1C Metabolism - Mintz 3/10/16 Flashcards
two key methyl group (1C) donors
1. THF (tetrahydrofolate)
- de novo purine synthesis
- thymidylate synthesis
2. SAM (S-adenosylmethionine)
- epi synthesis
- DNA methylation
dietary folate (form)
folates are packaged conjugated to a polyglutamyl chain
aka polyglutamates
folate absorption
occurs in jejunum
can’t be absorbed as polyglutamates : have to be broken down
folate conjugase breaks polyglutamates → monoglutamates
- inhibited by phenytoin (anticonvulsant)
- production can be compromised in bowel irritation (tropical sprue, celiac sprue)
monoglutamates are absorbed
- alcohol, oral contraceptive pills: inhibit monoglutamate uptake
folate conjugase
required for adequate folate absorption (because turns polyglutamate into absorbable monoglutamate)
- conjugase production can be compromised by bowel irritation
- tropical sprue: bacterial origin, causes int infl and malabs
- celiac sprue: allergic origin (ex. gluten/gliadin)
THF synthesis in humans
key enzyme: dihydrofolate reductase (DHFR)
folate → DHF → THF
- inhibited by methotrexate (competitive inhibitor) and aminopterin - both chemotherapy agents
methotrexate
how to get around the bad?
competitive inhibitor of DHFR - compromises THF synthesis from folate
chemo agent/autoimmune tx that inhibits DHFR → halts nucleotide synth → cell death in rapidly dividing cells
- myelosuppression
- mucositis
- acute kidney injury
- dermatitis
- CNS disturbances
- GI upset
how do you avoid the toxicities that come with it?
- supplement with folinic acid (leucovorin - activated form of folate) → combats neurotox, GI tox, myelosuppresive effects of methotrexate
how does leucovorin fix methotrexate-assoc toxicities without also rescuing cancer cells?
- methotrexate is more highly polyglutamated in cancer cells (compared to in normal cells)
- more glutamate? better affinity for DHFR
- leucovorin has a tendency to accumulate in normal cells than in cancer cells
therefore, DHFR in cancer cells stays occupied by polyglutamated methotrexate, while leucovorin that accumulates in normal cells is converted to THF (bypassing DHFR)
bacterial THF synthesis
- drugs that block it
reasoning: blocking folate synthesis in bacteria would interfere with nt synthesis, kill them
PABA → folic acid [dihydropteroate synthetase]
- sulfonamides inhibit DHPS
folic acid → THF [bacterial version of DHFR]
- trimethoprim inhibits bacterial DHFR
pre-rxn prep of THF
THF needs to be primed to donate a C group
- type of molecule from which THF takes a C group will determine the rxn which it can take place in
formate : de novo purine synth
Gly, Ser, formaldehyde : thymidilate synth
SAM synthesis
L-methionine + ATP → SAM + 3P
[SAM synthetase]
after it donates its methyl group, SAM → S-adenosyl homoCys → homoCys (bad!!!!)
- SAM methyl group donation is involved in DNA synthesis and norepi → epi synthesis
homocysteine
elevations in plasma homoCys → oxidative damage, inflammation, endothelial dysfunction
- indep risk factor for occlusive vascular disease (unclear whether it’s a cause or a marker…)
***levels of homoCys are inversely related to folate, B6, and B12
disposing of homocysteine
homoCys →→ Cys [vit B6]
- less important
homoCys + 5methyl THF → Met + THF
[methionine synthase; cofactor: B12 derivative]
- important!!! regenerates THF and gives you Met, which can be used to make SAM
folate trap
B12 deficiency slows rxn:
n5-methylTHF + homoCys → THF + Met
- traps cell’s folate supply as n5-methylTHF → hinders ability to make other folate derivatives → leads to depletion of cell nt reserves
- also leads to less SAM!
- affects methylation of DNA
together, affect nt/epi/a.a./complex lipid synthesis and lots of other stuff
markers of B12 deficiency
- homocysteine buildup
- methylmalonic acid buildup
[B12 needed as cofactor for methylmalonyl CoA → succinyl CoA]
- macrocytic anemia (nuclear maturation impaired, cytoplasmic maturation normal)
- peripheral neuropathy with sensorimotor dysfx
-
subacture combined degen of the cord
- loss of myelin in posterior (touch, vibration, proprioception) and lateral (movement) columns
- failure to regen SAM → no methylation (important for myelin maintenance)
- spinocerebellar tract demyelination → ataxia
- dementia
- smooth, sore tongue w/ papillae degen
markers of folate deficiency
- how to distinguish from B12 def
- macrocytic anemia (nuclear maturation impaired, cytoplasmic maturation normal)
- identical to B12 EXCEPT:
- NO NEUROLOGICAL DISEASE
- NO METHYLMALONIC ACID BUILDUP
