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SFM Biochem > Nucleotide Metabolism > Flashcards

Nucleotide Metabolism Flashcards

1
Q

What is the difference between a nucleotide and a nucleoside?

A

Nucleotides are phosphate esters of nucleotides.
Nucleoside = nitrogenous base + sugar
Nucleotide = nitrogenous base + sugar + phosphate
Ex/ Nucleotide = Adenine monophosphate, Adenine diphosphate, Adenine Triphosphate (ATP)

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2
Q

What are the two ways (generally) purine nucleotides can be produced?

A 
De Novo synthesis (liver, cytosol) - producing activated sugar first and constructing purine (through 9 step process) onto the ribose sugar 
Salvage Pathway (organelles) - First making the purine base, then added the ribose sugar to it
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3
Q

What are the two ways (generally) that pyrimidine nucleotides can be produced?

A 
De Novo Synthesis (liver, cytosol, mitochondria) - formation of pyrimidine ring structure followed by addition of ribose phosphate
Salvage Pathway (organelles) - formation of pyrimidine nucleotides from pyrimidine bases (RNA/DNA) then adding activated sugar
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4
Q

What are major mechanisms for depletion of amino acid pool?

A

Protein synthesis (amino acids -> proteins)
Metabolism/degradation of amino acids to ammonia and carbon skeleton
Production of other nitrogen containing compounds (nucleotides)

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5
Q

What are the 4 major steps of purine synthesis?

A

Phase I: activation of ribose-5-phosphate (from PPP) to make PRPP
Phase II: Convert activated PRPP to even more activated molecule (phosphoribosylamine) —RATE LIMITING
Phase III: Construction of inosine monophosphate (IMP) branch point purine ring
Phase IV: Conversion of IMP into adenosine and guanosine (deoxy) nucleotides

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6
Q

What happens in phase I of purine synthesis?

A

Activation of ribose 5-phosphate:
Ribose 5-phosphate (from PPP) is phosphorylated to 5-phospho-a-D ribosyl 1-pyrophosphate (PRPP) which is it’s ACTIVE form.
Rxn utilizes ATP -> AMP and enzyme: PRPP synthetase

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7
Q

How is phase I of purine synthesis regulated?

A

Phase I: Activation of ribose 5-phosphate to 5-phospho-a-D ribosyl 1-pyrophosphate
Enzyme: PRPP synthetase
Requires ATP
Allosterically activated by phosphate levels - Pi levels signal cellular activity due to ATP consumption (high ATP -> activation)
Negatively regulated by levels of purine nucleotides (GMP, AMP, IMP) - feedback inhibition

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8
Q

What happens in Phase II of purine synthesis?

A

RATE LIMITING STEP

Activated PRPP is converted into phosphoribosylamine (PRA))
(PRPP + Glutamine —> PRA + Glutamate)
Enzyme: Glutamine phosphoribosyl pyrophosphate amidotransferase
Glutamine phosphoribosyl pyrophosphate amidotransferase substitutes pyrophosphate (of PRPP) with amino group (from glutamine) at C-1’ of PRPP. To generate phosphoribosylamine (PRA)

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9
Q

How is Phase II of purine synthesis regulated?

A

Phase 2: PRPP + Gln —> PRA + Glu RATE LIMITING STEP
Enzyme: glutamine phosphoribosyl pyrophosphate amidotransferase
Allosterically activated by PRPP levels
Negatively regulated by purine nucleotide levels (GMP, AMP, IMP) - Negative feedback inhibition

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10
Q

What happens in phase III of purine synthesis pathway?

A

PRA enters 9 step ring synthesis to construct IMP (branch point in purine synth)
***Consumes ATP (4 equiv)
2 C’s from formal-THF (folate derivative), 1 C from CO2, remaining C’s and N’s from Gln, Gly, and Asp

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11
Q

What regulates Phase III of purine synth?

A

Methotrexate (inhibition)

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12
Q

What happens in Phase IV of purine synthesis?

