nucleotide biosynthesis
DESCRIPTION
NUCLEOTIDE BIOSYNTHESIS. N. N. O. C. C. C. C. P. P. P. ribose. nt biosynthesis. reduction rxns. NADPH. 1. Functions of Nucleotides Are Diverse. 1. 2. 3. in carbohydrate, lipid, protein, and nucleic acid synthesis. 4. 5. 6. Nucleotide Assembly. (source of carbons). - PowerPoint PPT PresentationTRANSCRIPT
1NUCLEOTIDE BIOSYNTHESIS
Functions of Nucleotides Are Diverse
1.
2.
3.
6.
5.
4.
in carbohydrate, lipid, protein, and nucleic acid synthesis
Nucleotide Assembly
O
C
C C
C
OHOH
PPP
N
N
ribose nt biosynthesisNADPH reduction rxns
carbon skeleton
(source of carbons)
H (NADPH)
(nitrogen source)
CH2(N2)
2Nucleotide Synthesis
activated ribose (PRPP) + baseactivated ribose (PRPP) + ATP + amino acids (CO2 + N2)
sugar ring is activated at the
O
C
C C
C
OHOH
P CH2
HH H
H
OH
ribose-5-PO45-phospho-ribosyl-1-pyrophosphate
-configurationO
C
C C
C
OHOH
P CH2
HH H
H
OP
P
Activation of the Ribose Sugar for Nt Biosynthesis
2nd step
1st step
O
C
C C
C
OHOH
P CH2
HH H
H
OP
P
O
C
C C
C
OHOH
P CH2
HH H
H
NH2
N9 of base
3
O
C
C C
C
OHOH
P CH2
HH H
H
NH2N9 of Pu base
amine is now attachedin the configuration
this becomes the-glycosidic bond
PRPP amidotransferase
R5P
PRPP
5-phopho--ribosyl amine
inosine monophosphate
(ring assembly)
AMP
ADP
ATP
GMP
GDP
GTP
inhibitors of PRPPamidotransferse
Source of Purine Ring Constituents
N
N
N
N3
1
2
6
4
5 7
9
8
purine ring
4Purine Nucleotide Biosynthesis
10-formyl-tetrahydrofolate
N
N
N
N2HN
H
O H
H
N
CH2
R
5Purine Biosynthesis Pathway
PURINE PATHWAY
O
C
C C
C
OHOH
P CH2
HH H
H
OP
P
(5-phospho-ribosyl-1-pyrophosphate)
O
C
C C
C
OHOH
P CH2
HH H
H
NH2
amidophosphoribosyltransferase
GLN + H2O GLU + PPi
O
C
C C
C
OHOH
P CH2
HH H
H
NH
CO
CH2
NH2
glycinamide ribotide (GAR)
GAR synthetase
ADP + Pi
R5P
NH
O C
CH2
HN
ribose-5-phosphate(R5P)
CH
O
formylglycinamideribotide (FGAR)
GAR transformylase
N10-formyl-THF
THF
(tetrahydrofolates aremethyl/formyl donors)
NH
C
CH2
HN
R5P
CH
OHN
FGAM synthetase
AIR synthetase
ATP ADP + Pi
ATP + GLN
+ H20
ADP + GLU + Pi
6
5-aminoimidazole ribotide (AIR)
NC
HC
N
R5P
CH
H2N
5 memberimidazole
ring
NC
C
N
R5P
CH
H2N
O C
OAIR carboxylase
carboxyaminoimidazole ribotide
now have 4 membersof the 5 member ringATP
+
HCO3
ADP+Pi
NC
C
N
R5P
CH
H2N
C
O
CH
C O
O
NH
CCH2
O
O
CH
C O
O
NH
CCH2
O
O
5-aminoimidazole-4-(N-succinylocarboxamide)
ribotide (SACAIR)
ADP + Pi
ATP
5 of the 6 ring members
NC
C
N
R5P
CH
H2N
C
O
H2NCH
C O
O
C
CH
O
O
fumarate
SACAIRsynthetase
5-aminoimidazole-4-carboxamide ribotide
(AICAR)
adenylosuccinatelyase
THF
NC
C
N
R5P
CH
C
O
H2N
NH
CHO
