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Metabolism and Biochem > Nucleotides > Flashcards

Nucleotides Flashcards

1
Q

What are 3 types of nucleotides in order of decreasing abundance?

A

1) ATP
2) Ribonucleotides (mM)
3) Deoxyribonucleotides (uM range)

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2
Q

What is the main structural difference between purines and pyrimidines?

A

Purines: bicyclic
Pyrimidines: monocyclic

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3
Q

What are the 3 structural components of nucleotides?

A

1) Inorganic phosphate
2) 5 Carbon sugar (D-ribose or 2-Deoxy-D-Ribose)
3) Nitrogenous base (purine or pyrimidine)

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4
Q

What is the structural difference between a nucleotide and nucleoside?

A

Nucleoside no phosphate, only nitrogenous base and ribose sugar

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5
Q

What are 2 structural components of a nucleoside and how are they bonded?

A

1) Nitrogenous base (purine/pyrimidine)
2) Ribose sugar (D-ribose or 2-Deoxy-D-Ribose)
- bonded by ß-N-glycosidic bond

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6
Q

A nucleoside is (more/less) water soluble than its free base?

A

More soluble

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7
Q

Why does coffee and tea make you feel more energetic?

A

Caffeine and Theophylline both inhibit Phosphodiesterase
→ prevent breakdown of cAMP (responsible for feeling energetic) to AMP

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8
Q

Explain the acid-base nature of nucleotides.

A

Strong acid
- ionisation of phosphate groups

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9
Q

Which nucleotide is an important methyl donor?

A

S-Adenosylmethionine

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10
Q

Which nucleotide is an important sulfur donor?

A

3’-Phosphoadenosine 5’-phosphosulphate (PAPS)

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11
Q

What are 4 examples of pyrimidines?

A

1) Cytosine
2) Thymine
3) Uracil
4) 5-Methylcytosine
5) Dihydrouracil (t-RNA)
6) Pseudouracil (t-RNA, eukaryotic r-RNA)

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12
Q

What are 4 examples of purines?

A

1) Adenine
2) Guanine
3) Hypoxanthine (t-RNA)
4) Xanthine (metabolism)
5) Uric acid (metabolism)
6) 7-methylguanine (5’-cap of mRNA)

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13
Q

Where do the C and N atoms of the purine ring come from?

A

C:
HCO3- → C6
Glycine → C4,5
Formate → C2,8

N:
Aspartate amine → N1
Glutamine amide → N3, N9
Glycine → N7

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14
Q

What are the (i) activator and (ii) inhibitor of PRPP synthesis in Eukaryotic Purine synthesis?

A

Activator: Pi

Inhibitor: Purine ribonucleotides (ADP, GDP)

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15
Q

What is needed in PRPP synthesis in Eukaryotic Purine synthesis?

A

Ribose-5-P → PRPP
- via PRPP synthetase
- ATP → AMP (ATP Dependent)
- Mg2+ cofactor

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16
Q

What are 2 ways to synthesise purine and pyrimidine ribonucleotides?

A

1) De novo pathway (10 steps)

2) Salvage pathways

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17
Q

What are the (i) activator and (ii) inhibitor of 5-phosphoribosylamine synthesis (PRPP aminotransferase rxn) in Eukaryotic Purine synthesis?

A

Activator: PRPP

Inhibitor: AMP, GMP

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18
Q

What is the moa of PABA analogs (Sulfonamide) and why do they not affect humans?

A

PABA analogs → CI bacterial folic acid (and thus DNA) synthesis
- CI of DHP synthase → ↓tetrahydrofolate → ↓purine synthesis

BUT humans cannot synthesise folic acid (no effect)

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19
Q

What is the moa of methotrexate?

A

Folic acid analog (anti-cancer)
- CI of dihydrofolate reductase → ↓tetrahydrofolate
→ ↓purine synthesis → ↓DNA replication

20
Q

What is the moa of mycophenolic acid?

A

Immunosuppressant
- CI of IMP dehydrogenase
- ↓nucleic acids in T and B cells → prevent graft rejection

21
Q

How are NTP, GTP and ATP (nucleoside triphosphatases) formed?

A

NMP → NDP → NTP
- NMP kinase → NDP kinase
- 2 ATP → 2 ADP

GMP → GDP → GTP
- GMP kinase → NDP kinase
- 2 ATP → 2 ADP

ADP→ATP
- via oxphos

22
Q

Where do the C and N atoms of the pyrimidine ring come from?

A

C:
HCO3- → C2
Aspartate → C4,5,6

N:
Aspartate → N1
Glutamine amide → N3

23
Q

NTPs are synthesised from NMPs using (specific/non-specific) NMP kinases and (specific/non-specific) NDP kinases.

A

NMP → specific NMP kinase → non-specific NDP kinase → NTP

24
Q

How are UTP and CTP formed?

A

UMP → UDP → UTP
- NMP kinase → NDP kinase →
- 2 ATP → 2 ADP

UTP → CTP
- CTP synthetase
- Gln + ATP → Glu + ADP

25
Q

What is the difference between CP I and II?

A

1) Location
I → mitochondria, II → Cytosol

2) Pathway
I → Urea cycle, → II → pyrimidine synthesis

3) N source
I → Ammonia, II → γ-amine group of glutamine

4) Regulators:
I → activated by N-acetylglutamate
II → activated by PRPP, inhibited by UTP

26
Q

How does pyrimidine synthesis regulation differ in mammalian and prokaryotic (eg. E. coli) cells?

