24. Onecarbon metabolism

1
24. One-carbon metabolism
2
Synthesis of some important biological compounds
requires transferring individual methyl groups
The purine ring contains two methenyl carbons
that are introduced individually. These
one-carbon units do not come from CO2, which is
more oxidized.
Also recall methylation of dopamine
3
There are three main biological carriers of
reduced one-carbon units
cobalamin coenzymes (derivatives of vitamin B12)
derivatives of tetrahydrofolic acid (THF, folate)
4
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, but that doesnt involve
one-carbon metabolism.
5
Methionine can be regenerated from
S-adenosylhomocysteine
ROCH3
ROH
S-adenosyl-homocysteine
H
homocysteine
H2O
methionine
A vitamin B12 coenzyme participates in this step.
Dietary deficiency of either folate or B12 can
result in homocysteinemia.
adenosine
6
Tetrahydrofolate is derived from the vitamin
folic acid
tetrahydrofolate (THF)
p-aminobenzoic acid
folate (folic acid)
sulfanilamide inhibits bacterial growth by
competetively inhibiting incorporation of
p-aminobenzoic acid into folate.
7
1-carbon derivatives of tetrahydrofolate have
three levels of reduction
H2O
most oxidized
N10-formyl-tetrahydrofolate
most reduced
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Serine and glycine are the main dietary sources
of 1-carbon units
N5,N10-methylene-tetrahydrofolate
THF
OH
Gly
-O2C?CH2?NH3
H
OH
CO2 NH3
-O2C?CH2?NH3
Gly
NAD
NADH H
9
Vitamin B12 coenzymes contain a Co atom that can
bind a variety of ligands
cyanocobalamin (Vitamin B12)
5?-deoxyadenosyl-cobalamin
CH2
CN
Methyl and hydroxyl groups also occur as ligands
10
Methylcobalamin (B12) donates a methyl group to
homocysteine and is regenerated by methyl-THF
11
Only a few reactions that require cobalamin
coenzymes are known to occur in humans
B12
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.
12
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 depletion of intrinsic
factor is called pernicious anemia. Loss of
intrinsic factor, an autoimmune disorder, is
relatively frequent in elderly people.
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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. Some
studies have concluded that adding folate to food
also has decreased deaths from heart attacks
stroke, but this is uncertain.
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?
14
Mammals convert methionine to cysteine via
cystathionine
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.
Hyperhomocysteinemia also has been linked to risk
of atherosclerosis.
serine
homocysteine
NH3
-O2C?CH?CH2?CH2?SH
cystathionine synthase
Vitamin B6 (pyridoxine) deficiency results in
hyperhomocysteinemia.
cystathionine
H2O
cystathionine lyase
NH3
Human fetuses lack cystathionine lyase. Human
milk is richer in cysteine than cows milk.
cysteine
a-ketobutyrate