Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Metabolic Pathways (BMSC 230) > Nucleotide Metabolism - General > Flashcards

Nucleotide Metabolism - General Flashcards

1
Q

Is there a dietary requirement for nucleic acids? Why?

A

There is essentially no dietary requirement for nucleic acids since we have the synthetic pathways to make as much of the building blocks for DNA and RNA as we need (PPP). We also have the ability to make all of the purines and pyrimidines that we need as well.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Nucleic acid digestion occurs in the _____

A

lumen of the small intestine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

The first thing that happens in nucleic acid digestion is that the nucleic acids are acted on by _____, which do what? What are the products from this reaction?

A

Nucleases, hydrolyze the phosphodiester bonds that connect the individual nucleotides together. The products of this enzymatic activity are monophosphate nucleotides.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Monophosphate nucleotides are then acted on by _____ to remove the phosphate groups, which produces _____, which are molecules that have a purine or pyrimidine molecule linked to a ribose or deoxyribose sugar.

A

Phosphatases, nucleosides

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

While some of the nucleosides are acted on by _____ which hydrolyze the linkage between the sugar and nitrogenous base, most of the nucleosides are absorbed into the _____

A

Nucleosidases, enterocyte (cells lining the small intestine)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

_____ are the major end-product of nucleic acid digestion

A

Nucleosides

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Only about ___% of the nucleosides that are absorbed are reutilized for nucleic acid synthesis, and ___% of this is used by the rapidly regenerating enterocytes. What happens to the rest of them?

A

5%, 25%. Most of the nucleosides are further degraded after being absorbed.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

All nucleotides consist of what 3 things?

A
  1. Nitrogenous base (adenine, guanine, cytosine, uracil (RNA) and thymine (DNA))
  2. Ribose (RNA) or deoxyribose (DNA) sugar
  3. One or more phosphate groups
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

How do deoxyribose and ribose differ?

A

These two sugars differ only in that ribose has an –OH group on carbon 2 while deoxyribose has an –H.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is the difference between nucleosides and nucleotides?

A

Nucleosides are similar to nucleotides except that they have no phosphate group

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Other than DNA and RNA, what are 4 other functions of nucleotides and nucleosides?

A
  1. The nucleotide ATP is the major currency of energy in biological systems
  2. Adenine-based nucleotides are components of three major coenzymes (NAD, FAD, CoA)
  3. Nucleotides are often linked to other biomolecules to form activated substrates (UDP-glucose vs glucose in glycogen synthesis)
  4. Some nucleotides and nucleosides are cellular and physiological regulators (cAMP, adenosine and it’s effect on the heart)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Why is UDP-glucose more reactive than regular glucose in glycogen synthesis?

A

UDP is a good leaving group, and thus facilitates the addition of glucose onto a growing glycogen chain. In fact, UDP is linked to most sugars regardless of the specific type when they are used in synthetic reactions.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What effect does adenosine have on the heart? Where is adenosine produced? How is adenosine used therapeutically?

A

It decreases the heart rate and reduces the force of contraction. It is naturally produced in the heart and serves to keep our heart rate in check. It is used therapeutically to treat specific types of tachycardia (rapid heart rate).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Purine-based nucleotides can be synthesized in cells by one of two different pathways, what are they?

A
  1. de novo Pathway: synthesized from “scratch”, using other molecules to donate the carbon and nitrogen atoms needed
  2. Salvage Pathway: salvages existing purine bases and converts them to nucleotides
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

In the de novo pathway, what is the overall strategy?

A

The overall strategy is to start with ribose-5-P, a pentose sugar, and then to build the purine ring on this sugar to form both purine nucleotides (AMP and GMP).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

The precursors that contribute atoms to the purine ring in the de novo pathway are these 5 things. What biomolecule is an important contributor?

A
  1. Glutamine
  2. Aspartate
  3. Glycine
  4. CO2
  5. Formate (carried by tetrahydrofolate)

Amino acids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Carbon 1 in ribose-5-P where the purine ring will be built in the de novo pathway is not very reactive. How is it made reactive?

