SYLLABUS 16: Methylation Reactions in Biological Systems: Vitamin B12 Metabolism Flashcards
is met essential or nonessential aa?
essential
why is Met important
- protein synthesis
- it’s the major biological methylating agent used in synthesis of imp biochemicals
what is SAM
s-adenosyl methionine, the methylating agent produced in the methionine adenosyl transferase rxn
Met + ATP -> SAM + 3Pi
what are some important compounds whose synthesis requires a methyl group from SAM?
epinephrine
creative
methylated nucleotides
phosphatidylcholine
melatonin
what happens is SAM gives up its methyl group
converted to S-adenosyl homocysteine, SAH, which is hydrolyzed to adenoside + homocysteine
how can homocysteine become methionine again?
what inhibits this rxn?
homocysteine can accept a methyl group from the vitamin cofactors N5-methyl tetrahydrofolate and B12, cobalamine
high levels of methionine inhibit this reaction b/c do not need to generate methionine
what is the active methyl cycle
Methyl-tetrahydrofolate carries methyl group on N-5 of its structure
N5-CH3-THF transfers the methyl group to vitamin B12, cobalamine => methyl cobalamine
methyl cobalamine transfers the methyl to homocysteine => methionine
what is the purpose of the transulfuration pathway
to convert methionine -> homocysteine -> cysteine in conditions of sufficient methionine available, when do not need more methionine
describe the transulfuration pathway
- homocysteine reacts w/ serine, forms cystathionine, via cytathionine synthase, a PLP requiring enzyme
* is feedback inhibited by high levels of cysteine* - cystathionine is hydrolzed by cystahionase, also requires PLP, to cysteine + a-ketobutyrate
a-ketobutyrate -> propionyl coA -> succinyl CoA -> TCA cycle
is serine an essential amino acide?
is cysteine
serine: no
cysteine: semi; can be biosynthesized from serine + met
when is propionyl CoA produced during aa metabolism?
from a-KB, which came from cystathione, which came from serine + methionine
from valine, isoleucine, and threonin e
what’s the fate of succinyl CoA?
- can be further oxidized in TCA cycle for energy
- can be metabolized to OAA and eventually to gulcose during gluconeogenesis
- can produce heme
what does propionyl CoA -> succinyl CoA require?
vitamin B12
what mammalian reactions require vitamin B12?
- conversion of homocysteine -> methionine
- conversion of propionyl CoA -> succinyl CoA
how is transulfuration pathway involved in oxidative stress mitigation?
it produces cysteine, which is 1 of 3 amino acids that make up GSH
so large amounts of cysteine are needed for GSH, not just for protein synthesis
thus transulfuration pathway is important as protectant against oxidative stress via cystein formation
fates of homocysteine?
1) go back, become methionine
2) become cysteine
what is homocystinuria
metabolic inborn error of metabolism in which large amounts of homocysteine accumulate
what does homocystinuria cause
neurological disorders/severe mental retardation
failure to grow and thrive
skeletal abnormalities
cardiovascular abnormalities
dislocation lens sockets
arthritis
what causes homocystinuria
deficiency of vitamins B6, B12, or THF
deficiencies in cystathione synthase or homocysteine methyl transferase
how do you treat someone w/ homocystinuria?
if it’s a vitamin cofactor that’s missing, then give them supplement of the cofactor- B6, B12
if the enzyme is deficient, though, must limit methionine in the diet, which is possible b/c it’s an essential aa, and add cysteine to the diet since methione is limited and cystine comes from methionine
what are part of the toxic effects on the body of high levels of homocysteine?
- elevated oxidative stress
- smooth muscle cell proliferation
vitamin B12 structure?
1 corrin ring of 4 pyrrole rings linked together, + central cobalt atom
at “rest”, 6th substituent: OH
what is the 6th substituent of Cobalt of Vitamin B12
- at rest
- as a drug
- during digestion
- as a vitamin cofactor?
