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Nucleotide Metabolism Part I

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Coenzyme components- 5'-AMP in FAD/NAD Activated intermediates ... How I hope to make this at least bearable if not mildly interesting. Purines and Pyrimidines ... – PowerPoint PPT presentation

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Title: Nucleotide Metabolism Part I


1
Nucleotide Metabolism(Part I)
  • November 19, 2003

2
Bases/Nucleosides/Nucleotides
Base Base
Base Sugar Phosphate Nucleotide
Base Sugar Nucleoside
Deoxyadenosine 5-triphosphate (dATP)
Adenine
Deoxyadenosine
3
Cellular Roles of Nucleotides
  • Energy metabolism (ATP)
  • Monomeric units of nucleic acids
  • Regulation of physiological processes
  • Adenosine controls coronary blood flow
  • cAMP and cGMP serve as signaling molecules
  • Precursor function-GTP to tetrahydrobiopternin
  • Coenzyme components- 5-AMP in FAD/NAD
  • Activated intermediates- UDP Glucose
  • Allosteric effectors- regulate themselves and
    others

4
How I hope to make this at least bearable if not
mildly interesting
  • Purines and Pyrimidines
  • Synthesis (de novo and salvage pathways)
  • Degradation
  • Relevant disease states
  • Relevant clinical applications (Monday)

You are not responsible for any structures
5
Purines and Pyrimidines
6
Synthesis Pathways
  • For both purines and pyrimidines there are two
    means of synthesis (often regulate one another)
  • de novo (from bits and parts)
  • salvage (recycle from pre-existing nucleotides)

7
Many Steps Require an Activated Ribose Sugar
(PRPP)
5
8
de novo Synthesis
  • Committed step This is the point of no return
  • Occurs early in the biosynthetic pathway
  • Often regulated by final product (feedback
    inhibition)

9
Purine Biosynthesis (de novo)
  • Atoms derived from
  • Aspartic acid
  • Glycine
  • Glutamine
  • CO2
  • Tetrahydrofolate
  • Also requires
  • 4 ATPs

Committed Step
Purines are synthesized on the Ribose ring
10
Purine Biosynthesis (de novo)
(A bunch of steps you dont need to know)
IMP
(Inosine Monophosphate)
ATP
GTP
AMP
GMP
Feedback Inhibition
11
Purine Degradation
Other species further metabolize uric acid
  • Sequential removal of bits and pieces
  • End product is uric acid
  • Uric acid is primate-specific

Excreted in Urine
Xanthine Oxidase
Xanthine
Uric Acid
12
Excess Uric Acid Causes Gout
  • Primary gout (hyperuricemia)
  • Inborn errors of metabolism that lead to
    overproduction of Uric Acid
  • Overactive de novo synthesis pathway
  • Leads to deposits of Uric Acid in the joints
  • Causes acute arthritic joint inflammation

Xanthine Oxidase
Xanthine
Uric Acid
13
Immunodeficiency Diseases Associated with Purine
Degradation
  • Defect in adenosine deaminase
  • Removes amine from adenosine
  • SCID- severe combined immunodeficiency
  • Bubble Boy Disease
  • Defect in both B-cells and T-cells (Disease of
    Lymphocytes)
  • Patients extremely susceptible to infection -
    hence the Bubble

Lymphocyte
14
Therapies for SCID
  • Can be diagnosed in infants through a simple
    blood test (white cell count)
  • Bone marrow transplant for infants
  • Familial donor
  • Continued administration of adenosine deaminase
    (ADA-PEG)
  • Gene therapy- repair defective gene in T-cells or
    blood stem cells

15
Salvage Pathway for Purines
Hypoxanthine or Guanine

PRPP
IMP or GMP PPi
Hypoxanthineguanosylphosphoribosyl
transferase (HGPRTase)
Adenine

PRPP
AMP PPi
Adeninephosphoribosyl transferase (APRTase)
16
Lesch-Nyhan Syndrome
  • Absence of HGPRTase
  • X-linked (Gene on X)
  • Occurs primarily in males
  • Characterized by
  • Increased uric acid
  • Spasticity
  • Neurological defects
  • Aggressive behavior
  • Self-mutilation

