Chapter 8 Metabolism of Nucleotides

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Chapter 8 Metabolism of Nucleotides

The biochemistry and molecular biology department
of CMU
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Section 1 Introduction

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

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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.

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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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Section 2 Synthesis of Purine Nucleotides

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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.

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• 1. Element sources of purine bases

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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
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5. Regulation of de novo synthesis

• The significance of regulation
• (1) Fulfill the need of the body, without
  wasting.
• (2) GTPATP

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Regulation of de novo synthesis of purine
nucleotides
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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.

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The course of salvage pathway

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• HGPRT Hypoxanthine-guanine phosphoribosyl
  transferase
• APRT Adenine phosphoribosyl transferase
• Absence of activity of HGPRT leads to
  Lesch-Nyhan syndrome.

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2.3 Exchange between purines
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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.

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Regulation of ribonucleotide reductase

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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.

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1. Purine analogs

• 6-Mercaptopurine (6-MP) is a analog of
  hypoxanthine.

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• 6-MP nucleotide is a analog of IMP

de novo synthesis
amidotransferase
IMP
6-MP
6-MP nucleotide
AMP and GMP
HGPRT
salvage pathway
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2. Amino acid analogs

• Azaserine (AS) is a analog of Gln.

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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.

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• 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.

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Allopurinol a suicide inhibitor used to treat
Gout
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Section 4 Synthesis of Pyrimidine Nucleotides

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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
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2. Synthesis of UMP

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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
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3. Synthesis of CTP

• Amidation at the nucleoside triphosphate level.

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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.

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dTMP synthesis at the nucleoside monophosphate
level.
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5. Regulation of de novo synthesis

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4. 2 Salvage pathway
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4. 3 Antimetabolites of pyrimidine nucleotides

• Antimetabolites of pyrimidine nucleotides are
  similar with them of purine nucleotides.

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1. Pyrimidine analogs

• 5-fluorouracil (5-FU) is a analog of thymine.

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dTMP
dUMP

5-FdUMP
5-FU
5-FUTP
Synthesis of RNA
Destroy structure of RNA
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2. Amino acid analogs

• AS inhibits the synthesis of CTP.
• 3. Folic acid analogs
• MTX inhibits the synthesis of dTMP.

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4. Nucleoside analogs

• Arabinosyl cytosine (ara-c) inhibits the
  synthesis of dCDP.

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Section 5 Catabolism of Pyrimidine Nucleotides
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Summary of purine biosynthesis

IMP
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Summary of pyrimidine biosynthesis

UMP