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BIOC 311 > Nucleotide Metabolism > Flashcards

Nucleotide Metabolism Flashcards

1
Q

What are the general differences between the Salavage and de novo pathways?

A

de novo pathway:
- Synthesisi of nucleotides from small starting materials → amino acids, ribose, CO2, etc.
- Highly conserved in eukaryotes (main source for bacteria)

Salvage pathway:
- Recovery of “bases” for making new nucleotides
- More divergent, varied
- More important for human → recycle bases from dietary nucleotide sources

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2
Q

What are the starting materials of the de novo Purine pathway?

A
  • PRPP
  • Glutamine
  • Aspartate
  • CO2
  • Glycine
  • Formate

→ Formation of Iosine Monophosphate (IMP)

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3
Q

What are the starting materials of the Pyrimidine de novo pathway?

A
  • CO2 (HCO3-)
  • Glutamine
  • Aspartate
  • PRPP

→ Formation of Uridine Monophosphate (UMP)

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4
Q

What is the structural characteristic of the “base”?

A

It is the aromatic part

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5
Q

What is the difference between “-side” and “-tide”?

A

“-side” → no phosphate
“-tide” → phosphosugar

*Nucleotide = Nucleoside phosphate

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6
Q

Wha is the structural difference between Purine and Pyrimidines?

A

Purine → 2 rings (5 and 6 members)

Pyrimidine → 1x 6 membered ring

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7
Q

At what positions are the Nitrogens in purine and pyrimidine bases?
At which position is the sugar attached?

A

All odd position except for 5:
Purine → 1, 3, 7, 9
*9th position links to the ribose

Pyrimidine → 1, 3
*1st position links to the ribose

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8
Q

What are the 2 types of sugar found in nucleotides?

A

Ribonucleotides → RNA

Deoxyribonucleotides → DNA (misses O attached to 2’C)

Both:
- b-glycosidic bond → sugar-base linkage (1’C called anameric carbon)
- D sugar → furanose conformation (in biology, all sugars are found as D isomers)

*beta bond → above
alpha bond → bellow

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9
Q

What are the names of the metabolites of nucleotide de novo pathway?

A

*Base → Nucleoside → Nucleotide

Purine pathway:
Hypoxanthine → Inosine → Inosinate (IMP)
Xanthine → Xanthosine → Xanthylate (XMP)

Pyrimidine pathway:
Orotate (orotic acid) → Orotidine → Orotidylate (OMP)
Uric acid (only found in its base form)

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10
Q

What nucleoside are also drugs/therapeutics?

A

Caffeine → 1,3,7-Trimethylxanthine
Theobromine (in chocolate)

Dideoxycytidine → missing 2 Oxygens on the ribose, bound to Cytosine
AZT → bound to Thymine base

*Oral drugs can be bases or nucleosides, but rarely nucleotides → injected in inactive form and have to be phosphorylated to become active in the body (become nucleotides)

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11
Q

Where do the different atoms of a purine base originate from?

A

Aspartate amine → N1
Formate → C2
Glutamine amide → N3
Glycine → C4-C5-N7
HCO3- → C6
Formate → C8
Glutamine amide → N9

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12
Q

What are the general features of de novo synthesis of purines?
(regulated steps? how many steps? how many high-energy phosphate bonds?)

A

Purine ring assembled on ribose phosphate

Step 1 → 5-phosphoribose → PRPP
Step 2 → PRPP → 5-phosphoribosylamine
- Regulation at steps 1 and 2
- pathway committed at step 2 (PRPP can be used for other pathways)

Total of 11 steps to make IMP (inosine monophosphate)
7 “high energy” phosphate bonds

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13
Q

What occurs in the 1st step of the purine de novo pathway?

A

Synthesis of PRPP → a key intermediate in nucleic acid & amino acid synthesis
- Tightly regulated

PRPP is an a-sugar anomer → inversion to b at the next step

a-D-Ribose-5-phosphate → {ribose phosphate pyrophosphokinase, consumes 1ATP} → PRPP

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14
Q

What does PRPP stand for?

