nucleotide metabolism chapter 10. function of neucleotides precursors for rna and dna synthesis ...
TRANSCRIPT
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Nucleotide metabolism
Chapter 10
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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
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Section 10.2
Nucleotide Synthesis and Degradation
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Digestion and absorption of nucleotide
Nucleoprotein
Protein Nucleic acid
NucleasesNucleotide
Nucleotidase
Phosphate NucleosideNucleosidase
Base Ribose
Absorption Blood
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Metabolism of Purine nucleotides Biosynthesis of purine nucleotides
de novo synthesis 从头合成 salvage pathway 补救合成
GMPAMP
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1.De novo synthesis of purine nucleotides
CO2 Glycine
One carbon
unitOne carbon
unit
Glutamine
Aspartate
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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
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R-5-P( 5’-phosphoribose )
ATPAMP
PRPPK
Gly, one carbon units, Gln, CO2, Asp involved step by step IMP
AMP
GMP
H2N-1-R-5´-P( 5´-phosphoribosyl-amine )
Gln
GluGlutamine PRPP amidotransferase
(GPRT)
PP-1-R-5-P ( 5’-phosph
oribose 1’-pyrophosphate, PRPP )
磷酸核糖焦磷酸
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Regulation of de novo synthesis of purine nucleotides
PRPPKPRPP
GPATPRA IMP
Adenyl-succinate
AMP ADP ATP
XMP GMP GDP GTP
++
_ _ _
__
IMP
Adenyl-succinate
XMP
AMP ADP ATP
GMP GDP GTPATP
GTP
_
_
++
R-5-P
ATP
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2. Salvage synthesis of purine nucleotides
Material:
PRPP, purine (conjunction)
nucleosides (phosphorylation)
Location:
brain and bone marrow
or
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adenine+ PRPP AMP + PPiAPRT
hypoxanthine+PRPP IMP + PPiHGPRT
guanine+ PRPP HGPRT GMP + PPi
adenosineAdenylate kinase
ATP ADPAMP
APRT: adenine phosphoribosyltransferase
HGPRT: hypoxanthine-guanine
phosphoribosyltransferase
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Degradation of purine nucleotides
nucleotide
nucleosides
ribose-1-phosphate purine
salvage pathway uric acid
Nucleotidase
Nucleoside phosphorylase
尿酸
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IMP
Neucleo-tidase
Excretion
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Metabolism of pyrimidine nucleotides Biosynthesis of pyrimidine nucleotides
de novo synthesis
salvage pathway
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1.De novo synthesis of pyrimidine nucleotides
Aspartate
Glutamine
CO21
54
3
62
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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.
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Process of de novo synthesis of UMP 1. formation of Carbamoyl phsphate (CP)
CO2 + glutamine + H2O + 2ATP
C
O
H2N O ~ PO32- + 2ADP + Pi
carbamoyl phosphate
Carbamoyl phosphate synt
hase (CPS )Ⅱ Ⅱ
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CPS-I CPS-II
肝细胞线粒体中
氨
N-乙酰谷氨酸
胞液(所有细胞)
谷氨酰胺
无
分布
氮源
变构激活剂
功能 尿素合成 嘧啶合成
CPS-I CPS-II
肝细胞线粒体中
氨
N-乙酰谷氨酸
胞液(所有细胞)
谷氨酰胺
无
分布
氮源
变构激活剂
功能 尿素合成 嘧啶合成
氨基甲酰磷酸合成酶 I、II 的区别The different between Carbamoyl phosphate synthaseⅠ,Ⅱ
Location
Source of nitrogen
Activator Function
NH3 Glutamine
NoneN-acetylglutamate
Mitochondria of liver cells
cytosol of all cells
Formation of urea Formation of pyrimidine
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C
O
H2N O ~ PO32-
carbamoyl phosphate
+Aspartate
Carbamoyl aspartate
PRPPOrotate 乳清酸
UMP
2. Formation of UMP
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ATP ADP
UMPKUDP
NDK
ATP ADP
UTP
CTP synthase
GlnATP
GluADP
3. Synthesis of CTP, dTMP or TMP
dCMPdUDP
dUMP
dTMP
TMP synthase
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Regulation of de novo synthesis of pyrimidine nucleotides
ATP + CO2+ glutamine
Carbamoyl phosphate
UMP
Carbamoyl aspartate
UTP CTP
aspartate
ATP + 5-phosphate ribosePRPP
Pyrimidine nucleotides-
+
-
-
-Purine nucleotides-+
1.Activated by substrates
2. Inhibited by products
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Salvage pathway of pyrimidine nucleotides
Uracil + PRPP UMP + PPi
Uracil phosphate ribosyltransferase
Uridine + ATPUridine kinase
UMP +ADP
Uracil + 1-phosphoribose Uridine + Pi
Uridine phosphorylase
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nucleotide
nucleosides
phosphoribose pyrimidine
Degradation of pyrimidine nucleotides
Nucleotidase
Nucleoside phosphorylase
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Cytosine
NH3
Uracil
dihydrouracil H2O
CO2 + NH3
β-alanine
Thymine
β-ureidoisobutyrate
H2O
Acetyl CoA
TAC
liver
Urea
+ +
β-aminoisobutyrate
Succinyl CoA
TAC Glucose
Excreted in urine
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Deoxyribonucleotide biosynthesis
NDP dNDP
Ribonucleotide reductase
dNDP + ATP kinase
dNTP + ADP
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Biosynthesis of NDP and NTP
AMP ADP ATP
ADPATP
Kinase
ADPATP
Kinase
XMP XDP XTP
YDPYTP
Kinase
YDPYTP
Kinase
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Section 10.3
Dysmetabolism of nucleotides and antimetabolites
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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
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Risk Factors Obesity/being overweight more common in men than women Certain medicines Certain foods and alcoholic beverages Genetics Enzyme defect
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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
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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.
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Antimetabolites
The analogs of ribonucleotide metabolite intermediates synthesized artificially.
Can interfere, inhibit and block the ribonucleotide metabolism.
Used as drugs.
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Purine ribonucleotide metabolite analogs
6-mercaptopurine(6-MP)
Hypoxanthine (6-MP)
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Pyrimidine ribonucleotide metabolite analogs :
5-fluorouracil(5-FU),
(T) (5-FU)
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NAD+
AMP
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Biological oxidation Respiratory 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
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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
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ALT, AST (function) SAM, PAPS, GSH, Dopamine , creatine ph
osphate (function, formation) Ammonia, One Carbon Units
carrier, source, utilization Hyperammonemia, PKU, Albinism
damage, mechanism
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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 nucle
otides
products , Gout Deoxyribonucleotide biosynthesis