Transcript Nucleotide

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 从头合成
salvage pathway 补救合成
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
R-5-P
（5’-phosphoribose）
Gln
Glu
H2N-1-R-5´-P
（5´-phosphoribosyl-amine）
Gly, one
carbon units,
Gln, CO2,
Asp involved
IMP
step by step
磷酸核糖焦磷酸
AMP
GMP
Regulation of de novo synthesis of
purine nucleotides
_ _
_
+
Adenylsuccinate
+
R-5-P PRPPK
GPAT
PRPP
_PRA
ATP
_
IMP
XMP
_
GTP
Adenylsuccinate
IMP
XMP
AMP
+
GMP
ATP
_
AMP ADP ATP
ADP
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: hypoxanthine-guanine
phosphoribosyltransferase
Degradation of purine nucleotides
nucleotide
Nucleotidase
nucleosides
Nucleoside phosphorylase
ribose-1-phosphate
purine
salvage pathway
uric acid
尿酸
IMP
Neucleo
-tidase
Excretion
Metabolism 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 different
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乳清酸
PRPP
UMP
3. Synthesis of CTP, dTMP or TMP
UMPK
UDP
ATP ADP
ATP
CTP
synthase
NDK
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
aspartate
-
Carbamoyl aspartate
+
PRPP
UMP
UTP
1. Activated by
substrates
2. Inhibited by products
-
-
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
Uridine + Pi
Uridine kinase
Uridine + ATP
UMP +ADP
Degradation of pyrimidine nucleotides
nucleotide
Nucleotidase
nucleosides
Nucleoside phosphorylase
phosphoribose
pyrimidine
Cytosine
Thymine
NH3
Uracil
β-ureidoisobutyrate
dihydrouracil
H2 O
H2 O
+ CO2 + NH3 +
β-alanine
β-aminoisobutyrate
liver
Acetyl CoA
Urea Succinyl
CoA
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（痛风）：pain and tenderness,
redness, heat, swelling and joint
inflammation
Causes：too much uric acid forms crystals
in joints and cause inflammation
Risk Factors
 Obesity/being
overweight
 more common in men than women
 Certain medicines
 Certain foods and alcoholic beverages
 Genetics
 Enzyme defect
Medication
 xanthine-oxidase
inhibitors, 黄嘌呤氧
化酶抑制剂
allopurinol 别嘌呤醇
 uricosurics, 促尿酸尿剂
 urate oxidases 尿酸氧化酶
 Limit
your consumption of certain types of
meat：beef, pork, lamb, and “organ meats”
(such as liver, kidney, and brain), as well as
meat extracts and gravies.
 Reduce or eliminate alcohol consumption,
especially beer.
 Reduce your use of oatmeal, dried beans,
spinach, asparagus, cauliflower, and
mushrooms
 High consumption of seafood is associated
with an increased risk of gout.
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
ribonucleotide metabolite
analogs :
5-fluorouracil(5-FU),
(T)
(5-FU)
NAD+
AMP
Biological oxidation
Chain and its composition ，
How many Respiratory Chain in the
mitochondria? What is the sequence of
them?
 Oxidation Phosphorylation and the
mechanism of it
 the regulation of it (Cyanide)?
 P/O ratio
 How many ATP produced by Respiratory
Chain? How to use cytosolic NADH ?
 energy-rich compounts
 Respiratory
Protein catabolism
 Nitrogen
Balance,
Essential Amino Acids ,
Complementary effect,
Putrefaction,
Amino acid metabolic pool,
Ketogenic amino acids,
Ketogenic and glucogenic amino acids.
 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, PKU, 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 ，Gout
 Deoxyribonucleotide biosynthesis