Download Nucleotide Synthesis Nucleotides Origin of Atoms Nucleotide

Nucleotides
Nucleotide Synthesis
purine
Main functions:
a. to form components of nucleic
acids, DNA and RNA
b. to form components of essential
cofactors (ATP, NAD, FAD,
CoA)
base
CO2
O
O
O-P-O-CH
O
O
||
C
methyl THFA
CH
HN
carbamyl P
N
H
N
O
Purine ring
amide of gln
N
ORIGIN of ATOMS
N
C
methyl
THFA
O
glycine
C
O
P
HO
O
O-P-O-CH
O
ORIGIN of ATOMS
O
||
C
asp HN
N
N
|
N
N
HN
sugar
Location in cell: in cytoplasm of
most cells
pyrimidine
OH
OH
aspartate
CH
C
pyrimidine ring
N
uracil
hypoxanthine
Origin of Atoms
- all atoms in the pentose sugar
and phosphates of
nucleotides originate from
PRPP
O
O=P-O CH
O H
ribose-5-P
O
O
O
O-P-O ~ P = O
O
O
from ATP
Nucleotide Metabolism
Endproducts:
purine path - AMP, GMP
pyrimidine path -UMP
Pyrimidine de novo path
Pyrimidine de novo path
COO
HC-NH3
NH2 -C-O-P-O
CH2
O
C=O asp
carbamyl P
ATCase O
O
NH2
O
O= C
O-C=O
CH2
CH
NH
COO
C=O
CH2
HN
NH2
O-C=O
CH2
CH
NH
COO
O= C
O= C
N
H
O
Me-THFA
C
DHFA
||
HN
CH
HN
OC
CH
C
O
C
thymine
C-CH3
uracil
O
N
P
CH
N
P
• thymine nucleotides are found in DNA
• uracil nucleotides are found in RNA
• rapidly dividing cells must replicate
DNA rapidly and require rapid
production of thymine nucleotides
• by preventing formation of thymine
nucleotides, rapidly dividing cells are
killed
Water-soluble vitamins
and their cofactors
- many vitamins are converted to
adenine nucleotides cofactors
inside cells
- specific kinase enzymes condense
vitamin with ATP to produce the
active form of the cofactor
orotic
acid
Thymine vs. Uracil
nucleotides
Thymine nucleotides
• thymine containing nucleotides
are formed from uracil nucleotides
CH
COO
Thiamin / TPP
thiamin + ATP
A-r
N
N
N N S
thiamin-PP + AMP
A-r-P
P~P~P
TPP is the cofactor in oxidative
decarboxylations (CO2 is removed in a
redox reaction)
e.g. pyr
acetyl CoA
Riboflavin / FMN
riboflavin + ATP
N
N
N
FMN + Pi
N
A-r-P~P~P
N
FMN / FAD
N
FMN + ATP
N
N
N
N
N
N
FMN is a cofactor in oxidation/reduction
reactions.
e.g. in the ETS system
N
N
C-NH2
O
P
FAD is a cofactor in oxidation/reduction
reactions, accepting H atoms.
e.g. succinate
fumarate
NMN +
P~P
N
C-NH2
O
NAD + + P~P
A-r -P~P~P
C-NH2
O
N
N
N
P~P~ P N
N
N
r
P
r
NMN is the precursor for NAD
NAD+ is cofactor in redox
reactions
r
isocitrate +
KG + NAD:H
+ H+
NAD+ participates in oxidations where
a hydride ion (H:) and proton are
removed from the substrate.
C-NH2
O
N
P~P
N
N N
r
pyridoxal/pyridoxal P
(PLP)
H O
C
NAD+
N
NMN / NAD+
NMN + P~P
P
N
A-r-P~P
Niacin / NMN
niacotinamide + Pr-PP
N
A-r-P~P~P
P
P
FAD + P~P
H
C-OH
H
+
ATP
N
pyridoxal + A-r-P~P~P
H O
C
H O
C-O-P-O
H O
+
N
PLP + A-r-P~P
PLP is required in all transamination
reactions.
Biotin / N-carboxybiotin
biotin + HCO3 + ATP
HN
HO-C=O
O-
NH
S
N-carboxybiotin
+ ADP + P
O-
S
DHfolate
THfolate
serine
glycine
methyl-THFA
methyl-THfolate
adds methyl group in
many cellular reactions
Methotrexate inhibits
THFA formation
X
DHFA
THFA
ser
THFA
R
THFA and methyl transfer
reactions
• FA
DHfolate
thymine-dr-P uracil-dr-P
N-carboxybiotin is used in carboxylations.
• folate
• folate
N -C=O
N
CH-CH-CH-CH-COO
Folic acid / THFA
X
gly
methyl-THFA
THFA is required for many
methyl transfer reactions in pathways
Chemotherapy
• methotrexate is a structural anolog of
folate and prevents conversion of
folate to THFA in cells
• only THFA can receive methyl
group from serine
• in presence of methotrexate THFA is
not formed; no T nucleotides are
formed and DNA synthesis stops
Chemotherapy
THFA
ser
thymine-r-P uracil-r-P
gly
methyl-THFA
THFA
Thymine nucleotides are not made
and DNA synthesis is stopped.
• rapidly dividing cells die when
DNA is not replicated; slowly
dividing cells usually survive
• methotrexate kills cancer cells but
must be followed immediately by
Leucovorin, methyl THFA , to
rescue the normal (non-cancer)
cells
Synthesis of Nucleotides
and vitamin cofactors
Tracing pathways
- most human cells make nucleotides
by condensing nucleosides with
ATP
Using C14 - labelled alanine , show
a plausible route (metabolic
pathways) by which each of the
following compounds may
become labelled with C14.
- all the water-soluble vitamins must be
activated, often by condensing the
vitamin with ATP to form a
nucleotide cofactor
glycogen
glu
glu
c. acetylCoA
g-6-P
r-5-P
a. glucose
b. tripalmitate
glu
citrate
f-6-P
glu
g-6-P
f-6-P
gly.P
f-1,6-diP
3-PG
OAA
pyr
PEP
malate
malate
DHAP
pyr
OAA
f-1,6-diP
gly.P
pyr
malate
DHAP
3-PG
acetyl Co A
citrate
OAA
isocitrate
succinate
succ.CoA
G
OAA
pyr
OAA
m
malate
pyr
PEP
malate
pyr
ala
pyr
malate
OAA
b. ala to tripalmitate
a. ala to glucose
ala
DHAP
c
malate
OAA
ala
pyr
acetyl CoA
tripalmitate
citrate
palmitate
citrate
c. ace. CoA
glucose
ala
pyr
tripalmitate
OAA
malate
malate OAA
glycerolP DHAP
PEP
Tracing pathways
a. OAA to pfk
Using C14 - labelled OAA , show
a plausible route (the metabolic
pathways) by which each of the
following compounds may
become labelled.
a. phosphofructokinase
b. palmitate
b. OAA to palmitate
OAA
PEP
pyr
c.acetyl CoA
palmitate
pyr
c. citrate
acetyl CoA
citrate
OAA
asp
asp-tRNA
protein - pfk