A

5-Phosphorybosyl-a-pyrophosphate

*2 phosphoates = pyrophosphate → are below so in alpha position

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15
Q

What occurs in step 2 of de novo purine synthesis?

A

PRPP → {amidophosphorybosyl transferase} → b-5-Phosphoribosylamine
- Glutamine in the N donor → becomes Glutamate
- H2O is used for hydrolysis of PPi → 2Pi which drives the entire reaction

At C1, the a-pyrophosphate is replaced by b-NH2, where the purine will be Anomeric inversion

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16
Q

Which are the 2 nitrogen donors of all nucleotide synthesis pathways?

A

Glutamine → Give N from side chain → Glutamate (replaced by Oxygen)

Aspartate (Aspartic acid) → Gives N from backbone → Fumarate

*Involves ATP or sometimes GTP → form a phosphoester intermediate
The reaction: Aldehyde (R=O) → {phosphoester intermediate} → Amine (R-NH2)

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17
Q

What is a nucleoside?
What is a Ribotide?

A

Nucleoside: Base + Ribose
Ribotide: Ribose + phosphate(s)

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18
Q

What are the steps for synthesis of the 1st cycle in the Purine de novo synthesis pathway?

A

Starting product: b-5-Phosphoribosylamine
End product: AIR (5-Aminoimidazole ribotide → side chain of Histidine + ribose-5-phosphate) = 1st 5-membered ring

  1. Addition of Glycine → 3 atoms of the cycle (C-C-N) + complex regulation (consumes ATP, GAR synthetase)
  2. C from N10-formyl THF (HC=O, transformylase)
  3. N from glutamine to replace C=O for 2nd cycle (uses ATP, synthetase)
  4. Cyclization → Nucleophulic attack by enamine N9 on C=O, by AIR synthetase (consumes ATP)
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19
Q

What are the steps for building the 2nd cycle in the purine de novo synthesis pathway?

A

AIR → CAIR → SACAIR → AICAR → FAICAR
7. Addition of HCO3- (consumes ATP, carboxylase)
8. N from aspartate in 2 steps → N-succinyl intermediate (Aspartate, consumes ATP, synthetase) → (9) released as fumarate (lyase)
10. C from N10-formyl THF (AICAR transformylase) → FAICAR

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20
Q

What is AICAR?

A

It is an analog of Adenosine Monophosphate → capable of stimulating AMP-dependent protein kinase (AMPK)

*Considered as performance-enhancing drug

AICAR = AICA ribonucleotide found in purine de novo pathway

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21
Q

What reactions does transformylase catalyse?

A

Addition of a C from tetrahydroformal
→ Steps 4, 10 of purine de novo synthesis pathway
*Does NOT consume ATP

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22
Q

What reactions do synthases catalyze?

A

Addition of Nitrogens from a Nitrogen donor (or N nucleophilic attack in step 6 to close the 1st ring)
*Consumes ATP

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23
Q

What nucleoside and nucleotide is associated with AICA ribonucleotide?

A

*9th step of purine de novo synthesis
Nucleoside: acadesine
Nucleotide: ZMP

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24
Q

What is the last step of the purine de novo synthesis pathway?

A

Step 11: Synthesis of IMP
FAICAR → {IMP cyclohydrolase, release H2O} → Inosine Monophosphate (IMP)

  • Closes the 2nd (6-membered) ring
  • Dehydration
  • No ATP required
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25
Q

What is IMP and its role in de novo purine synthesis?

A

IMP = Inosine monophosphate

  • Purine base intermediate
  • Branch point for AMP & GMP biosynthesis (feedback regulated)
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26
Q

What allows for regulation of the IMP branch point → AMP or GMP?

A

AMP requires Aspartate & GTP → Adenylosuccinate → {release fumarate} → AMP

GMP requires Glutamine & ATP (via XMP)
IMP → {NAD+ → NADH, dehydrogenase, to add =O} → XMP → {Glutamine + ATP + H2O, GMP synthase change =O to -NH2} → GMP

*The ratios of ATP and GTP available to catalyze these reactions regulate (feedback) the synthesis of AMP vs GMP

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27
Q

Form Purine Monophosphates, which enzyme catalyse the formation of Diphosphates?

