, which are responsible, in part, for the secretion of intrinsic factor, a protein essential for subsequent absorption of vitamin B12 in the ileum. Treatment is to give B12.
The AA Tyrosine is the precursor for what compounds?
Dopamine
Epinephrine
Norepinephrine
Melanin
Thyroxine
Note the ine suffix
The AA Tryptophan is the precursor for what compounds?
Melatonin
Serotonin
Niacin
Note the onin suffix