A

Mammalian:
- regulation at CPS II
- activator: PRPP, ATP
- inhibitor: UTP, CTP
- also regulated at OMPDC (inhibited by UMP)

Prokaryotic:
- regulation at ATCase
- activator: ATP
- inhibitor: CTP

27
Q

What is orotic aciduria?

A

High orotate in urine
- by low activity in either (i) OMPDC or (ii) Orotate phosphoribosyltransferase (OPRTase)
- Type I: Both, Type II only OMPDC

→ megaloblastic anemia and poor growth (↓ pyrimidine synthesis)

  • Rx: Uridine, Cytidine, salvage enzymes (to bypass de novo pathway)
28
Q

In the biosynthesis of deoxyribonucleotides, reduction occurs at (sugar/nucleotide level)

A

Ribonucleotides

29
Q

How does ribonucleotide reduction in deoxyribonucleotides biosynthesis in humans differ from L. leichmanii and E. coli?

A

Humans same as E. coli
NDP → dNDP
- ribonucleotide diphosphate reductase
- cofactor: Fe

L. leichmanii
NTP → dNTP
- ribonucleotide triphosphate reductase
- cofactor: B12, dihydrolipoate

30
Q

The _______-dependant ribonucleotide reductase in eukaryote deoxyribonucleotide biosynthesis requires ________ as a reducing agent by using reducing equivalents from ________.

A

Fe-dependant

Requires Thioredoxin
uses NADPH

31
Q

What are 3 sites for regulation of ribonucleotide reductase?

A

1) Activity site:
- ATP → activate
- dATP → inhibit

2) Specificity site
- determines which substrate can bind to catalytic site

3) Catalytic site
- for substrate

32
Q

How are the ribonucleotides dCTP, dTTP, cGTP, dATP synthesised in exactly the same ratio (1:1:1:1)?

A

Start at high ATP
→ ATP occupy both activity and specificity site
→ allows reduction of CDP and UDP
→ form dCTP (1st) and dTTP (2nd) respectively

→dTTP can occupy specificity site
→ allow reduction of GDP
→ forms dGTP

→dGTP can occupy specificity site
→ allow reduction of ADP
→ forms dATP

(when dTTP, dGTP, dATP in specificity site → inhibit reduction of CDP, UDP, etc. to prevent prior rxn)

33
Q

How does mammalian ribonucleotide reductase regulation differ in E. coli?

A

dGTP inhibits reduction of CDP and UDP in mammalian but not E. coli cells

34
Q

What is the resultant molecule from all purine catabolism?

A

Uric acid

35
Q

How is DNA catabolised into purines/pyrimidines?

A

1) DNA/RNA → mononucleotides
- Nucleases/ phosphodiesterases

2) Mononucleotides → nucleosides
- Mononucleotide phosphatatses

3) Nucleosides → purines/ pyrimidines
- Phosphorylases

36
Q

What are 3 pathologies related to defective purine metabolism?

A

1) Lesch-Nyhan Syndrome (salvage)

2) Gout (degradation)

3) SCID (dNDPs)

37
Q

What is Lesch-Nyhan syndrome?

A

Sex-linked congenital severe HGPRT deficiency (purine salvage enzyme)
- mostly males
→ accumulation of PRPP → activate de novo pathway
→ ↑ rate of purine synthesis and ↑ uric acid

→ neurological abnormality:
- mental retardation
- bizarre behaviour (aggressive, destructive, self-mutilation)

38
Q

What is gout?

A

Painful arthritic joint inflammation due to deposition of sodium urate crystals (tophi)

  • caused by ↑↑uric acid in blood and other bodily fluids
  • can also cause renal calculi
  • mainly males
39
Q

What is the committing step of purine synthesis?

A

Ribose-5-P → PRPP
- via PRPP synthetase
- ATP → AMP (ATP Dependent)
- Mg2+ cofactor

40
Q

What are 2 pathophysiological factors for gout and what are the implicated enzymes?

A

1) Impaired uric acid excretion
2) excessive uric acid production

i) HGPRT deficiency → ↑PRPP

ii) G6Pase deficiency (Von gierke’s Type I) → ↑G6P, ↑R5P, ↑PRPP, ↑uric acid, ↑lactic acid)

iii) Overactivity of PRPP synthetase

41
Q

What is SCID?

A

Severe Combined Immunodeficiency Disease
- 30% a/w Adenosine deaminase (ADA) deficiency
→ T and B cells cannot proliferate → lack of immune response

42
Q

How does adenosine deaminase deficiency lead to SCID?

A

↓ADA → ↑Adenosine/Deoxyadenosine
→ ↑dATP → bind to activity site of NDP reductase
→ inhibit NDP binding and reduction
→ ↓dNTP for DNA synthesis
→ ↓immune cell proliferation

43
Q

How is orotic aciduria treated?

A

1) Uridine, Cytidine
2) salvage enzymes (to bypass de novo pathway)

44
Q

What is the moa of Acyclovir?

A

Anti-viral
- purine analog (acycloguanosine)
→ activated by specific HSE-thymidine kinases only in infected cells

→ acyclovir phosphorylated to triphosphate form

→ Acycloguanosine substrate for HSV-specific DNApol → chain termination

45
Q

What is the moa of AZT?

A

Anti-HIV
- AZT → AZT triphosphate → block HIV replication via RNA-dependent DNA pol

46
Q

What is the moa of hydroxyurea?

A

Anti-cancer
- quenches free radical on NDP reductase’s catalytic site
→ ↓DNA synthesis and replication

47
Q

What is the moa of 5-flurouracil?

A

Anti-viral
- Uracil analog
- converted to 5FdUMP → inhibit thymidylate synthase → ↓dTMP synthesis → ↓viral replication

Metabolism and Biochem (8 decks)

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