Title: Chapter 8 Metabolism of Nucleotides
1Chapter 8 Metabolism of Nucleotides
The biochemistry and molecular biology department
of CMU
2Section 1 Introduction
3Degradation of nucleic acid
Nucleoprotein
Nucleic acid
Protein
Nuclease
Nucleotide
Nucleotidase
Nucleoside
Phosphate
Nucleosidase
Base
Ribose
4Significances of nucleotides
- 1. Precursors for DNA and RNA synthesis
- 2. Essential carriers of chemical energy,
especially ATP - 3. Components of the cofactors NAD, FAD, and
coenzyme A
5Significances of nucleotides
(continue)
- 4. Formation of activated intermediates such as
UDP-glucose and CDP-diacylglycerol. - 5. cAMP and cGMP, are also cellular second
messengers.
6There are two pathways leading to nucleotides
- De novo synthesis The synthesis of nucleotides
begins with their metabolic precursors amino
acids, ribose-5-phosphate, CO2, and one-carbon
units. - Salvage pathways The synthesis of nucleotide
by recycle the free bases or nucleosides released
from nucleic acid breakdown.
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8Section 2 Synthesis of Purine Nucleotides
9 2.1 De novo synthesis
- Site in cytosol of liver, small intestine and
thymus - Characteristics
- a. Purines are synthesized using
5-phosphoribose as the starting material step by
step. - b. PRPP is active donor of R-5-P.
- c. AMP and GMP are synthesized further at the
base of IMP.
10 - 1. Element sources of purine bases
112. Synthesis of IMP
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163. Synthesis of AMP and GMP
174. Formation of NDP and NTP
-
- AMP ATP 2 ADP
-
- NDP ATP NTP ADP
Adenylate kinase
nucleoside diphosphate kinase
185. Regulation of de novo synthesis
- The significance of regulation
- (1) Fulfill the need of the body, without
wasting. - (2) GTPATP
19Regulation of de novo synthesis of purine
nucleotides
20 2.2 Salvage pathway
- The significance of salvage pathway
- a. Save the fuel.
- b. Some tissues and organs such as brain and
bone marrow are only capable of synthesizing
nucleotides by a salvage pathway.
21The course of salvage pathway
22 - HGPRT Hypoxanthine-guanine phosphoribosyl
transferase - APRT Adenine phosphoribosyl transferase
- Absence of activity of HGPRT leads to
Lesch-Nyhan syndrome.
23 2.3 Exchange between purines
24 2. 4 Formation of deoxyribonucleotide
- Formation of deoxyribonucleotide involves the
reduction of the sugar moiety of ribonucleoside
diphosphates (ADP, GDP, CDP or UDP). - Deoxyribonucleotide synthesis at the nucleoside
diphosphate level.
25 26 Regulation of ribonucleotide reductase
27 2. 5 Antimetabolites of purine nucleotides
- Antimetabolites of purine nucleotides are
structural analogs of purine, amino acids and
folic acid. They can interfere, inhibit or block
synthesis pathway of purine nucleotides and
further block synthesis of RNA, DNA, and
proteins.
281. Purine analogs
- 6-Mercaptopurine (6-MP) is a analog of
hypoxanthine.
29 - 6-MP nucleotide is a analog of IMP
de novo synthesis
amidotransferase
IMP
6-MP
6-MP nucleotide
AMP and GMP
HGPRT
salvage pathway
302. Amino acid analogs
- Azaserine (AS) is a analog of Gln.
313. Folic acid analogs
- Aminopterin (AP) and Methotrexate (MTX)
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33Section 3 Catabolism of Purine Nucleotides
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37 - Uric acid is the excreted end product of purine
catabolism in primates, birds, and some other
animals. - The rate of uric acid excretion by the normal
adult human is about 0.6 g/24 h, arising in part
from ingested purines and in part from the
turnover of the purine nucleotides of nucleic
acids.
38 - The disease gout, is a disease of the joints,
usually in males, caused by an elevated
concentration of uric acid in the blood and
tissues. The joints become inflamed, painful, and
arthritic, owing to the abnormal deposition of
crystals of sodium urate. The kidneys are also
affected, because excess uric acid is deposited
in the kidney tubules.
39Allopurinol a suicide inhibitor used to treat
Gout
40Section 4 Synthesis of Pyrimidine Nucleotides
41 4.1 De novo synthesis
- Characteristics
- The enzymes mostly lie in cytosol, but some
enzymes exist in mitochondria. - The pyrimidine ring is first synthesized, then
combines with PRPP. - UMP is first synthesized, then UMP is used for
synthesizing other pyrimidine nucleotides.
421. Element source of pyrimidine base
432. Synthesis of UMP
44Difference of carbamoyl phosphate
synthetase?and ?
CPS? CPS?
location Mit(liver) Cytosol (all the cell)
source of nitrogen NH3 Gln
allosteric agent AGA none
function urea synthesis pyrimidine biosynthesis
45 463. Synthesis of CTP
- Amidation at the nucleoside triphosphate level.
474. Formation of dTMP
- The immediate precursor of thymidylate (dTMP) is
dUMP. - The formation of dUMP either by deamination of
dCMP or by hydrolyzation of dUDP. The former is
the main route.
48dTMP synthesis at the nucleoside monophosphate
level.
495. Regulation of de novo synthesis
50 4. 2 Salvage pathway
51 4. 3 Antimetabolites of pyrimidine nucleotides
- Antimetabolites of pyrimidine nucleotides are
similar with them of purine nucleotides.
521. Pyrimidine analogs
- 5-fluorouracil (5-FU) is a analog of thymine.
53 dTMP
dUMP
5-FdUMP
5-FU
5-FUTP
Synthesis of RNA
Destroy structure of RNA
542. Amino acid analogs
- AS inhibits the synthesis of CTP.
- 3. Folic acid analogs
- MTX inhibits the synthesis of dTMP.
554. Nucleoside analogs
- Arabinosyl cytosine (ara-c) inhibits the
synthesis of dCDP.
56Section 5 Catabolism of Pyrimidine Nucleotides
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58 59Summary of purine biosynthesis
IMP
60Summary of pyrimidine biosynthesis
UMP