A

Diphosphates via base specific kinases (non-specific for ribose/deoxyribose)

Adenylate kinase: (d)AMP + ATP ←→ (d)ADP + ADP
Uridylate kinase: (d)UMP + ATP ←→ (d)UDP + ADP

∆G~0, thermodynamic equilibrium, depends on the concentration ratios → [ADP]/[AMP] = [ATP]/[ADP]

∆G ~ 0 => [ADP][AMP]/[AMP][ATP] = 1

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28
Q

From Purine diphosphate, which enzymes catalyse the formation of triphosphates?

A

Triphosphates via ubiquitous non-specific kinase → Nucleoside diphosphate kinase

(d)NDP + (d)N’TP ←→ (d)NTP + (d)N’DP

∆G~0, thermodynamic equilibrium, depends on the concentration ratios → [UTP]/[UDP] = [ATP]/[ADP]

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29
Q

What are the relative intracellular amounts of nucleotides, base, nucleosides & PRPP in E. Coli?

A

~ 7x more RNA than DNA
~ 7x more NTP that dNTP
~ 7x more NTP than NDP
~ 7x more NDP than NMP
RNA/NTP > DNA/dNTP > NDP > NMP

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30
Q

What are the main mechanisms of regulation of purine de novo synthesis?

A
  1. Feedback inhibition by nucleotides (AMP/GMP and ADP/GDP → IMP branch point)
  2. Feedback inhition by nucleotides → Steps 1 and 2
  3. Feedforward by PRPP (for Step 2 which has PRPP as a substrate)
  4. Inhibition & stimulatio for AMP and GMP syn
    *AMP, ADP, ATP are all nucleotides
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31
Q

What is Tetrahydrofolate? What is it used for?

A
  • Most versatile enzyme cofactor known
  • Carries 1 carbon «unit» in 3 different oxidation states
  • Carries 1 carbon «unit» in 5 different chemical forms
  • From folic acid (found in leaves) → humans get it from their diet (eating salad)
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32
Q

What are Sulfonamides? (sulfa drugs)

A

Antibiotics
Bacteria synthesize folate de novo from p-aminobenzoic acid while human get it from food (salad)
Due to their similarity to p-aminobenzoic acid (the central section of THF)→ they inhibit synthesis of folate
*Since some bacterias synthesize their own folate, these drugs inhibit the synthesis → imapirs capcity to synthesize nucleotides → death

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33
Q

What are the different Oxidation levels of Tetragydrofolate (THF)? What groups are carried? What are the corresponding THF derivatives?

A

*THF is a Carbon carrier, can carry carbon under 3 forms

Methanol → most reduced (3x H) → carries Methyl (-CH3) → Derivative = N5-Methyl-THF
Formaldehyde → (2x Hs) → carries Methylene (-CH2-) → Derivative = N5, N10-Methylene-THF
Formate → most oxidized (1H) → 3 different carried groups
a) Formyl (-CH=O) → N5-Formyl-THF,N10-formyl-THF
b) Formimino (-CH=NH) → N5-Formimino-THF
c) Methenyl (-CH=) → N5,N10-Methenyl-THF

34
Q

What are the 3 uses of the THF metabolism?

A
  1. Methionine cycle (5-Methyl-THF)
  2. Thymidylate synthase (N5,N10-methylene-THF)
  3. Purine de novo (N10-Formyl-THF)
35
Q

Who should take folic acid supplements and why?

A

Pregnant women → prevent neural tube defects in embryos

36
Q

What is the most abundant form of guanine in the cells? GDP? GMP dGTP? GTP? Guanosine?