17
X-linked Diseases
  • Why are X-linked diseases generally more
    prevalent in males?
  • Females have two X chromosomes - have mosaicism
  • Males have a single X chromosome

XY
XX
18
Biosynthesis of Pyrimidines
  • Synthesized from
  • Glutamine
  • CO2
  • Aspartic acid
  • Requires ATP

Uracil
Cytosine
  • Pyrimidine rings are synthesized independent of
    the ribose and transferred to the PRPP (ribose)
  • Generated as UMP (uridine 5-monophosphate)

19
Regulation of Pyrimidine Biosynthesis
  • Regulation occurs at first step in the pathway
    (committed step)
  • 2ATP CO2 Glutamine carbamoyl phosphate

20
Hereditary Orotic Aciduria
  • Defect in de novo synthesis of pyrimidines
  • Loss of functional UMP synthetase
  • Gene located on chromosome III
  • Characterized by excretion of orotic acid
  • Results in severe anemia and growth retardation
  • Extremely rare (15 cases worldwide)
  • Treated by feeding UMP

21
Why does UMP Cure Orotic Aciduria?
UMP
Carbamoyl Phosphate
Orotate
Feedback Inhibition
  • Disease (-UMP)
  • No UMP/excess orotate
  • Disease (UMP)
  • Restore depleted UMP
  • Downregulate pathway via feedback inhibition
    (Less orotate)

UTP
22
Biosynthesis Purine vs Pyrimidine
Purine
Pyrimidine
  • Synthesized on PRPP
  • Regulated by GTP/ATP
  • Generates IMP
  • Requires Energy
  • Synthesized then added to PRPP
  • Regulated by UTP
  • Generates UMP/CMP
  • Requires Energy

Both are very complicated multi-step process
which your kindly professor does not expect you
to know in detail
23
Pyrimidine Degradation/Salvage
  • Pyrimindine rings can be fully degraded to
    soluble structures (Compare to purines that make
    uric acid)
  • Can also be salvaged by reactions with PRPP
  • Catalyzed by Pyrimidine phosphoribosyltransferase

Degradation pathways are quite distinct for
purines and pyrimidines, but salvage pathways
are quite similar
24
Wait a minuteSo far weve only made GMP, AMP,
and UMP
So how the heck are we supposed to make DNA?
We need the dNTPs according to the Know-it-All
Professor who taught us that a couple of months
ago
25
Two Problems
  • These are monophosphates (i.e. GMP)- we need
    triphosphates (i.e. GTP) for both DNA and RNA
    synthesis
  • These are ribonucleotides- thats fine for RNA
    but we also need to make DNA

Synthesis of ribonucleotides first supports the
RNA world theory
26
Specific Kinases Convert NMP to NDP
Nucleoside Monophosphates
Nucleoside Diphosphates
Monophosphate Kinases
NMP
NDP
  • Monophosphate kinases are specific for the bases

Adenylate Kinase
Guanylate Kinase
27
Conversion of Ribonucleotides to
Deoxyribonucleotides
BASE
BASE
Ribonucleotide Reductase
Deoxyribonucleoside
Ribonucleoside
Somehow we need to get rid of this oxygen
28
Ribonucleotide Reductase
  • Catalyzes conversion of NDP to dNDP
  • Highly regulated enzyme
  • Regulates the level of cellular dNTPs
  • Activated prior to DNA synthesis
  • Controlled by feedback inhibition

29
dNDP to dNTP (the final step)
  • Once dNDPs are generated by ribonucleotide
    reductase a general kinase can phosphorylate to
    make the dNTPs
  • So far weve made GTP, ATP, and UTP (which can be
    aminated to form CTP)
  • What about TTP?

Youll have to tune in Monday
30
Plan for Monday
  • Brief Explanation of how dUMP is converted to
    dTMP
  • Some clinically relevant treatments based on
    these pathways that are used to combat
  • Cancer
  • Bacterial Infections
  • Viral Infections

31
Take Home Concepts from Todays Lecture
  • Nucleotides can be made through two pathways
  • (de novo and salvage)
  • Pathways are regulated by feedback inhibition
  • Specific degradation pathways exist
  • Molecular basis of metabolic diseases mentioned
  • What steps are necessary to generate a dNTP from
    the initial NMP made
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