N10-formyl-THF(formyl donor)
5-formaminoimidazole-4-carboxamide ribotide
(FAICAR)
AICAR transformylase
all 6 ringmembers
7
H2O
IMP cyclohydrolase
NC
C
N
CH
C
O
HN
NH
HC
O
C
C C
C
OHOH
P CH2
HH H
H
8
aspartate isthe N donor
glutamine isthe N donor
IMP is the precursorfor purine exocyclic
nt modifications
Pyrimidine Synthesis
Pyrimidine ring assembled attachment to the ribose sugar
O
N
N
43
2 6
5
1O
NH2
CO
O PO3
CH2
NH2
O
OH
C
C
O
OH
C
H
two components joined ring is closed
(precursor of UMP)
9
2 ATP + HCO3 + GLN + H2O carbamyl phosphateGLU
carbamyl phosphate synthetase II
PRPP and IMP (from PU synthesis)
pyrimidine nucleotides
Why not regulate Pu and Pyr synthesis at PRPP synthetase??
R5P PRPP PRPPsynthetase
5-phospho--ribosyl amine
Pu nts
PRPP amido transferase
Pyr ntscarbamyl PO4
synthetase II
The synthesis of carbamyl phosphate and regulation of pyrimidine biosynthesis
Why??
inhibitsinhibits
10Pyrimidine Biosynthesis
OA
OH OH
CH2PPP
OA
OH OH
CH2PP
H C OO
O
H2O
C
H
C O
O
NH3
CCH2 CH2
O
H2N
PYRIMIDINE PATHWAY
+
+
PO
NH2C O
P
C
H
C O
O
NH3
CCH2 CH2
O
HO
(building the Pyr ringstarting with carbonate)
(ATP supplies energy &
phosphate)
start with4 substrates
carbamoyl phosphatesynthetase
1
2
1
2
aspartate transcarbamylase
C
H
C O
O
NH3
CCH2
O
HO
C O
O
H
HO C
O
CH2
CH
NOC
NH2
P
constituents of Pyr are now joined
H2Odihydroorotase
(dehydration)
11
H
C O
O
H
C
O
CH2
CH
NOC
HNquinonereducedquinone
dihydroorotatedehydrogenase
C O
O
H
C
O
CH
C
NOC
HN
double bond formation
O
C
C C
C
OHOH
P CH2
HH H
H
OP
P
(5-phospho-ribosyl-1-pyrophosphate)
O
C
C C
C
OHOH
P CH2
HH H
orotate phosphoribosyl
transferase
C O
O
C
O
CH
C
NOC
HN
configuration
-configuration
in contrast to the purines, the base is synthesized before attachment to ribose
H
O
C
C C
C
OHOH
P CH2
HH H
C
O
CH
CH
NOC
HNOMP
decarboxylase
CO2
12
13two points concerning nucleotide biosynthesis
1.
2.
diphosphate / triphosphate synthesis
XMP XDP XTP
source of ATP
deoxyribonucleotide synthesis
ubiquitous enzyme found in all organisms
substrate
O
C
C C
C
OHOH
CH2
HH H
H
basePPO
C
C C
C
HOH
CH2
HH H
H
basePP
ribonucleotide reductase
ribonucleotide reductase
XDPs
14ribonucleotide reductase “redox” rxn
(like cytochromes inoxidative phosphorylation)
ribonucleotide reductase recycled through a series of oxidation - reduction steps/rxns
ribonucleotide reductase (E. coli)
( XTP / XDP / XMP binding sites )
( inhibitors and activators of Pu and Pyr pathways )
NADPH
NADPoxidized
reducedthioredoxin
reduced
thioredoxin
oxidized
reduced
ribonucleotide reductase
ribonucleotide reductase
oxidized