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Nucleotide Metabolism. Bases/Nucleosides/Nucleotides. Base= Base. Base + Sugar + Phosphate= Nucleotide. Base + Sugar= Nucleoside. Deoxyadenosine 5’-triphosphate (dATP). Adenine. Deoxyadenosine. Cellular Roles of Nucleotides. Energy metabolism (ATP)*

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bases nucleosides nucleotides
Bases/Nucleosides/Nucleotides

Base=

Base

Base + Sugar + Phosphate=

Nucleotide

Base + Sugar=

Nucleoside

Deoxyadenosine

5’-triphosphate

(dATP)

Adenine

Deoxyadenosine

cellular roles of nucleotides
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
how i hope to make this at least bearable if not mildly interesting
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 (Friday)

You are not responsible for any structures

purines and pyrimidines

Two

Purines

Adenine

Guanine

Two

Pyrimidines

Thymine/Uracil

Cytosine

Purines and Pyrimidines
synthesis pathways

Salvage Pathway

de novo Pathway

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)
de novo synthesis

X

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)
purine biosynthesis de novo

X

Inhibited by

AMP, GMP, IMP

Purine Biosynthesis (de novo)
  • Atoms derived from:
    • Aspartic acid
    • Glycine
    • Glutamine
    • CO2
    • Tetrahydrofolate
  • Also requires
    • 4 ATP’s

Committed Step

Purines are synthesized on the Ribose ring

purine biosynthesis de novo10
Purine Biosynthesis (de novo)

(A bunch of steps you don’t

need to know)

IMP

(Inosine Monophosphate)

ATP

GTP

AMP

GMP

Feedback

Inhibition

purine degradation
Sequential removal of bits and pieces

End product is uric acid

Uric acid is primate-specific

Purine Degradation

Other species

further metabolize

uric acid

Excreted in

Urine

Xanthine

Oxidase

Xanthine

Uric Acid

excess uric acid causes gout

X

Allopurinol

Avoid:

Offal foods such as liver, kidneys, tripe, sweetbreads and tongue

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

immunodeficiency diseases associated with purine degradation
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

therapies for scid
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
salvage pathway for purines
Salvage Pathway for Purines

Hypoxanthine

or

Guanine

+

PRPP

= IMP or GMP + PPi

Hypoxanthineguanosylphosphoribosyl transferase

(HGPRTase)

Adenine

+

PRPP

= AMP + PPi

Adeninephosphoribosyl transferase

(APRTase)

lesch nyhan syndrome
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
total aside on x linked diseases
Total Aside on X-linked Diseases
  • Why are X-linked diseases generally found only in males?
  • Females have two X chromosomes - would need to mutate both copies to see a recessive phenotype
  • Males have a single X chromosome

XY

XX

Think about

Fragile X Syndrome

biosynthesis of pyrimidines
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)
regulation of pyrimidine biosynthesis

X

Inhibited by UTP

If you have lots of UTP around this means you won’t

make more that you don’t need

Feedback Inhibition

Regulation of Pyrimidine Biosynthesis
  • Regulation occurs at first step in the pathway (committed step)
  • 2ATP + CO2 + Glutamine = carbamoyl phosphate
hereditary orotic aciduria
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
why does ump cure orotic aciduria
Disease (-UMP)

No UMP/excess orotate

Disease (+UMP)

Restore depleted UMP

Downregulate pathway via feedback inhibition (Less orotate)

X

UMP

Synthetase

Why does UMP Cure Orotic Aciduria?

UMP

Carbamoyl

Phosphate

Orotate

Feedback

Inhibition

UTP

biosynthesis purine vs 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

Biosynthesis: Purine vs Pyrimidine

Purine

Pyrimidine

Both are very complicated multi-step process which

your kindly professor does not expect you to know in detail

pyrimidine degradation salvage
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

wait a minute so far we ve only made gmp amp and ump
Wait a minute:So far we’ve 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

two problems
Two Problems
  • These are monophosphates (i.e. GMP)- we need triphosphates (i.e. GTP) for both DNA and RNA synthesis
  • These are ribonucleotides- that’s fine for RNA but we also need to make DNA

Synthesis of ribonucleotides first

supports the RNA world theory

specific kinases convert nmp to ndp

AMP + ATP

GMP + ATP

2ADP

GDP + ADP

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

conversion of ribonucleotides to deoxyribonucleotides

Conversion of Ribonucleotides to Deoxyribonucleotides

BASE

BASE

Ribonucleotide

Reductase

Deoxyribonucleoside

Ribonucleoside

Somehow we need to get rid of this oxygen

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

You’ll have to tune in tomorrow

plan for tomorrow
Plan for Tomorrow
  • 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
take home concepts from today s lecture
Take Home Concepts from Today’s 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