A

GTP

37
Q

Why is DNA the genetic material?
(and not RNA)

A
  1. Removing the 2’OH makes the DNA phosphodiester backbone more stable
    → 2’OH attacks the phophate from backbone
  2. The base thyine allows spontaneuous deamination of cytosine (→ Uracil) to be detected) because uracil is not a possible base of DNA
38
Q

Wht is the result of deamination of the adenine, cytosine and guanine bases?

A

Adenine → Hypoxanthine
Guanine → Xanthine
Cytosine → Uracil

39
Q

Which between DNA or RNA is more reduced/oxidized?
At what level is the transition of RNA → DNA done?

A

DNA is more reduced
Carried at the level of DNPs (diphosphates) by the enzyme: ribonucleotide reductases

Reductase because the 2’ O is removed → add an H (reduction)

40
Q

What is the electron donor/reducing equivalent of ribonucleotide reductases?

A

NADPH → FADH2 → HS-SH → HS-SH → dNDP
1. Thioredoxin reductase
2. Thioredoxin
3. Ribonucleotide reductase

Pass through thiols (cysteine residues) of thioredoxin reductase to thioredoxin and to finally RR

41
Q

What is the reducing power and the oxidizing power in the cell?

A

Reducing power → NADPH
*NADPH/NADP+ = 100

Oxidizing power → NAD+
NAD+/NADH = 1000

42
Q

What is the structure/structural regulation of ribonucleotide reductase?

A

Heterodimer (dimer of homodimers)

2 Allosteric sites on each regulatory subunit:
- Activity controlled by ATP/dATP levels
- Specificity controlled by dATP/dGTP/dTTP
*2 types of feedback regulation to maintain equilibrated levels of dNTPs

Catalytic subunit:
Stable enzyme has a tyrosine free radical
- Inhibited by hydroxyurea (converts tyrosine radical → tyrosine)

Bacteria often encode their own RR as they depend on it for DNA synthesis → target for many antibiotics or cancer treatments

Other types of RR exist with B12, Fe/S or other cofactors than tyrosine

43
Q

What DNA repair mechanism is induced when Uracil is mistakenly incorporated into DNA?

A

Base excision repair
1. Uraci-DNA glycosylase cleave Uracil base → apurinic site
2. Apurinic/Apyrimidinic (AP) endonuclease cleaves DNA backbone
3. Resynthesis from complementary strand
*Excessive repair causes mutations

44
Q

How does the Pyrimidine pathway decreases the odds of dUTP to get incorporated into DNA?

A

A specific enzyme UTPase hydrolyzes dUTP → dUMP to decrease its concentration and prevent its incorporation

*Incorporation of dUTP mimics deamination of cytosine, which is recognized by DNA repair mechanisms

45
Q

In the pyrimidine pathway, in what order are the different end-products synthesized?
CTP, dCTP, UTP, dTTP

A

Start with Aspartate → Uridylate (UMP) → UTP
A) UMP → UTP → CTP → RNA
B) UMP → UTP → CTP → CDP →dCDP → dCTP → DNA
C) UMP → UDP → dUDP → dUTP → dUMP → dTMP → dTTP → DNA

46
Q

What are the origins of the different atoms of the pyrimidine ring?

A

C-C-C-N → Aspartate
N → Glutamine amide
C → HCO3-

47
Q

Between the purine and the pyrimidine pathway, what is the difference between the where the rings are assembled?

A

Pyrimidine ring is assembled separately, phosphoribose (PRPP) added at the end to make nucleotide

Purine ring is assembled from the Nitrogen which is first added to PRPP (assembled on the ribotide)

48
Q

What are the first step of de novo pyrimidine synthesis?

A
  1. 2ATP + Glutamine + HCO3- + H2O → Carbamoyl phosphate + 2ADP + Glutamate + Pi
    Enzyme = Carbamoyl phosphate synthetase

2 enzymes in animals:
- In mitochondria for urea cycle
- In cytosole for pyrimidine synthesis
*Allows step 1 regulation in animals
Bacteria have only 1 enzymes for both pathways so regulation of the pyrimidine synthesis is done at step 2

49
Q

What was aspartate transcarbamoylase well studied for?

