One Carbon Metabolism Flashcards
What are the two key methyl group donors?
THF and SAM
Donates methyl groups in de novo purine synthesis and thymidylate synthesis
THF
Donates a methyl group in epinephrine synthesis and DNA methylation
SAM
All natural folates are conjugated to a polyglutamyl chain and are commonly called
Polyglutamates
Converts polyglutamase to monoglutamate (folate) for absorption
Folate conjugase
Folate conjugase is inhibited by
Phenytoin
Which two things inhibit monoglutamate uptake?
Oral Contraceptives (OCPs) and alcohol
Essential for adequate absorption of dietary folates
Conjugase
Conjugase production may be compromised by
Bowel irritation
Bowel irritation probably arising from bacterial origin, causes intestinal inflammation and malabsorption
Tropical Sprue
Similar outcome, but the original irritation is due to an allergic response, for example to gliaden (a component in gluten)
Celiac Sprue
Inhibit dihydrofolate reductase (DHFR) which converts folate to THF
Methotrexate and Aminopterin
An inhibitor of THF synthesis
Methotrexate
Potent chemotherapeutic agent and treatment for autoimmune disorders that competitively inhibits Dihydrofolate Reductase (DHFR)
Methotrexate
Can adversely affect normal dividing cells of the body
Methotrexate
Due to toxicities associated with high dose methotrexate therapy, hat can be used to bypass the metabolic block of methotrexate?
Folinic acid (leucorvin)
Effective at combating the neurotoxicity, GI toxicity, and myelosuppression effects of methotrexate
Folinic acid (leucorvin)
The active form of folate
Folinic acid
More highly polyglutamated in cancer cells than normal cells
Methotrexate
The more highly polyglutamation increases cancer cells methotrexate affinity for
DHFR
Accumulates more readily in normal cells than cancer cells
Leucorvorin
Can be converted to THF by bypassing DHFR
Leucorvorin
The sulfonamide antibiotics selectively kill bacterial cells by inhibiting
DHPS
An enzyme unique to bacteria, that is essential for THF synthesis
DHPS
Also selectively kills bacteria by preferentially inhibiting bacterial DHFR compared with the same enzyme in humans
Trimethoprim
A patient presents with a urinary tract infection and is prescribed a combination drug containing trimethoprim and sulfamethoxazole. These drugs are effective because they do what?
Inhibit bacterial THF synthesis
The type of molecule from which THF takes a Carbon group determines the reaction in which it can
Participate in
For example, N-Formyl-THF can only be used in
Purine synthesis
Or, in the case of N,N-Methylene-THF, the THF only participates in
Thymidylate synthesis
The megaloblastic anemia of a patient with folate deficiency is most likely cause by a decreased conversion of
dUMP to dTMP
After donating its methyl group SAM becomes S-adenosyl homocysteine, which is quickly hydrolyzed to
Homocysteine
Elevations in plasma homocysteine levels promote
Oxidative damage, inflammation, and endothelial dysfunction
An independent risk factor for occlusive vascular disease
Homocysteine
Plasma homocysteine levels are inversely related to levels of
Folate, B12, and B6
Used in the conversion of homocysteine to cysteine
B6
To clear homocysteine, we get the reaction of homocysteine + N-methylTHF which yields methionine and THF. This reaction requires
B12
Slows the conversion of Homocysteine and N5MethylTHF to Methionine and THF
B12 deficiency
Thus, the cell’s folate supplies become trapped as
N-methylTHF
Without THF available to make other folates, we see a depletion in the supply of cell
Nucleotides
A Vitamin B12 deficiency can lead to the accumulation of
Methylmalonyl CoA
Elevated levels of homocysteine and methylmalonic acid are biomarkers for
B12 deficiency
The catabolism of valine and isoleucine as well as the degradation of odd-chain fatty acids leads to
Propionyl CoA
Propionyl CoA is converted to
Methylmalonyl CoA
Degraded to succinyl CoA via a B12 dependent reaction
Methylmalonyl CoA
Can be used in the citric acid cycle
Succinyl CoA
What are the consequences of B12 deficiency?
Macrocytic anemia, peripheral neuropathy, spinal cord degeneration, ataxia
A smooth, sore tongue, with atrophy of the papillae signifies
B12 deficiency
Failure to regenerate methionine prevents SAM regeneration, this means no
-important to myelin maintanence
Methylation
Identical to B12 deficiency, except there is no neurological disease
Folate deficiency
Elevations in homocysteine, but not methylmalonic acid, and also an enlarged tongue, are symptoms of
Folic acid deficiency