A

To make it reactive, ATP is used to add a pyrophosphate group onto carbon 1, to form phosphoribosylpyrophosphate (PRPP).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

The first purine product of the de novo pathway is _____. What two nucleotides is this product a precursor of?

A

Inosine monophosphate (IMP). IMP is a purine which is the precursor for both AMP and GMP, which are formed by two pathways that branch from IMP.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

The GMP and AMP formed from IMP can be converted into what 4 nucleotides? What are these substrates for?

A
  1. ATP
  2. GTP
  3. dATP
  4. dGTP

These are substrates for RNA and DNA synthesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

The first and committed step of de novo synthesis is catalyzed by what enzyme? What does the enzyme do?

A

Glutamine-PRPP amidotransferase, initiates the assembly of the purine ring on the ribose sugar by transferring an amino group from glutamine onto the ribose sugar.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

The remaining steps of the de novo pathway that lead to the synthesis of IMP incorporate atoms from what 5 things? What is required for this?

A
  1. Glycine
  2. Another glutamine
  3. Aspartate
  4. CO2
  5. N10-formyl-tetrahydrofolate.

ATP is required

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Once IMP has been synthesized in the de novo pathway, what happens to it?

A

it can either be used for AMP synthesis or for GMP synthesis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

For IMP to be converted to AMP, what must happen? What provides the energy for this reaction?

A

To form AMP, a molecule of aspartate is used as a donor of an amino group. GTP hydrolysis is used to provide energy to drive the reaction forward.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

In the conversion of GTP to AMP in the de novo pathway, why is GTP hydrolyzed rather than ATP?

A

This branch of the pathway is used to synthesize AMP and is responding to signals in the cell that more adenine-based nucleotides, most likely ATP, is in short supply. The last thing we would want to do is to use up a molecule of ATP to produce a molecule of AMP. So instead, GTP is used.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

For IMP to be converted to GMP from the de novo pathway, what donates an amino group? What is used to provide energy for this reaction?

A

Glutamine donates an amino group to the ring rather than aspartate. ATP rather than GTP is used as a provider of energy (makes sense; why consume a molecule of GTP to make a molecule of GMP?)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What enzyme in the de novo pathway is regulated primarily and by what 3 things? What kinds of inhibition are involved?

A

Allosteric inhibition of glutamine-PRPP amidotransferase by end products of the pathway:

  1. IMP
  2. AMP
  3. GMP

Two types of feedback inhibition:

  1. Concerted inhibition by the three end products.
  2. Sequential inhibition that occurs when AMP or GMP inhibit the first committed step in the branch of their specific pathway, which causes IMP to build up and inhibit glutamine-PRPP amidotransferase.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

The Salvage Pathway involves the chemical joining of _____ that are generated in the cell during normal turnover and degradation of nucleic acids and nucleotides.

A

Free purine bases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

The purines that are salvaged in the salvage pathway are these 3:

A
  1. Adenine
  2. Guanine
  3. Hypoxanthine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Hypoxanthine results from what?

A

The deamination of adenine that occurs naturally and quite frequently in the cell.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

Carbon 1 on ribose 5-P is not very reactive in the salvage pathway; instead, _____ is used as the activated form to which purines are attached to the sugar.

A

Phosphoribosylpyrophosphate (PRPP)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What two enzymes use PRPP as the activated form to which purines are attached to ribose-5-P in the salvage pathway?

A
  1. Adenine phosphoribosyltransferase (APRT) catalyzes the attachment of adenine to PRPP, with the release of PPi which drives the reaction forward, to form AMP (minor pathway in cells, since much of the free adenine is deaminated to hypoxanthine)
  2. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) uses hypoxanthine and guanine that are linked to PPRP by the enzyme to form IMP and GMP respectively
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

_____ is the major enzyme responsible for the salvaging of purines in the cell

A

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What is Lesch-Nyhan Syndrome caused by? Where is this gene located? What does this mean for who is primarily effected?