A

*Step 2 of pyrimidine de novo synthesis

Well-studied example of allosteric regulation
- Activated by ATP
- Inhibited by CTP
→ Affects the Km of the enzyme (affinity)

50
Q

What occurs in step 2 of the pyrimidine de novo synthesis pathway?

A
  1. Carbomoyl phosphate + Aspartate → Carbamoyl aspartate + Pi
    Enzyme = Aspartate transcarbamoylase (ATCase)

*All atoms are there + COO- group because charged groups prevent the ring from diffusing out of the cell
*Bacteria regulate this step

51
Q

How are different steps of the pyrimidine de novo pathway coupled?

A

Channeling between Steps 1, 2 and 3
Intermediate goes to the mitochondrial membrane for step 4
Channeling between steps 5 and 6

Allows to increase throughput, decrease cellular concentrations of intermediates
Channeling is done by mulitple enzymes assembling in complexes

*Channeling only occurs in eukaryotes because bacteria needs enzyme 1 to be isolated because it sevres the urea cycle as well

52
Q

What does the loss of the enzymes responsible for steps 5 and 6 of pyrimidine de novo synthesis lead to?

A

Leads orotic aciduria
- Caused by build up in Orotate

53
Q

What occurs in step 3 and 4 of the pyrimidine de novo synthesis pathway?

A

Step 3 → Close the pyrimidine ring
Carbamoyl aspartate → {Dihydroorotase} → Dihydroorotate + H2O
*Dehydration

Step 4 → Oxidation (makes double bond)
Dihydroorotate + Quinone → {dihydroorotate dehydrogenase} → Reduced quinone + Orotate
*Occurs in the mitochondrial membrane → 2 electrons → CoQ

54
Q

What occurs in steps 5 and 6 of the pyrimidine de novo synthesis pathway?

A

Step 5 → put Orotate onto the ribotide
Orotate + PRPP → {orotate phosphoribosyl transferase} → PPi + OMP
*OMP = UMP + COO-
Step 6 → Removal of COO- to make UMP
OMP → {OMP decarboxylase} → UMP + CO2

55
Q

What is another way to see orotate?

A

Orotate = Uracil + COO-

*The COO- which prevents the base to diffuse out of the cell

56
Q

What reaction allows the synthesis of CTP?
(After pyrimidine de novo synthesis)

A

*At level of the triphosphates
- N from glutamine

UTP + Glutamine + ATP + H2O → {CTP synthetase} → CTP + Glutamate + ADP + Pi

*From UMP, → specific kinase → UDP → non-specific kinase → UTP

57
Q

What are the main ways of regulation of pyrimidine synthesis?

A

Animals → regulation at step 1
Bacteria → regulation at step 2 (ATCase)

Inhibition by pyrimidine nucleosides triphosphates (feedback)
Activation by ATP and PRPP (feedforward)

*ATCase → activated by ATP and inhibition CTP

58
Q

Why does ribonucleotide reductase use NADPH as a source of reduction?

A
  1. The direction of the enzyme reactions depends on the concentration of reactants
  2. [NADPH] > [NADP+] while [NADH] < [DNA+]
  3. Base-specific nucleotide kinases determine which nucleotide becomes diphosphates
  4. NADPH drives thioredoxin reduction
59
Q

X activates and Y inhibits ATCase in an allosteric manner. This happens at Z aspartate concentration.

A

ATP activates and CTP inhibits ATCase in an allosteric manner
This happens at LOW aspartate concentrations (al high aspartate concentrations, the enzyme is saturated no matter ATP or CTP concentrations)
*2nd step of pyrimidine de novo synthesis

60
Q

How many ATPs are used to make CMP from UMP?
What might be an advatange of using UTP to make CTP?

A

UMP → UDP → UTP → CTP → CDP → CMP
- Consumes 1 ATP for the amination of UTP → CTP
- The other ATPs are regained back on the other side

Advantage:
The cell has much higher levels of triphosphates that monophosphates (~50X) so the Km of the enzyme can much higher (no need for such high affinity)

61
Q

How can Uracil end up in DNA?
What is the main solution?

