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Biochemistry II > Nucleotide metabolism I > Flashcards

Nucleotide metabolism I Flashcards

1
Q

What is the difference btw nucleosides and nucleotides.

A
  • nucleoside: base (purine/pyrimidine) + sugar (ribose/deoxy-R)
  • nucleotide: base + sugar + phosphate (MP, DP, TP)

<u>REMEMBER:</u> nucleo<u><strong>T</strong></u>ide = <u><strong>T</strong></u>hree diff. things

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2
Q

What does the -ate ending indicate?

ex: adenylate

A

nucleotide monophosphate

→ AMP

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3
Q

How is DNA and RNA of ingested food metabolized?

A
  1. intestine
    DNA/RNA → polynucleotides → nucleotides → bases
  2. bases taken up into blood stream
  3. then
    • enter extrahepatic tissues
    • enter liver, here degraded to urate
  4. ​​urate enters blood stream again + excreted via urine
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4
Q

How do extrahepatic tissues and liver differ in their nucleotide metabolism?

A
  • liver:
    • able of de novo synthesis of nucleotides
    • able to break down purines + release urate into blood stream
  • extrahepatic tissues: only salvage reactions
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5
Q

Which enzyme catalyzes the common substrate for purine and pyrimidine synthesis?

Reaction.

A

PRPP synthetase

ATP + ribose-5-P → PRPP + AMP

→ phosphoribosyl pyrophosphate then used

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6
Q

Where does the ribose-5-P used for the synthesis of PRPP originally come from?

A
  • glc-6-P
  • fru-6-P

⇒ enter PPP, ribose-5-P formed

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7
Q

What are purine salvage reactions?

Which group of enzymes catalyzes these reactions?

A

purine bases formed during degradation of RNA/DNA can be used to synthesize nucleotides

done by phosphoribosyl transferases (PRT)

→ important in extrahepatic tissues since they are unable to undergo de novo synthesis of purines

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8
Q

Which enzymes are responsible for salvage reactions of AMP, IMP and GMP?

A

base + PRPP → nucleotide + PPi

  • adenine phosphoribosyl transferase (APRT)
    adenine + PRPP → AMP + PPi
  • hypoxanthine-guanine PRT (HGPRT)
    guanine/hypoxant. + PRPP → GMP/IMP + PPi
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9
Q

Differentiate btw de novo synthesis and salvage reactions of purine nucleotides.

A

IMP = common intermediate

de novo synthesis:

  • IMP formed in 10 steps
  • then either AMP, or GMP formed via 2 further reactions

salvage reactions:

  • directly IMP, AMP and GMP formed
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10
Q

Which enzyme catalyzes the rate-limiting step of purine synthesis?

Reaction.

A

Gln PRPP amidotransferase
first step of purine synthesis

PRPP + Gln
→ 5’-phosphoribosyl-amine + PPi + Glu

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11
Q

Where do the C/N atoms of the purine ring originate from?

A
  • N1 = Asp
  • C2, 8 = N10-formyl H4F
  • N3, 9 = Gln
  • C4, 5, N7 = Gly
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12
Q

AMP is synthesized in 2 steps from IMP.

Which enzyme catalyzes the first step?

Reaction.

A

adenylsuccinate synthetase

IMP + Asp + GTP → GDP + Pi + adenylosuccinate

→ N of AMP is originally from Asp

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13
Q

AMP is synthesized in 2 steps from IMP.

Which enzyme catalyzes the final conversion of adenylosuccinate to AMP?

Reaction.

A

adenylosuccinase (ASA)

adenylosuccinate → AMP + fumarate

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14
Q

GMP is synthesized in 2 steps from IMP.

Which enzyme catalyzes the first step?

Reaction.

A

IMP dehydrogenase

IMP + H2O + NAD+ → NADH + XMP

XMP = xanthosine monophosphate

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15
Q

GMP is synthesized in 2 steps from IMP.

Which enzyme catalyzes the final conversion of XMP to GMP?

Reaction.

A

GMP synthetase

XMP + Gln + ATP → AMP + PPi + Glu + GMP

→ N of GMP is originally from Gln

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16
Q

What is special about the function of the enzymes involved in the de novo synthesis of IMP?

