This document provides information about folate (vitamin B9) metabolism. It begins with an overview of how folate is involved in amino acid metabolism and the connections to nucleic acid synthesis. Subsequent sections describe the details of folate conversions in the body, inhibitors of key enzymes, and consequences of folate deficiency such as megaloblastic anemia. The roles of related B vitamins such as B12 in folate metabolism are also discussed.

1. Author: Robert Lyons, Ph.D., 2008
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3. M1 Renal:
Folate Metabolism
Dr. Robert Lyons
Assistant Professor, Biological Chemistry
Director, DNA Sequencing Core
Web: http://seqcore.brcf.med.umich.edu/mcb500
Fall 2008

4. Amino Acid metabolism
Folate metabolism
Amino acids
Met
Methylene Cycle
Glu, Gln, THF
Asp, NH 3
Urea
oxaloacetate
DNA
P u rin e s P y rim id in e s
RNA
Uric Acid (energy)
fumarate
TCA Cycle Nucleic Acid metabolism
R. Lyons

5. Folate (“One-Carbon”) Pathways
Click on any blue box to see details
(Start with the section with ‘Diet’ and follow the paths with red arrows)
Methyl-THF
Connects to Donation of one carbon
Amino Acids (from Ser, Gly)
THF Methionine
Cycle Cycle
Methylene-THF
THF THF
Diet: DHF DHF
Formyl-THF
Folate Folate
Connects to Purine Thymidylate
Nucleic Acids biosynthesis synthetase
lectures
R. Lyons

6. Folic Acid is Synthesized By Bacteria
NH2 N N H
O COO- O
HN H H
O
N CH2 N C ( N CHCHCH2 C
2 )n OH
O O
NH2 C OH NH2 S NH2
O
Para-aminobenzoic sulfanilamide
acid (PABA)
R. Lyons
Dietary folate: folic acid (meats, green veggies)
*requires* the intestinal enzyme Conjugase for absorption.

7. NH2 N N H
O COO- O
HN H H
( )n
F ol ic ac id
N CH2 N C N CHCHCH2 C OH
O 2
NADPH + H
+
H NADP
+
NH2 N N H
-
Di hy d ro fo l at e H O COO O
HN H H
O
N CH2 N C ( N CHCH2CH2 C )n OH
NADPH + H+
H +
NADP
NH2 N N H
H O COO- O
T et ra hy d ro fo la te HN H H
O
N
H
CH2 N C ( N CHCH2CH2 C )n OH
H
R. Lyons

8. NH2 N N H
O COO- O
HN H H
( )n
F ol ic ac id
N CH2 N C N CHCHCH2 C OH
O 2
NADPH + H
+
H NADP
+
NH2 N N H
-
Di hy d ro fo l at e H O COO O
HN H H
O
N CH2 N C ( N CHCH2CH2 C )n OH
NADPH + H+
H +
NADP
NH2 N N H
H O COO- O
T et ra hy d ro fo la te HN H H
O
N
H
CH2 N C ( N CHCH2CH2 C )n OH
H
R. Lyons
Inhibitors of DHFR are important therapeutics:
Methotrexate - chemotherapy
Trimethoprim - inhibits bacterial DHFR
Pyrimethamine - inhibits malarial DHFR

9. H2 O H
H -
COO- COO NH2 N N H
NH2 N N H H
H + +
NH C H
+
NH C H + HN +
HN + 3 3 N CH2
N CH2 O H
O H CH2 OH H CH N (etc)
H NH (etc) 2
seri ne glycine
N 5 , N10 methylene
Tetrahydrofolate tetrahydrofolate
NH+
4
CO2 H
H NAD +
NADH
COO
- NH2 N N H
NH2 N N H H
H + + NH C H HN +
HN + 3 N CH2
N CH2 O H
O H H CH N (etc)
H NH (etc) 2
glycine
N 5 , N 10 methylene
Tetrahydrofolate tetrahydrofolate
R. Lyons

10. N 5 methyl Biosynthesis of
tetrahydrofolate methionine
NAD+
+
NADH + H
Gly N 5, N10 methylene Biosynthesis of
Ser tetrahydrofolate thymidylate
NADP +
+
NADPH + H
N 5, N
10 methenyl
tetrahydrofolate
H2 O
N10 formyl Biosyntheses of
tetrahydrofolate purines
H
H
NH N N H
NH N N H 2
2 H
H HN +
HN + N CH2
N CH2 O H H
O H N (etc)
CH NH (etc)
3 O C
H
N 5- methyl N 10 formyl
-
tetrahydrofolate tetrahydrofolate
R. Lyons

