10' Onecarbon metabolism

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10. One-carbon metabolism
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Some important biological compounds are formed
partly from units of individual, reduced carbon
atoms
purines
creatine
5-methylcytosine
phosphatidylcholine
Also recall methylation of dopamine
These one-carbon units do not come from CO2,
which is more oxidized.
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There are three main carriers of reduced
one-carbon units
cobalamin coenzymes (derivatives of vitamin B12)
derivatives of tetrahydrofolic acid (THF)
S-adenosylmethionine (SAM)
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S-adenosylmethionine (SAM) is formed from
methionine and ATP
methionine
ATP
A adenine
Pi PPi
SAM
SAM also serves as a precursor of the polyamines
spermidine and spermine
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Methionine can be regenerated from
S-adenosylhomocysteine
ROH
ROCH3
S-adenosyl-homocysteine
SAM
H
Pi PPi
ATP
H2O
homocysteine
methionine
THF
A vitamin B12 coenzyme participates in this step.
Dietary deficiency of either folate or B12 can
result in homocysteinemia.
adenosine
N5-methyltetrahydrofolate
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Tetrahydrofolic acid is derived from the vitamin
folic acid
tetrahydrofolate (THF)
p-aminobenzoic acid
folate (folic acid)
sulfanilamide inhibits bacterial growth by
competetive inhibition of incorporation of
p-aminobenzoic acid into folate
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1-carbon derivatives of tetrahydrofolate have
three levels of reduction
N5,N10-methenyl-tetrahydrofolate
H2O
most oxidized
N10-formyl-tetrahydrofolate
N5,N10-methylene-tetrahydrofolate
N5-methyl-tetrahydrofolate
most reduced
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Serine and glycine are the main dietary sources
of 1-carbon units
N5,N10-methylene-tetrahydrofolate
THF
H
OH
Ser
Gly
-O2C?CH2?NH3
H
OH
CO2 NH3
-O2C?CH2?NH3
Gly
NAD
NADH H
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Vitamin B12 coenzymes contain a Co atom that can
bind several different ligands
cyanocobalamin (Vitamin B12)
5?-deoxyadenosyl-cobalamin
CH2
CN
Methyl and hydroxyl groups also occur as ligands
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Only a few reactions that require cobalamin
coenzymes are known to occur in humans
Methylmalonyl-CoA is formed from propionyl-CoA,
which is generated by catabolism of Met, Ile, Val
and fatty acids with an odd number of carbons.
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Vitamin B12 deficiency causes neurological
defects anemia

• neurological defects, beginning with loss of
  peripheral sensation
• anemia
• methylmalonic aciduria
• secondary deficiency of folic acid

B12
N5,N10-methylene-THF
N5-methyl-THF
THF
homocysteine methionine
Most cases of vitamin B12 deficiency result from
lack of intrinsic factor, a protein that is
produced in the stomach and is necessary for
uptake of B12 in the small intestine. B12
deficiency caused by lack of intrinsic factor is
called pernicious anemia.
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Folate deficiency also causes neurological
defects and anemia
Adequate levels of folate are particularly
critical during the development of the nervous
system. A shortage of folate in this period can
cause neural-tube defects, including spina
bifida.
Folate deficiency is probably the most common
vitamin deficiency. Since addition of folate to
flour in the U.S. began in 1996, neural-tube
birth defects have decreased by 20. A recent
study concluded that adding folate to food also
has decreased deaths from heart attacks stroke
by 48,000/year.
Anemia caused by folate deficiency is very
similar to that caused by B12 deficiency
(pernicious anemia). If the problem is
pernicious anemia, supplementing dietary folate
might remedy the anemia but not prevent damage to
the nervous system. What compound could you look
for in urine to distinguish between folate and
B12 deficiency?
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Mammals can convert methionine to cysteine
homocysteine
cystathionine synthase (PLP)
SAM
cystathionine
cystathionine lyase (PLP)
Met is an essential amino acid for humans. Cys
is non-essential if the diet contains enough Met.
a-ketobutyrate
PLP pyridoxal phosphate
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Clinical and nutritional aspects of homocysteine
metabolism
Homocysteinuria caused by a mutation in the gene
for cystathionine synthase is associated with
elevated risk of coronary heart disease.
serine
homocysteine
NH3
-O2C?CH?CH2?CH2?SH
Vitamin B6 (pyridoxine) deficiency results in
homocysteinemia.
cystathionine
H2O
NH3
Human fetuses lack cystathionine lyase. Human
milk is richer in cysteine than cows milk.
cysteine
a-ketobutyrate