A

8 steps are catalyzed by 3 multifunctional enzymes

only 2 steps have their own enzymes

  • step 1: Gln PRPP amidotransferase
  • step 8: adenylosuccinase (ASA)
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17
Q

How much energy is needed for de novo synthesis of

  • IMP
  • AMP
  • GMP
A
  • IMP: 6 ATP equ.
  • AMP: + 1 GTP
  • GMP: + 2 ATP equ.
18
Q

What is the importance of AMP kinase during exercise?

Reaction.

A

exercise leads to a decrease in cellular ATP which activates AMP kinase (AMPK)

2 ADP ⇔ ATP + AMP

also phosphorylates multiple downstream targets involved in other E metabolism pathways, leading to:

  • acceleration of all ATP-producing pathways
  • deceleration of all ATP-consuming pathways

⇒ preserves the cellular ATP concentration
by incr. the cellular AMP concentration

19
Q

What is the function of the purine nucleotide cycle?

Where does it happen?

A

in cytosol of skeletal myocytes
uses the excess AMP generated in muscle during exercise to fuel TCA cycle

→ incr. rates of oxidative phosphorylation in muscle

20
Q

The purine nucleotide cycle is composed of 3 enzyme-catalyzed reactions.

Which reaction is unique to this cyle and not involved in normal purine metabolism?

A

AMP deaminase

AMP + H2O → NH3 + IMP

→ now IMP can be used for new AMP synthesis to generate fumarate to fuel TCA cycle
(first by action of adenylosuccinate snythetase, then adenylossucinase)

21
Q

Which products are formed in the purine nucleotide cycle?

What is their physiological role?

A
  • fumarate fuels TCA cycle
  • NH3 released into blood stream, later converted in kidney used to buffer lactate/ketone bodies produced during exercise in muscle
  • excess IMP converted to inosine, released into blood stream, degraded to urate for excretion in liver

⇒ ↑NH3, ↑urate during exercise

22
Q

What is the consequence of a myoadenylate deaminase deficiency?

A

AMP cannot enter purine nucleotide cycle
most common inherited metabolic dysfunction in skeletal muscle

  • fatigue
    due to excess adenosine in brain/muscle after exercise
  • muscle pain, cramping, weakness
    probably due to incr. lactate levels/adenosine

​NOTE: NH3, urate are NOT elevated during exercise

23
Q

What causes Lesch-Nyhan syndrome?

Consequence + symptomes?

A

hypoxanthine-guanine PRT deficiency
purine bases cannot be recycled in salvage reactions, converted to urate in liver

⇒ hyperuricemia + ↓GTP level in basal ganglia

symptomes:

  • only in males (X-chromosomal recessive)
  • mental retardation
  • self-mutilation, aggression
24
Q

How is PRPP synthetase inhibited?

A
  • AMP
  • GMP

​→ are purine nucleotides (sort of product inhibition)

25
Q

Gln PRPP amidotransferase catalyzes the rate-limiting step of purine synthesis.

How is it regulated?

A

allosterically

  • activated by: PRPP (substrate)
  • inhibited by: IMP, GMP, AMP (product inhibition)
26
Q

How do AMP and GMP regulate the synthesis of purines?

A

sort of product inhibition, inhibit their formation on 3 levels:

  1. both inhibit formation of common precursor IMP (PRPP synthetase, Gln PRPP amidotransferase)
  2. inhibit their own synthesis
    • ​​AMP: adenylosuccinate synthetase
    • GMP: IMP dehydrogenase

​⇒ signalling, there’s already enough of us, we don’t need to produce more

27
Q

How do ATP and GTP regulate the synthesis of purines?

A
  • ATP: activates GMP synthetase
    (second step of GMP synthesis)
  • GTP: activates adenylsuccinate synthetase​
    (first step of AMP synthesis)

don’t understand the physiological concept behind this, just remember it

28
Q

What are the basic steps of purine catabolism?

Where does it mainly happen?

A

mainly in liver

  1. purine nucleotide → purine nucleoside
  2. … → purine base
  3. … → xanthine
  4. … → urate

→ urate eventually released into bloodstream, excreted via urine

29
Q

Which enzymes catalyze the catabolism of purine nucleotides?

Reaction scheme.

Name the individual products.