A

Conversion of IMP to dATP or dGTP
2 pathways:
A Pathway: IMP —> adenylosuccinate monophosphate (requires GTP, adenylosuccinate synthetase) —> AMP (adenylosuccinase) —> ADP —> ATP or dADP —> dATP
G Pathway: IMP —> XMP (*oxidation - requires NAD+ —> NADH; IMP dehydrogenase)
XMP + Gln —> GMP (consumes ATP; releases AMP + PPi and Glu)
GMP —> GDP —> GTP or dGDP—> dGTP

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13
Q

How is Phase IV of purine synthesis regulated?

A

Negatively Feedback: AMP inhibits rxn of IMP —> adenylosuccinate (adenylosuccinate synthetase)
GMP inhibits rxn of IMP —> XMP (IMP dehydrogenase, ***RATE LIMITING STEP OF GTP SYNTH)

Cross-regulation: AMP synth requires GTP
GMP synth requires ATP

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14
Q

How is purine synthesis regulated?

A

Feedback inhibition: accumulation of end-product inhibits its own synthesis
AMP/GMP inhibits formation of PRPP, phosphoribosyl amine (PRA), and IMP

Cross-regulation: AMP synth requires GTP/stimulated by GMP
GMP synth requires ATP/stimulated by AMP
(for DNA/RNA synthesis, concentration of end products need to be closely regulated)

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15
Q

What is an anti metabolite?

A

Therapy targeting nucleotide synthesis

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16
Q

What is Methotrexate? What does it do?

A

Methotrexate is an antineoplastic agent used for cancer treatment by targeting DNA synthesis in rapidly dividing cancer cells.

  • Structurally similar to Dihydrofolate
  • Methotrexate COMPETITIVELY INHIBITS dihydrofolate reductase (converts dihydrofolate into bio active tetrahydrofolate) thus cannot form methylene-THF (methyl carrier for rxn of dUMP —> dTMP)
  • Methotrexate prevents oxid of NADPH by DHFR
  • By reducing formation of dTMP —> reduce DNA synthesis. —> selectively inhibit DNA synth in cancer cells
17
Q

How does Methotrexate impact purine synthesis?

A

Phase III of purine synth: 9 step ring assembly requires formyl-THF (f-THF). f-THF comes from m-THF. Therefore methotrexate inhibits conversion of dihydrofolate to tetrahydrofolate —x inhibits production of m-THF —x production of f-THF

18
Q

What is Fluorouracil? What does it do?

A

Fluorouracil is a cancer treatment that targets DNA metabolism. Usually used at topical treatment for basal cell carcinoma, warts, injected into tissue for colon, esophageal, breast, cervical cancer.
Specifically targets pyrimidine synthesis.
Targets thymidylate synthase- enzyme catalyzes dUMP —> dTMP (targets same step as methotrexate but different chemical target)
Limits formation of dTMP —X DNA synthesis of cancer cells

19
Q

What are “sulfa drugs”?

A

Antibacterial agents in the sulfonamide family that selectively disrupt DNA replication in bacteria

20
Q

How do Sulfa drugs work?

A

Bacteria synthesis THF using dihydropteroate synthetase and PABA (p-aminobenzoic acid)
Sulfa drugs mimic the PABA substrate and are competitive inhibitors of dihydropteroate sythetase which halts the THF formation, disrupts nucleotide synthesis and disrupts bacterial DNA synthesis.

21
Q

What is Acyclovir?

A

Acyclovir is an antiviral agent that is a synthetic nucleoside analogue

22
Q

How does Acyclovir work?

A

Target step: Thymidine kinase phosphorylates the nucleotide deoxythymidine (dT) to generate dTMP using ATP as the phosphoryl donor.
Acyclovir has a base that more closely resembles guanosine than dT (deoxythymidine).
Thymidine kinase preferentially phosphorylates acyclovir, instead of the nucleotide deoxythymidine (dT), for incorporation into DNA synthesis.
Viral TK affinity is much higher for acyclovir than dT. However, Acyclo-dGTP inhibits viral DNA polymerase thus terminating viral DNA replication
Used for treating chicken pox, shingles, and HPV/HSV

23
Q

Describe purine catabolism

A

Purine catabolism = breaking down GMP and AMP to Uric acid
GMP dephosphorylated to give –> Guanosine loses ribose group to give —> Guanine is deaminated to give —> Xanthine
AMP de-phosphorylated to give –> Adenosine is deaminated (via adenosine deaminase) to give —> Inosine loses ribose group —> Hypoxanthine is oxidized to give —-> Xanthine
GMP and AMP breakdown are 2 converging pathways that meet at Xanthine

Xanthine is then oxidized (via xanthine oxidase) to give Uric Acid

24
Q

What does Adenosine Deaminase do? What happens if its defective?

