Chapter 10
Nucleotide metabolism
Function of neucleotides
 Precursors
for RNA and DNA synthesis
 Energy substance in body (ATP)
 Physiological Mediators (cAMP)
 Components of coenzymes (NAD+)
 Allosteric effectors and donor of
phosphate group (phosphorylation)
 Formation of activated intermediates
UDP-glucose, CDP-choline
Section 10.2
Nucleotide Synthesis
and Degradation
Digestion and absorption of nucleotide
Nucleoprotein
Protein
Nucleic acid
Nucleases
Nucleotide
Nucleotidase
Phosphate
Nucleoside
Nucleosidase
Base
Ribose
Absorption
Blood
Metabolism of Purine nucleotides
 Biosynthesis
of purine nucleotides
de novo synthesis
salvage pathway
AMP
GMP
1.De novo synthesis of purine nucleotides
CO2
Glycine
Aspartate
One
carbon
unit
One
carbon
unit
Glutamine
 Characteristics
of de novo synthesis of
purine nucleotides
1. in cytosol
2. form IMP first, then synthesize AMP
and GMP from IMP.
3. formation of purines is based on the
ribosyl group of 5’-phosphoribose
PP-1-R-5-P（ 5’phosphoribose 1’pyrophosphate, PRPP）
Glutamine PRPP
amidotransferase
(GPRT)
AMP ATP
PRPPK
Gln
Glu
H2N-1-R-5´-P
（5´-phosphoribosyl-amine）
Gly, one
carbon units,
Gln, CO2,
Asp involved
IMP
step by step
AMP
GMP
R-5-P
（5’-phosphoribose）
PP-1-R-5-P（ 5’phosphoribose 1’pyrophosphate, PRPP）
Glutamine PRPP
amidotransferase
(GPRT)
AMP ATP
PRPPK
Gln
Glu
H2N-1-R-5´-P
（5´-phosphoribosyl-amine）
Gly, one
carbon units,
Gln, CO2,
Asp involved
IMP
step by step
AMP
GMP
R-5-P
（5’-phosphoribose）
Regulation of de novo synthesis of
purine nucleotides
_ _
_
+
Adenylsuccinate
+
R-5-P PRPPK
GPAT
PRPP
_PRA
ATP
_
IMP
XMP
_
GTP
IMP
Adenylsuccinate
AMP
ADP
+
XMP
+
GMP
ATP
_
AMP ADP ATP
GDP
ATP
GTP
GMP
GDP GTP
2. Salvage synthesis of purine
nucleotides
 Material:
or
PRPP, purine (conjunction)
nucleosides (phosphorylation)
 Location:
brain and bone marrow
adenine+ PRPP
APRT
HGPRT
hypoxanthine+PRPP
guanine+ PRPP
adenosine
AMP + PPi
IMP + PPi
HGPRT
GMP + PPi
Adenylate kinase
AMP
ATP
ADP
APRT: adenine phosphoribosyltransferase
HGPRT: inosine-guanine phosphoribosyl transferase
Degradation of purine nucleotides
nucleotide
Nucleotidase
nucleosides
Nucleoside phosphorylase
ribose-1-phosphate
purine
salvage pathway
uric acid
IMP
Neucleo
-tidase
Excretion
Metabolsm of pyrimidine nucleotides
 Biosynthesis
of pyrimidine nucleotides
de novo synthesis
salvage pathway
1.De novo synthesis of pyrimidine
nucleotides
Glutamine
3
4
5
Aspartate
CO2
2
6
1
 Characteristics
of de novo synthesis of
pyrimidine nucleotides
1. mostly in cytosol
2. form UMP first, then synthesize other
pyrimidine nucleotides from UMP.
3. in the synthesis of UMP, pyrimidine
ring is formed first , then combined with
PRPP.
Process of de novo synthesis of UMP
 1.
