12.11.08: Folate Metabolism

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1. Author: Robert Lyons, Ph.D., 2008

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

4. Glu,Gln,
Asp,NH
3
AminoAcidmetabolism
Folatemetabolism
NucleicAcidmetabolism
Methylene
THF
Met
Cycle
Purines Pyrimidines
UricAcid
Urea
Aminoacids
DNA
RNA
(energy)
TCACycle
fumarate
oxaloacetate
R. Lyons

5. Methylene-THF
Methyl-THF
Formyl-THF
Donationofonecarbon
(fromSer,Gly)
Connectsto
AminoAcids
Purine
biosynthesis
Thymidylate
synthetase
Connectsto
NucleicAcids
lectures
Diet:
THF
THF
Cycle
Methionine
Cycle
Folate(“One-Carbon”)Pathways
Clickonanyblueboxtoseedetails
(Startwiththesectionwith‘Diet’andfollowthepathswithredarrows)
DHF
Folate
THF
DHF
Folate
R. Lyons

6. C
O
NH
OH
2
H
-
N
CH
2
N
N
H
(
N
H
CH
COO
CHCH
22
C
O
)
n
O
N
N
H
Folic Acid is Synthesized By Bacteria!
C
O
NH
2
OH
Para-aminobenzoic
acid(PABA)
S
O
O
NH
2
NH
2
sulfanilamide
Dietary folate: folic acid (meats, green veggies)!
*requires* the intestinal enzyme bConjugase` for absorption.!
R. Lyons

7. C
O
NH
OH
Tetrahydrofolate
2
H
-
N
CH
2
N
N
N
H
H
N
H
H
H
(
N
H
CH
COO
CHCH
22
C
O
)
n
O
H
C
O
NH
OH
Dihydrofolate
2
H
-
N
CH
2
N
N
H
N
H
H
H
(
N
H
CH
COO
CHCH
22
C
O
)
n
O
N
C
O
NH
OHFolicacid
2
H
-
N
CH
2
N
N
H
(
N
H
CH
COO
CHCH
22
C
O
)
n
O
N
N
H
NADPH+H
NADPH+H
NADP
NADP
+
+
+
+
R. Lyons

8. C
O
NH
OH
Tetrahydrofolate
2
H
-
N
CH
2
N
N
N
H
H
N
H
H
H
(
N
H
CH
COO
CHCH
22
C
O
)
n
O
H
C
O
NH
OH
Dihydrofolate
2
H
-
N
CH
2
N
N
H
N
H
H
H
(
N
H
CH
COO
CHCH
22
C
O
)
n
O
N
C
O
NH
OHFolicacid
2
H
-
N
CH
2
N
N
H
(
N
H
CH
COO
CHCH
22
C
O
)
n
O
N
N
H
NADPH+H
NADPH+H
NADP
NADP
+
+
+
+
Inhibitors of DHFR are important therapeutics:!
!Methotrexate - chemotherapy!
!Trimethoprim - inhibits bacterial DHFR!
!Pyrimethamine - inhibits malarial DHFR!
R. Lyons

9. NH
3
C
COO
CH
H
2
serine
HO
OH
+
+
-
2
+
NH
2
H
N
CH
2
N
N
N
H
N
H
H
O H
(etc)CH
+
N,Nmethylene
tetrahydrofolate
5 10
2
NH
3
C
COO
H
H
-
glycine
+
NH
2
H
N
CH
2
N
N
N
H
NH
H
H
O H
(etc)
+
Tetrahydrofolate
H
+ +NH
3
C
COO
H
H
-
glycine
NH
2
H
N
CH
2
N
N
N
H
N
H
H
O H
(etc)CH
+
N,Nmethylene
tetrahydrofolate
5 10
2
NH
2
H
N
CH
2
N
N
N
H
NH
H
H
O H
(etc)
+
Tetrahydrofolate
H
NAD
+
NADH
CO
2
NH
4
+
R. Lyons

10. Gly
Ser
N,Nmethylene
tetrahydrofolate
5 10
Nmethyl
tetrahydrofolate
5
N,Nmethenyl
tetrahydrofolate
5 10
Nformyl
tetrahydrofolate
10
NADP
NADPH+H
+
+
HO
2
NAD
NADH+H
+
+
Biosynthesisof
methionine
Biosynthesisof
thymidylate
Biosynthesesof
purines
NH
2
H
N
CH
2
N
N
N
H
NH
H
H
O H
(etc)CH
+
N-methyl
tetrahydrofolate
5
3
NH
2
H
N
CH
2
N
N
N
H
N
H
H
O H
(etc)
OC
+
N-formyl
tetrahydrofolate
10
H
H
R. Lyons