- at rest, = OH
- as a drug, = CN
- during digestion, = CN -> OH
- vitamin cofactor, = methyl, methylcobalamine, or deoxyadenosine, deoxyadenosyl cobalamine
how is deoxyadenosyl B12 formed
Cobalamine, B12 + ATP -> deoxyadenosyl B12 + 3pi
catalyzed by deoxyadenosyl transferase
in what reaction is deoxyadenosyl-B12 a cofactor
methylmalonyl mutase reaction when methylmalonyl CoA -> succinyl CoA
what’s connection between methylmalonyl CoA and B12?
propionyl CoA is made from the breakdown of 4 amino acids, isoleucine, valine, Met, Threonine, and odd-chain fatty acids
Propionyl Co A -> D methyl-malonyl Co A -> L-methylmalonyl Co A -> succinyl Co A
L-methylamlonyl CoA -> succinyl CoA requires using the cofactor form of Vitamin B12, Deoxyadenosyl to do a rearrangement reaction with a free radical intermediate which the mutase uses
without it get disease
what causes methylmalonyl aciduria?
if the rearrangement reaction w/ free radical from L-methylmalonyl CoA -> succinyl CoA doesn’t occur
due to:
- absence of the mutase
- deficiency in vitamin B12
- defiency of the transferase that makes B12
what does methylmalonyl aciduria result in?
severe mental retardation
death
GI irritation
treatment of methylmalonyl CoA?
restrict Met, Val, The, Isoleucine in diet
what causes pernicious anemia?
deficiency in vitamin B12
what are some critical biochem components which are produced from methylation rxns?
epinephrine, creatine, methylated nucleotides, phosphatidylcholine, and melatonin.
what regulates whether homocysteine is converted to Met or Cysteine? is cysteine an essential amino acid?
whether homocysteine is converted to methionine or cysteine is controlled by high
levels of methionine, which inhibit homocysteine from becoming methionine
cysteine is thus essential when met is high
what cofactors are needed for homocystein methyl transferase (methionine synthase) reaction?
N5-methyl-THF and B12
how can you treat homocystenuria?
by either supplementing the patient’s diet with B6 or
B12 if it’s the cofactor that’s missing, or if it’s the enzyme that’s missing, then limit
methionine in the patient’s diet, and add in cysteine, since limiting methionine means
less cysteine will be produced
what ultimately happens to the carbon skeleton of homocysteine (met) after transsulfuration?
Through transsulfuration, the carbon skeleton of homocysteine is converted to aketobutyrate,
which is decarboxylated to propionyl CoA, which is metabolized to
succinyl CoA, which can be oxidized in the TCA cycle for energy, or metabolized to OAA
and eventually glucose via gluconeogenesis, or can produce heme.
why is vitamin B12 necessary? what specific compounds require B12 for ultimate conversion to succinyl CoA?
Vitamin B12 is necessary because it’s a crucial cofactor in many metabolic reactions –
including conversion of homocysteine to methionine and conversion of propionyl CoA to
succinyl CoA. L-methylmalonyl CoA requires Vitamin B12 as a cofactor to do a
rearrangement reaction involving B12 as a free radical intermediate to become Succinyl
CoA.
what causes methylmalonyl aciduria and how is it treated?
Methylmalonyl aciduria is caused by a B12 deficiency, absence of the mutase, or
deficiency of the transferase that makes B12, any of which leads to inability to convert
L-methylmalonyl CoA to Succinyl CoA. This is treatable by restricting Met, Val, The, and
Isoleucine in the diet, since these are all precursors to Propionyl CoA.
what causes pernicious anemia? how is it treated?
stomach parietal cells make Intrinsic Factor which is needed to bind and absorb dietary B12 in the ileum
pernicious anemia happens when you get autoimmune destruction of these parietal cells
so the pathway to absorbing B12 gets disrupted
treat by giving IV B12 or forms that can be absorbed w/o IF