formation of Carbamoyl phsphate (CP)
CO2 + glutamine + H2O + 2ATP
Carbamoyl phosphate
synthaseⅡ (CPSⅡ)
O
H2N C
O ~ PO32-
carbamoyl phosphate
+ 2ADP + Pi
The diffirents
between Carbamoyl
phosphate
氨基甲酰磷酸合成酶
I、II 的区别
synthaseⅠ,Ⅱ
CPS-I
Location
分布
Mitochondria of
肝细胞线粒体中
liver
cells
氨3
NH
Source
氮源 of
nitrogen
变构激活剂
Activator
N-乙酰谷氨酸
N-acetylglutamate
功能
Function
尿素合成
Formation
of urea
CPS-II
cytosol of all
胞液（所有细胞）
cells
Glutamine
谷氨酰胺
无
None
Formation
嘧啶 合成of
pyrimidine
2. Formation of UMP
O
H2 N C
O ~ PO32- +
Aspartate
carbamoyl phosphate
Carbamoyl aspartate
Orotate
PRPP
UMP
3. Synthesis of CTP, dTMP or TMP
UMPK
UDP
ATP ADP
CTP
synthase
NDK
ATP
UTP
ADP
Gln
ATP
Glu
ADP
dUDP
dCMP
dTMP
dUMP
TMP synthase
Regulation of de novo synthesis
of pyrimidine nucleotides
ATP + CO2+ glutamine
+
Carbamoyl phosphate
1. Activated by substrates
2. Inhibited by products
aspartate
-
Carbamoyl aspartate
+
PRPP
UMP
UTP
-
Purine nucleotides
ATP + 5-phosphate ribose
-
Pyrimidine nucleotides
CTP
-
Salvage pathway of pyrimidine nucleotides
Uracil + PRPP
Uracil phosphate
ribosyltransferase
Uracil + 1-phosphoribose
UMP + PPi
Uridine
phosphorylase
UMP +ADP
Uridine kinase
Uracil ribonucleoside + ATP
UMP +ADP
Degradation of pyrimidine nucleotides
nucleotide
Nucleotidase
nucleosides
Nucleoside phosphorylase
phosphoribose
pyrimidine
Cytosine
Thymine
NH3
Uracil
β-ureidoisobutyrate
dihydrouracil
H2O
H2O
+ CO2 + NH3 +
β-alanine
β-aminoisobutyrare
liver
Acetyl CoA
Succinyl CoA
Urea
TAC
TAC
Glucose
Excreted
in urine
Deoxyribonucleotide biosynthesis
Ribonucleotide
reductase
dNDP
NDP
kinase
dNDP + ATP
dNTP + ADP
Biosynthesis of NDP and NTP
AMP
Kinase
ATP
XMP
ADP
Kinase
YTP
ADP
YDP
Kinase
ATP
XDP
ADP
Kinase
YTP
ATP
YDP
XTP
Section 10.3
Dysmetabolism of nucleotides
and antimetabolites
Dysmetabolism of nucleotides
 Caused
by the genetic defect or
regulatory abnormality of some enzymes
participating nucleotide metabolism.
Gout：pain and tenderness, redness,
warmth, and swelling in some joints
Causes：too much uric acid forms
crystals in joints and cause inflammation
Antimetabolites
 The
analogs of ribonucleotide metabolite
intermediates synthesized artificially.
 Can interfere, inhibit and block the
ribonucleotide metabolism.
 Used as drugs.
 Purine
ribonucleotide metabolite analogs
6-mercaptopurine(6-MP)
Hypoxanthine
(6-MP)
 Pyrimidine
analogs :
ribonucleotide metabolite
5-fluorouracil(5-FU),
(T)
(5-FU)
 Amino
acid analogs
azaserine(AS)
 Folic acid analogs
methotrexate(MTX)
 Nucleoside analogs:
arabinosyl cytosine(ara-c),
cyclo-cytidine(cyclo-c)
 Metabolite analogs applied to
ribonucleotide reductase
hydroxyurea(HU)
NAD+
AMP
Lipid metabolism
β-Oxidation (Ketone Bodies),
degradation of glycerophospholipids,
cholesterol
key enzymes, main steps, products
 synthesis of palmitic acid,
triacylglycerols, glycerolphospholipids,
cholesterol
key enzymes, main steps, material
 Lipolysis,
•Essential Fatty Acids, lipoproteins
(classification, function) , HSL
•Hyperlipoproteinemia,
hypercholesterolemia,
ketonemia, ketonuria, ketoacidosis
reason or mechanism.
Protein catabolism
 Nitrogen
Balance, Essential Amino
Acids , Complementary effect,
Putrefaction, Amino acid metabolic pool,
Ketogenic amino acids, Ketogenic and
glucogenic amino acids.
 Digestion of dietary proteins,
degradation of protein, deamination,
decarboxylation
key enzymes, main pathway, main
products
 ALT, AST (function)
•SAM, PAPS, GSH, Dopamine , creatine
phosphate (function, formation)
•Ammonia, One Carbon Units
carrier, source, utilization
•Hyperammonemia, PUK, Albinism
damage, mechanism
Nucleotide metabolism
 Function
of neucleotides
 de novo synthesis of purine and pyrimidine
nucleotides
material, character, main steps,
 Salvage pathway of purine and pyrimidine
 Degradation of purine and pyrimidine
nucleotides
products
 Deoxyribonucleotide biosynthesis
Homework
 Explain
the following concepts:
Essential Amino Acids, Lipolysis
Amino acid metabolic pool
lipoproteins
 Simple questions:
1. describe the source, transport and
metabolic pathway of ammonia.
2. what do you know about ketoacidosis?