A

5’ nucleotidases
specific for each purine nucleotide

monophosphate nucleotide + H2O → nucleoside + Pi​

  • AMP → adenosine
  • IMP → inosine
  • XMP → xanthosine
  • GMP → guanosine
30
Q

Which enzymes catalyze the catabolism of purine nucleosides?

Reaction scheme.

Name the individual products.

A

purine nucleoside phosphorylases (PNPs)
again, specific for each nucleoside

nucleoside + Pi → purine base + ribose-1-P

  • inosine → hypoxanthine
  • xanthosine → xanthine
  • guanosine → guanine
31
Q

One purine nucleoside is not directly converted to its purine base.

Which nucleoside is it, how is catabolized instead?

Enzyme + reaction.

A

adenosine deaminase (ADA)
adenosine not directly converted to adenine

adenosine + H2O → NH3 + inosine

→ inosine then converted by its PNP to hypoxanthine

NOTE: don’t mix it up w/ <u>AMP deaminase</u> (purine nucleotide cycle)

32
Q

How are the purine bases catabolized?

Enzymes + reactions.

A

hypoxanthine and guanine are converted individually to common product xanthine

  • xanthine oxidase
    hypoxanthine + H2O + O2 → H2O2 + xanthine
  • guanase
    guanine + H2O → NH3 + xanthine

​according to lectures H2O2 is formed instead of NADH​

33
Q

How is xanthine catabolized?

Enyzme + reaction.

A

by xanthine oxidase

xanthine + H2O + O2 → H2O2 + urate

NOTE: same enzyme also catalyzes hypoxanthine to xanthine

​according to lectures H2O2 is formed instead of NADH

34
Q

What is primary hyperuricemia?

List reasons.

A

deficiencies in purine metabolism

  • PRPP overproduction
  • absence of purine salvage reactions
  • low ATP level, disturbed ATP metabolism
35
Q

Explain how PRPP overproduction can cause hyperuricemia.

2 examples for conditions that lead to PRPP overproduction.

A

↑PRPP → ↑purine synthesis → ↑urate

  • mutation in PRPP synthetase
    prevents allosteric inhibition → ↑ PRPP
  • Von Gierke disease = glucose-6Pase deficiency
    more G6P available for PPP, overproduction of ribose-5P → ↑ PRPP
36
Q

Which pathology would cause absence of purine salvage reactions?

How would this cause hyperuricemia?

A

e.g. HGRPT deficiency (Lesch-Nyhan syndrome)

hypoxanthine and guanine cannot be used to recover IMP and GMP, no synthesis of AMP possible

⇒ purine bases are transported to liver and degraded to urate for excretion

37
Q

How can a disturbed ATP metabolism cause hyperuricemia?

In which disease could such phenomenon be seen?

A
  • heavy exercise
    high energy consumption → ↓ATP → ↑AMP → ↑NH3, urate
  • hereditary fructose intolerance

deficiency of aldolase B → accumulation of F1P + trapping of Pi (fructokinase requires ATP) → inhibition of glucose production and reduced regeneration of ATP → ↑AMP → urate

heavy exercise leading to hyperuricemia is prbly rather a thing in theory than in real life o.O

38
Q

What is secondary hyperuricemia?

List reasons.

A

incr. amount of degradable purines due to breakdown of DNA, can be caused by

  • tissue damage
  • cancer​​, chemotherapy (= tumor lysis syndrome)
39
Q
  • don’t have to know, but I think a doctor should know -

What are symptoms of hyperuricemia?

What is the biochemical reason for it?

A

urate has low solubility in blood (especially in acidic pH range) ⇒ accumulates and forms

  • urate crystals: as can be seen in diapers (indicating Lesch-Nyhan syndyrome)
  • Na-urate crystals → causing lithiasis in hollow organs
  • tophi = urate accumulation in soft tissues/joints
    → inflammation reaction, pain (gout)
40
Q
  • don’t have to know, but I think a doctor should know -

Which medication can be administered to treat gout?

Mechanism.

A

allopurinol
= competitive inhibitor of hypoxanthine

converted by xanthine oxidase to oxopurinol

⇒ now hypoxanthine/xanthine in urine instead of urate (have higher solubility, don’t form crystals)

Biochemistry II (16 decks)

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