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Chapter 8 Metabolism of Nucleotides

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Chapter 8. Metabolism of Nucleotides. The biochemistry and molecular biology ... Degradation of nucleic acid ... Allopurinol a suicide inhibitor ... – PowerPoint PPT presentation

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Title: Chapter 8 Metabolism of Nucleotides


1
Chapter 8 Metabolism of Nucleotides

The biochemistry and molecular biology department
of CMU
2
Section 1 Introduction

3
Degradation of nucleic acid
Nucleoprotein
Nucleic acid
Protein
Nuclease
Nucleotide
Nucleotidase
Nucleoside
Phosphate
Nucleosidase
Base
Ribose
4
Significances 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

5
Significances of nucleotides
(continue)
  • 4. Formation of activated intermediates such as
    UDP-glucose and CDP-diacylglycerol.
  • 5. cAMP and cGMP, are also cellular second
    messengers.

6
There 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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8
Section 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

11
2. Synthesis of IMP
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3. Synthesis of AMP and GMP

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4. Formation of NDP and NTP
  • AMP ATP 2 ADP
  • NDP ATP NTP ADP

Adenylate kinase
nucleoside diphosphate kinase
18
5. Regulation of de novo synthesis
  • The significance of regulation
  • (1) Fulfill the need of the body, without
    wasting.
  • (2) GTPATP

19
Regulation 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.

21
The 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.

28
1. 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
30
2. Amino acid analogs
  • Azaserine (AS) is a analog of Gln.

31
3. Folic acid analogs
  • Aminopterin (AP) and Methotrexate (MTX)

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Section 3 Catabolism of Purine Nucleotides

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  • 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.

39
Allopurinol a suicide inhibitor used to treat
Gout
40
Section 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.

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1. Element source of pyrimidine base
43
2. Synthesis of UMP

44
Difference 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

46
3. Synthesis of CTP
  • Amidation at the nucleoside triphosphate level.

47
4. 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.

48
dTMP synthesis at the nucleoside monophosphate
level.
49
5. 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.

52
1. 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
54
2. Amino acid analogs
  • AS inhibits the synthesis of CTP.
  • 3. Folic acid analogs
  • MTX inhibits the synthesis of dTMP.

55
4. Nucleoside analogs
  • Arabinosyl cytosine (ara-c) inhibits the
    synthesis of dCDP.

56
Section 5 Catabolism of Pyrimidine Nucleotides
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Summary of purine biosynthesis

IMP
60
Summary of pyrimidine biosynthesis

UMP
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