11. C
H
COOCH
2
NH
3
(+)
(-)
CH
2
Methionine
Serine
C
H
COOCH
2
NH
3
(+)
(-)
HO
SCH
3
C
H
COOCH
2
NH
3
(+)
(-)
CH
2
S-AdenosylMethionine
SCH
3
ATP+
HO
2
PPi+
Pi
(+)
CH
2
O
H
HH
H
OHOH
Adenine
C
H
COOCH
2
NH
3
(+)
(-)
CH
2
Homocysteine
HS
C
H
COOCH
2
NH
3
(+)
(-)
CH
2
S-AdenosylHomocysteine
HS
(+)
CH
2
O
H
HH
H
OHOH
Adenine
Biosynthetic
Methylation
reaction
Methylacceptor
Methylatedacceptor
*
seeexamples
C
H
COOCH
2
NH
3
(+)
(-)
Cysteine
HS
(remainderof
homocysteine
degraded
forenergy)
tetrahydrofolate
N5methyl
tetrahydrofolate
Methionine Cycle!
And Biological!
Methyl Groups!
R. Lyons

12. NH
3
COOC CH
H
2
SH
-
CH
2
homocysteine
N-methylTHF
5
THF
NH
3
COOC CH
H
2
SCH
-
CH
2
methionine
3
+
+
vitaminB
12
R. Lyons

13. NH
2
H
N
CH
2
N
N
N
H
N
H
H
O H
(etc)CH
+
N,Nmethylene
tetrahydrofolate
5 10
2
NH
2
H
N
CH
2
N
N
N
H
NH
H
H
O H
(etc)
+
Tetrahydrofolate
H
Carbondonor
(e.g.serineorglycine)
NH
2
H
N
CH
2
N
N
N
H
NH
H
H
O H
(etc)CH
+
Nmethyl
tetrahydrofolate
5
3
NAD
+
NADH+H
+
methionine
homocysteine
R. Lyons

14. Other methyl acceptors:!
!DNA (lCpG Islandsz)!
!RNA!
C
OH
HO
HO
H
CH
2
NH
3
+
C
OH
HO
HO
H
CH
2
N
SAHSAM
CH
3
H
Epinephrine!
Norepinephrine!
NH
3
COOC CH
H
2
SCH
-
CH
2 3
+
ATP PP+P
ii
NH
3
COOC CH
H
2
SCH
- CH
2 3
+
CH
2
+
O
adenine
Methionine!
S-Adenosyl methionine!
R. Lyons

15. NH
3
COOC CH
H
2
SH
- CH
2
homocysteine
N-methylTHF
5
THF
carbon
donorNAD
+
NADH
NH
3
COOC CH
H
2
SCH
- CH
2
methionine
3
++
ATP
PP
+
P
i
i
NH
3
COOC CH
H
2
SCH
-
CH
2
S-adenosyl
methionine
3
+
CH
2
+
O
adenine
methylgroup
donatedto
biological
substrate
NH
3
COOC CH
H
2
S
- CH
2
S-adenosyl
homocysteine
+
CH
2
O
adenine
Adenosine
HO
2
vitaminB
12
R. Lyons

16. Folate Deficiencies: Symptom: megaloblastic anemia!
Dietary deficiency:!
Common especially in developing countries, lower
socioeconomic classes!
Gly
Ser
N,Nmethylene
tetrahydrofolate
5 10
Nmethyl
tetrahydrofolate
5
N,Nmethenyl
tetrahydrofolate
5 10
Nformyl
tetrahydrofolate
10
NADP
NADPH+H
+
+
HO
2
NAD
NADH+H
+
+
Biosynthesisof
methionine
Biosynthesisof
thymidylate
Biosynthesesof
purines
R. Lyons

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

18. THF
carbon
donor
NAD
+
NADH
510
homocysteinemethionine
other
THF
reactions
N-methylTHF
5
B
12
N,N-
methylene
THF
Folate Deficiency Secondary to B12 deficiency:
the bmethyl trap` hypothesis!
B12 is also critical in other
reactions, ones for which the
deficiency has serious
neurological consequences.!
N,Nmethylene
tetrahydrofolate
5 10
Nmethyl
tetrahydrofolate
5
Nformyl
tetrahydrofolate
10
Biosynthesisof
Methionine
Biosynthesisof
Thymidylate
Biosynthesesof
Purines
R. Lyons

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