A

Formation of dUTP:
- Ribonucleotide reductase (at level of diphosphates) is not specific for the base
- Uridylate kinase (UMP/dUMP → UDP/dUDP) is not specific for ribose vs deoxyribose → nucleoside diphosphate kiase (non-specific for anything)
- dUTP can also come from deamination of dCTP

Solution:
1. dUTPase degrades dUTP → dUMP
2. dUMP is then converted to dTMP by thymidylate synthase (level of monophosphates)

62
Q

What is the role of thymidylate synthase?

A

It converts dUMP → dTMP
- Adds a methyl which comes from N5,N10-methylene tetrahydrofolate
- Not expected because methylene has 2Hs and has to give a methyl in its most reduced for (CH3) to Uracil → methylene is reduced to methyl in exchange with oxidation of THF → DHF (dyhydrofolate)

  • Important target for drugs against cancer and bacteria → essential for thymine synthesis (DNA)
  • Required for DNA synthesis, but not RNA
  • Synthesis at the level of monophosphates

(dUMP coming from dUTP which we don’t want)

63
Q

What is an inhibitor of deoxythymidylate synthase?

A
  1. Fluorodeoxyuridylate (FdUMP):
    dUMP the normal substrate + fluor group where the methyl must be added
    - Competitive inhibition (binds in the substrate binding site)
    - Suicide inhibitor → binds to the enzyme and “kills” its activity
  2. Methotrexate, Aminopterin, Trimethoprim inhibits DHF → THF (by DHF reductase)
    *Electron donor = NADPH
    - THF analogs
    - Competitive inhibitors
    - Anti-cancer and antibacterial by preventing them to synthesize DNA
64
Q

Which enzyme allows to regenerate THF to do thymidylate synthesis over and over?
What is the TS cycle?

A

Dihydrofolate reductase
- Thymidylate synthesis requires reduction of the methylene → methyl to add it to the uracil and make thymine
- This requires oxidation of THF → DHF
- It then has to be reduced back the THF → called TS cycle
- NADPH = electron source
In the next step, A new methylene group is added to THF from serine

Cycle = Thymidylate synthase (N5,N10-Methylene-THF → DHF) → Dihydrofolate reductase (DHF → THF) → Serine hydroxymethyl transferase (THF → N5,N10-methylene-THF)

65
Q

What are salvage pathway enzyme also has a role in de novo synthesis?

A

Conversion of base → to ribonucleotide: Phosphooryibosyl transferase
PRPP + base X → rNMP + PPi

66
Q

What are different roles of the salvage pathway enzymes?

A

Conversion of base → ribonucleotide (Phosphoribosyl transferase)
Interconversion of bases a nucleosides (Nucleoside phosphorylase)
Conversion of nucleoside → nucleotide (nucleoside kinase)
Base exchange into deoxynucleosides (nucleoside transglycosylase)
Interconversion by base alterations (deaminases)
Reutilization of nucleotides (nucleoside monophosphate kinase & nucleoside diphosphate kinase)*seen as part of de novo pathway

67
Q

What is the role of Hypoxanthine/guanine phosphoribosyl transferase?
What disease is related to LOF of HGPRT?

A

PRPP + Purine → Purine ribonucleotide + PPi
BASE → NUCLEOTIDE (jump 2 levels, Slavage pathway)
The Purine can be Hypoxanthine (→ Inosinate) or Guanine (→ Guanylate)
*genetic loss of HGPRT activity causes Lesch-Nyhan disease
*Other enzymes for adenine + uracil (purines, but not this enzyme)

68
Q

What causes Lesch-Nyhan disease?

A

It is a genetic disease caused by the loss of Hypoxanthine/Guanine phosphoribosyl transferase (HGPRT)
Symptoms: gout and mental retardation

69
Q

What enzymes of the Salvage pathway allows formation of nucleosides?

