one-carbon metabolism Flashcards
one-carbon metabolism aka __ cycle
one-carbon metabolism aka folate cycle
production of glycine steps
- serine donates 1 carbon to THF (THF –> methylene-THF)
- this converts serine –> glycine (requires PLP, vit B6)
producing thymine
- methylene-THF –> DHF (1C donation, thymidylate synthase)
- thymidylic acid –> DNA-thymine
producing DHF
reducing folic acid (using NADPH)
producing THF
methylene-THF –> methyl-THF –> (requires B12) THF
__ is essential for production of THF
DHF is essential for production of THF
what catalyzes DHF reduction to THF
DFHR
requires NADPH
serine –> glycine requires
PLP (B6)
homocystein –> methionine requires
folate
B12
choline
folate and 1-carbon metabolism are important for epigenetics bc
they make SAM, a methyl donor
folate is essential to make
DNA thymine
DNA-adenine and guanine production
- serine donates 1C to THF (THF –> methylene THF)
- methylene THF –> formyl THF
- formyl THF is a 1C donor for DNA adenine and guanine
low riboflavin inhibits ability to make
DNA adenine and DNA guanine
how do we know to stop making methionine
SAM: indicates we have enough dietary methionine
fasting = __ SAM = make __ methionine
fasting = less SAM = make more methionine
producing Methionine, SAM, and homocysteine
- THF –> methylene-THF (serine donates 1C)
- methylene-THF –> methyl-THF (MTHFR) (requires riboflavin)
- homocysteine –> methionine (methyl-THF donates 1C) (needs B12)
- Methionine –> SAM (needs ATP)
- SAM –> homocysteine (B12)
B9/B12 independent methionine production
betaine (made from choline) can convert homocysteine to Met
formation of cysteine
- homocysteine –> cysteine (requires PLP)
__ inhibits MTHFR and stimulates CBS
this pushes us to use more __ to make more __
SAM inhibits MTHFR and stimulates CBS
this pushes us to use more methionine to make more cysteine
vitamin B6 supplement form
pyridoxine
vitamin B6 active cofactor
PLP
vitamin B6 excretion form
pyridoxic acid
how does B6 cross cell?
B6 is bulky so it is dephosphorylated to cross, then rephosphorylates and sent to blood
vitamin B6 rxns (5)
- transaminations
- decarboxylations
- heme synthesis
- one-carbon metabolism
- lipid and carb metabolism
vit B6 deficiency (4)
- microcytic anemia
- convulsions/EEG abnormalities
- hyperhomocysteinemia
- inflammatory disease
microcytic anemia =
smaller RBC that are pale (white in middle)
iron deficiency
low vit B6 = low pyridoxal phosphate = __ GABA = __
low vit B6 = low pyridoxal phosphate = decreased GABA = seizures
low pyridoxal phosphate can also cause decreased __, leading to __
low pyridoxal phosphate can also cause decreased serotonin, leading to depression
vit B6 and inflammation
low B6 = reduced PLP = increased inflammation
microcytic anemia cause
macrocytic anemia cause
microcytic anemia B6 deficiency
macrocytic anemia B9, B12 deficiency
vit B6 is associated with
blood
__ and __ are required in heme synthesis
vit B6 and iron are required in heme synthesis
measuring vit B6 status
plasma PLP concentration
(less common) measure PLP-dependent enzyme activity
oral Met to Trp loading tests
methionine load test
if you have a defect in enzyme,
homocysteine rises and won’t go down for awhile
tryptophan load test
in deficiency,
lots of xanthurenic acid is produced, bc there is no B6 to go down normal pathway
folic acid aka __ acid
folic acid aka pteroylglutamic acid
synthetic (unnatural) form of folate
folic acid
pteroylglutamic acid
folate is important in
DNA synthesis
anti-folate drugs
impair DNA synthesis
good for cancer, rheumatoid arthritis in small doses (anti-inflammatory)
dietary form of folate
PGA
folate is attached to
glutamic acid
reduced active form of folate is
THF
in high doses, how is folic acid transported
passive diffusion
which intestinal cell is folate transported across?