A

Catalyzes the irreversible deamination of Adenosine to Inosine
Deficiency results in Severe Combined Immunodeficiency (SCID)
Overproduction of erythrocyte isoform causes hemolytic anemia

25
Q

Why are the oxidation levels of purines significant?

A

Catabolic processes typically include steps where oxygen is added to the molecule to make it more polar. During purine catabolism:
Adenosine = 0 oxygen, Guanine and hypoxanthine = 1 Oxygen, Xanthine = 2 Oxygen, Uric acid = 3 oxygen
Uric acid as the end point of purine catabolism is the most oxidized.
Uric acid has an acidic proton and limited solubility in water that plays a key role in gout

26
Q

What is SCID?

A

Severe Combined Immunodeficiency
Associated with defective Adenosine deaminase (ADA) which converts Adenosine to Inosine.
Defective enzyme results in increase in adenosine and decrease in inosine
Adenosine subsequently converted to AMP and ADP and then to dADP and dATP
Increased dATP inhibits active site of ribonucleotide reductase that in turn blocks the formation of all other dNDPs
Decrease in dNDP and dNTP impairs DNA synthesis and leads to the compromised immune system
(Clinical manifestations: Failure to thrive, chronic diarrhea, thrush, recurrent infections)
***most common form is X-linked —“bubble boys”
Second most common form of ADA defect is ADA deficiency (autosomal rec)

27
Q

What is Xanthine oxidase?

A

Bifunctional enzyme that converts Hypoxanthine to xanthine and also converts Xanthine to Uric acid
Target for gout treatment
limit production for uric acid

28
Q

What is gout and what causes it?

A

Gout is characterized as high levels of uric acid in the blood
Primary hyperuricemia –> overproduction of uric acid
Secondary hyperuricemia —> under-excretion of uric acid
Results in extremely pain deposits of sodium urate in the joints of extremeties (gouty arthritis)– uric acid crystal deposits because uric acid is insoluble
Sodium urate deposits in the kidneys can cause damage
Diets rich in purines (bean, spinach, lentils) along with alcohol, meat and seafood can trigger episodes
Treatment: reducing amount of purines consumed in diet, allopurinol inhibits xanthine oxidase, increase levels of more soluble purines hypoxanthine and guanine

29
Q

Overview of pyrimidine catabolism

A

converted to readily metabolized ketogenic or glucogenic, water soluble compounds

  • malonyl CoA, methylmalonyl CoA, succinyl CoA
  • Uracil/cytosine –> malonyl CoA (ketogenic)
  • Thymine –> methylmalonyl CoA or succinyl CoA (glucogenic)
30
Q

What is the purpose of the salvage pathways?

A

Synthetic pathways require high energy consumption so we can salvage material from other places - preferable
Bases can be recovered during nucleotide turnover or digestion and can be reincorporated into nucleotides
dominates de novo synthesis for purines

31
Q

What are the two important enzymes for purine salvage pathways?

A 
Adenine phosphoribosyltransferase (APRT) generates AMP from adenine
- deficiency associated with Renal lithiasis
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) generates GMP or IMP from guanine or hypoxanthine
32
Q

What is Lesch-Nyhan Syndrome?

A

Associated with a deficiency in the hypoxanthine guanine phosphoribosyl-transferase (HGPRT) enzyme which converts guanine or hypoxanthine into GMP or IMP
severe form of primary hyperuricemia - does not use guanine and hypoxanthine in salvage pathway - instead shunted to form 6x normal amount of uric acid
Hyperuricemia leads to gout, urate kidney stones, poor muscle control, severe cognitive impairment and tendency for self-mutilation
<1.5% normal HGPRT activity, LNS presents with additional severe neurologic problems, including spastic cerebral palsy, choreoathetosis and self-destructive biting (fingers and lips)
>8% normal HGPRT activity results in Kelley-Seegmiller syndrome – goat and kidney destruction without neurological symptoms

SFM Biochem (2 decks)

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