A
  • Nucleoside phosphorylase
  • Nucleoside transglycosylase (exchange bases)
    *These enzyme are substrate-specific to avoid making thymine ribonucleotides
70
Q

What reaction does nucleoside phosphorylase catalyze?

A

Ribonucleoside or deoxyribonucleoside (beta anomer) → Ribose 1-P or Deoxyribose 1-P (alpha anomer, until add another base by nucleoside phosphorylase)
*Not 5’ phosphate, but ribose + beta-base at 1’C

71
Q

What reactions do nucleoside tranglycosylase catalyze?

A

Switch from 1 base to another on a ribose
Deoxyadenosine → (Deoxyribose 1-P alpha anomer) → Deoxythymidine
*Nucleoside phosphorylase can catalyze the subreactions

72
Q

What are different reactions of the salvage pahtway?

A
  1. Mutase (Ribose 5-P ←→ Ribose 1-P)
  2. Deaminase
  3. Phosphorylase
  4. Transglcycosylase
  5. Kinase (adds 5’ phosphate ro ribose)
  6. Transferase
  7. PRPP synthetase (ribose-5P → ribose-5P-1PPi, consumes 1 ATP)
73
Q

What is the general mechanism for purine degradation?

A

Funel downwards: nucleotide (monophosphate) → nuceloside → base (Hypoxanthine, Guanine) → Xanthine → uric acid

74
Q

What is the pathway of AMP degradation (purine)?

A
  1. AMP → {AMP deaminase} → IMP → {nucelotidase} → Inosine → {purine nucleoside phosphorylase, release Ribose 1-P) → Hypoxanthine → {xanthine oxidase} → Xanthine → {xanthine oxidase} → Uric acid
  2. AMP → {nuleotidase} → Adenosine → Inosine → same
    *Can deaminate at the level of AMP or at level of the bases
75
Q

What is the consequence of a loss of adenosine deaminase?

A

Genetic disease SCID (severe combined immunodeficiencies)

76
Q

What enzyme is inhibited for gout treatment?

A

Xathine oxidase → by inhibiting it, we prevent build up of uric acid through purine degradation

77
Q

What is the general role of nucleotidases?

A

Catalyze nucleotides → nucleosides by hydrolysis of the phosphate

78
Q

What is Gout?

A

Depositions of uric acid in joints
- Painful, prevalent in males, middle ages
- Thought to be due to excess meat
- More likely kidney dysfunction

Symptomatic of metabolic imbalance → exccess de novo purine synthesis (can be due to high PRPP levels which are feedforward activators)

79
Q

What is the important of Uric acid?

A

How is it important for pigeons?
- It if the final degradation product of purines
- Allows elimination of nitrogen in birds → with conservation of water
*Purine de novo pathway discovered by studying pigeons

Uric acid is not soluble when protonated (at low pH) → birds lower their pH → uric acid precipitates → white paste is excreted

80
Q

How is nitrogen eliminated in different species?

A
  • Uric acid is secreted by birds and primates
  • Marine invertabrates secrete NH4+ → cheapest way (ATPwise), but requires a lot fo water
  • Elimination costs a lot of water
  • To not use too much water, birds keep lower pH → uric acid precipitates when protonated
81
Q

What is the pathway of pyrimidine degradation?

A

Funnel downward: Nucleotide → nucleoside → base → uracil (Thymine)
1. Deamidate to carbonyl
2. reduce ring

CMP → {nucleotidase} → Cytidine → {Cytidine deaminase, release NH4+} → Uridine → {Uridine phosphorylase} → Uracil → {dihydrouracil dehydrogenase} → Dihydrouracil
UMP (dTMP) → {nucleotidase} → uridine (deoxythymidine) → Uracil → {dihydrouracil dehydrogenase} → Dihydrouracil

*Phosphorylase dissociates the ribose from the base (base specific)

82
Q

Why do sulfonamides act as anti-bacterial drugs?

A
  1. They are structural analogues of PABA (part of THF)
  2. They do not affect human cells because we don’t do synthesis of folate, we get it from diet

BIOC 311 (14 decks)

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