11. H
H (+) (-)
CH3 S CH2 CH C COO
(-) 2
CH3
S CH2
CH C
2
COO
CH2
NH
(+) 3
NH3
(+)
ATP + PPi + O
H2O Adenine
Pi
H H
Methionine H OH OH
H
S-Adenosyl Methionine
Methyl a cceptor
tetrahydrofolate
Bios ynthetic
*
Methylation see examples
reaction
N5 methyl Methylated acceptor
tetrahydrofolate
Methionine Cycle
H
(+)
HS CH2 CH C
2
H
COO
(-)
And Biological
HS CH2 CH2 C
NH3
COO
(-)
CH2
NH
(+) 3
O
Methyl Groups
(+)
Homocysteine
H
H OH OH
H
H
Adenine
H S-Adenosyl Homocysteine
(-)
HO CH C
2
COO
NH
(+) 3
Serine
H
(-)
HS CH2 C COO
NH
(+) 3
Cysteine
(remainder of
homocysteine
degraded
for energy)
R. Lyons

12. N 5 -methyl THF THF
+ +
NH NH3
3
- - CH2 CH2 SCH 3
OOC C CH2 CH2 SH OOC C
vitamin B12
H H
homocysteine meth ionine
R. Lyons

13. Carbon donor
H
H (e.g. serine or glycine)
NH2 N N H
NH2 N N H H
H HN +
HN + N CH2
N CH2 O H
O H CH N (etc)
H 2
NH (etc)
N5 , N
10 methylene
Tetrahydrofolate tetrahydrofolate
+
meth ionine NADH + H
homocyste ine H
NH2 N N H NAD+
H
HN +
N CH2
O H
CH NH (et
3
c)
N 5 methyl
tetrahydrofolate
R. Lyons

14. +
NH+ NH3
3 ATP PP + P - OOC +
-
OOC C CH2 CH2 SCH3
i i C CH2 CH2 SCH3
H H CH2
adeni ne
O
Methionine
S-Adenosyl methionine
HO
OH HO OH
HO +
C CH NH3
2
HO C CH2 N CH3
H H
H
Norepinephrine
SAM SAH Epinephrine
R. Lyons
Other methyl acceptors:
DNA ( CpG Islands )
RNA

15. NADH
carb on
NAD+ dono r
N 5 -methyl THF THF
+ NH+
NH3 3
-
-
O OC C CH2 CH2 SH OOC C CH2 CH2 SCH3
vitamin B12
H H
homocysteine meth ionine
ATP
Adenosine
PP
i
+
H2 O Pi
+
+
NH3 NH3
- +
-O OC C CH2 CH2 S OOC C CH2 CH2 SCH3
H CH2 H CH2
adenin e a denine
O S-ad enosyl O
S -adeno syl
meth yl group meth ionine
h omocys teine don ated to
bio logical
sub strate
R. Lyons

16. N 5 methyl Biosynthesis of
tetrahydrofolate methionine
NAD+
+
NADH + H
Gly N 5, N10 methylene Biosynthesis of
Ser tetrahydrofolate thymidylate
NADP +
+
NADPH + H
N 5, N
10 methenyl
tetrahydrofolate
H2 O
N10 formyl Biosyntheses of
tetrahydrofolate purines
R. Lyons
Folate Deficiencies: Symptom: megaloblastic anemia
Dietary deficiency:
Common especially in developing countries, lower
socioeconomic classes

17. Folate deficiency secondary to bowel irritation:
• Conjugase is essential for adequate absorption
of dietary folates
• Conjugase production may be compromised by
bowel irritation:
Tropical Sprue - bowel irritation probably
arising from bacterial origin, causes
intestinal inflamation and malabsorption.
Celiac Sprue - similar outcome, but the
original irritation is due to an allergic
response, for example to gliaden (a
component in gluten)

18. Folate Deficiency Secondary to B12 deficiency:
the methyl trap hypothesis
other
THF
reactions N 5 methyl Biosynthesis of
tetrahydrofolate Methionine
5 10 N 5 , N 10 methylene
N ,N - Biosynthesis of
tetrahydrofolate
N AD H methylene Thymidylate
THF
c ar bo n
N AD+ d on or N 10 formyl Biosyntheses of
tetrahydrofolate Purines
N 5-methyl THF THF
B12 is also critical in other
B12 reactions, ones for which the
deficiency has serious
hom ocyst eine m et hi on i ne
neurological consequences.
R. Lyons

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