jejunum
folate absorption
- remove glutamic acid residues so folate is less bulky
- PGA1 enters cell via H+ symporter
- PGA1 converted to reduced forms (aka methyl-THF)
- intestinal cell uses reduced folate or transports to portal circ
- FA can also directly enter in high doses via diffusion
3 functions of folate
1- carbon metabolism
1. DNA and RNA synthesis (TAG)
2. methionine recycling
3. SAM synthesis
folate deficiency
macrocytic (megaloblastic) anemia
hyperhomocysteinemia
NTDs
macrocytic anemia
larger blood cells with increased number of lobes
vitamin B12 aka
cobalamin
2 cofactor forms of cobalamin
methyl
deoxyadenosyl
vitamin B12 absorption
- B12 enters stomach attached to salivary R-binder
- parietal cells produce intrinsic factor: binds B12 in small intestine (duodenum)
- in ileum, B12 binds receptor, is absorbed (endocytosed) into lysosome
- lysosome released B12, sent into blood, bind to TC (trans-cobalamin) and is sent to tissues that need it
vit B12 functions (2)
- 1- carbon metabolism
- odd-chain fatty acid metabolism
vit B12 has same functions as
folate
vitamin B12 deficiency
macrocytic (megaloblastic) anemia
hyperhomocysteinemia
neurological disease
pernicious anemia
autoimmune disorder: loss of IF in stomach
leads to malabsorption of vit B12
assessment of B12 status
serum B12 bound to haptocorrin and transcobalomin
vit B12 malabsorption
- Atrophic gastritis
- Autoimmune production of IF or
parietal cell antibodies (pernicious
anemia) - Gastrectomy leading to loss of intrinsic factor
- Pancreatic insufficiency
- Bacterial overgrowth (H. Pylori)
- HIV infection
- Ileal disease and resection
methyl-folate trap
low dietary methionine = not enough SAM = methylation rxns can’t happen
intracellular vit B12 metabolism
- transcobalamin takes vit B12 to cells
- B12-cobalamin reduced to methyl-B12 (coenzyme for Met synthesis)
- some B12 in mito becomes adenosyl-B12 and is used to make succinyl-CoA
treating macrocytic anemia
you must find out if deficiency in vit B9 or B12 has caused it
treating vit B12 with folic acid causes neurological damage exacerbated by vit B12 deficiency
why does vit B12 deficiency cause the same problem as folate deficiency?
methyl-folate trap
methyl-folate trap
when folate –> methyl-THF it can only be used as a methyl-donor to convert homocysteine into methionine which requires B12
if you are low in B12, methyl-THF builds up
methyl-THF can’t be converted back to methylene-THF, so methyl-THF is trapped
what is the worst treatment for someone with vit B12 deficiency
folic acid!
2 causes of vit B12 deficiency
- dietary deficiency
- malabsorption
dietary deficiency of vit B12
- vegans and vegetarians
- low intake of animal foods
- takes years after strict vegan diet
malabsorption caused vitamin deficiency
- pernicious anemia
- atrophic gastritis
pernicious anemia
autoimmune disorder
no IF in stomach
can’t absorb pills or food vit B12
atrophic gastritis
loss of stomach acid
can’t absorb B12
usually mild deficiency
homocysteine increases risks of __ and __
homocysteine increases risks of atherosclerosis and myocardial infarction (MI)
B vitamin supplements cause lowered __ which reduces __
B vitamin supplements cause lowered homocysteine which reduces brain atrophy
PPIs like omeprazole inhibits transport of __ produced from parietal cells into lumen of stomach
SO, they can’t extract __
PPIs like omeprazole inhibits transport of H+ produced from parietal cells into lumen of stomach
SO, they can’t extract B12
metformin may interfere with absoprtion of __ complex by interfering with __ requirement for that absorptive process
metformin may interfere with absoprtion of vit B12-IF complex by interfering with Ca2+ requirement for that absorptive process
