METABOLISME

NUKLEOTIDA
Evi Umayah Ulfa
Nucleotides
Monomers for nucleic acid polymers
Nucleoside Triphosphates are important
energy carriers (ATP, GTP)
Important components of coenzymes
FAD, NAD
+
and Coenzyme A
NUCLEOTIDE SYNTHESIS:
DE NOVO AND SALVAGE PATHWAYS
De novo pathway
Synthesis from low
molecular weight
precursors (Liver)
Salvage pathway
Synthesis from
nucleosides or bases
that become available
through the diet or
from degradation of
nucleic acids
(Peripheral tissues)
DE NOVO PURINE SYNTHESIS
Source of Nitrogen
2 from Glutamine
1 from Aspartate
1 from Glycine
Source of Carbon
2 from Glycine
2 from N
10
-Formyl
tetrahydrofolate
1 from CO
2
Ribose 5 Phosphate
PRPP
5-Phosphoribosylamine
IMP
Adenylosuccinate
XMP
AMP
ADP
ATP
GMP
GDP
GTP
PRPP synthetase
Amido tranferase
Adenylosuccinate
synthetase
IMP dehydrogenase
PURINES ARE NOT MADE AS FREE BASES BUT AS NUCLEOTIDES
PP
i
DISPLACEMENT BY NH
2
INOSINE 5- MONOPHOSPHATE (IMP)
GLUTAMINE
GLYCINE + ATP
N
10
-FORMYL THF
GLUTAMINE + ATP
CO
2
ASPARTATE + ATP
N
10
-FORMYL THF
5-PRPP
ADDITION OF GLYCINE
FORMYL GROUP TRANSFER
NH
2
GROUP TRANSFER
ATP RING CLOSURE
COO
-
ADDITION
ASPARTATE ADDITION
FUMARATE LOSS
FORMYL GROUP TRANSFER
RING CLOSURE
1
2
3
4
5
6
7
8
9
10
Purine Degradation
GMP
Excess bases are converted to Urate, released
to the circulation and excreted through the Kidney
Diseases of Purine Metabolism:
Most common: Gout
Caused by excessive Urate
Urate has low solubility, high concentrations
precipitate faster than they can be cleared in Kidney
Leads to painful deposits in joints
Underexcretion of uric acid
Diet rich in purines/alcohol; deficient in dairy products
Increased purine degradation
Increased PRPP Synthetase activity
overproduction of PRPP = increased purine synthesis =
increased purine degradation = increased uric acid
production
Decreased/partial HGPRT activity
1) Deficiency of HGPRT = increased HX and G
2) Deficiency of HGPRT = accumulation of PRPP =
increased purine synthesis = increased uric acid
levels
3) Deficiency of HGPRT = decreased IMP and
GMP = decreased inhibitors for purine synthesis
GOUT - Causes
As with Purines, there are both de novo and
salvage pathways
PIRIMIDINE SYNTHESIS
De Novo Pirimidine
Synthesis
Synthesis of the
pyrimidine bases.
CPSII = carbamoyl
phosphate
synthetase II.
RR=ribonucleotide
reductase
FH2 and FH4 forms
of folate.
Aspartate
Transcarbamylase
Salvage of Pirimidine Base
pyrimidine
nucleoside
phosphoryla
se converts
the
pyrimidine
bases to
their
respective
nucleosides
specific nucleoside kinases react with the
nucleosides, forming nucleotides
Other products derived from Purines/Pyrimidines
Nucleotide sugars
e.g. UDP-Glucose or GDP Mannose
Coenzyme A (Adenine)
NAD (Adenine)
NADP (Adenine
FAD (Adenine)
Vitamin B
12
(Adenine)
Biopterin (Guanine)