A

An inherited mutation in the gene coding for HGPRT, which greatly reduces its activity. The gene is located on the X chromosome, so it is primarily males that are affected.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

What is the biochemical consequence of Lesch-Nyhan Syndrome? How does the body work around this, and what are the results of these two factors?

A

The biochemical consequence of this syndrome is that the salvage pathway is greatly impaired. Thus, in order to provide sufficient purines for the needs of the cell, the purine de novo synthesis pathway increases; Here’s how:

  • PRPP levels increase because less is consumed in the salvage pathway, providing more substrate for Gln-PRPP amidotransferase, which increases flux through the de novo pathway.
  • GMP and IMP levels drop due to the deficiency in HGPRT; reducing the allosteric inhibition on the de novo pathway.

These two factors result in high rates of de novo purine synthesis.

35
Q

What are the symptoms of Lesch-Nyhan syndrome? What is this caused by?

A

Severe neurological defects, including motor dysfunction, mental retardation, hostility, and compulsive self-mutilation, as well as gout. High levels of uric acid lead to gout, but the basis for the neurological effects is not well understood.

36
Q

Gout is caused by an elevation in _____, which is a product of what process?

A

Uric acid, purine degradation product

37
Q

Describe the 3 parts of purine degradation and what two ways this can lead to gout.

A
  1. Purine nucleotides are degraded by first removing the phosphate from AMP and GMP, forming the corresponding nucleosides.
  2. Adenosine is deaminated to inosine, then both inosine and guanosine have their ribose cleaved off through a hydrolytic reaction; this forms the purine bases guanine and hypoxanthine.
  3. Both of these are metabolized to xanthine, and finally to uric acid (urate is the sodium salt of this acid).

When concentrations of uric acid get too high in the blood, which can occur from overproduction or under-excretion of purines, uric acid crystallizes and deposits in joints and causes pain and inflammation; this condition is known as gout

38
Q

What two ways can gout be treated?

A
  1. Treatment of gout usually includes some dietary restrictions such as limiting consumption of meats and beer. Meat is very cellular, and thus contains high amounts of DNA and RNA which provide large amounts of purines; beer is also very high in purines (often insufficient by itself)
  2. Allopurinol is a substrate analog of hypoxanthine, and acts as an inhibitor of xanthine oxidase, the enzyme that produces uric acid in the degradative pathway
39
Q

The pyrimidines that are required in the cell (uracil, cytosine and thymine) are all made _____. What does this mean?

A

de novo. It means there is very little salvaging of pyrimidines that are obtained through the diet or that are released as free pyrimidines when nucleotides are degraded

40
Q

While purines are synthesized onto a ribose sugar, pyrimidines are _____.

A

Assembled separately and then added onto the ribose ring after the pyrimidine has been synthesized

41
Q

What 3 molecules provide all of the atoms needed for the synthesis of the pyrimidine ring?

A
  1. Glutamine
  2. CO2
  3. Aspartate
42
Q

_____ are needed in order to synthesize all three pyrimidines required.

A

Additional small modifications

43
Q

The first and rate-limiting step in pyrimidine synthesis is catalyzed by _____. What does the enzyme do? What molecule drives the reaction forward?

A

Carbamoyl phosphate synthetase II (CPS II). This enzyme essentially fuses the amino group from glutamine to CO2 (in the form of HCO3-) and a phosphate from ATP to form carbamoyl phosphate. The energy released from the hydrolysis of ATP drives this reaction forward.

44
Q

CPS I is used in the urea cycle and CPS II is used in pyrimidine synthesis. What are the differences and similarities?

A

Differences:

  1. Substrates
  2. Subcellular location → mitochondrial matrix (I), cytosol (II)
  3. Regulatory effectors →
    • I → + N-acetylGlu, arginine
    • II → + ATP, PRPP, - UTP
  4. Nitrogen donor → NH4+ (I), glutamine (II)

Similarities:

  1. Products → carbamoyl phosphate
45
Q

What is the first molecule formed in CTP synthesis? What subsequently happens to this molecule? What is produced?

A

The first pyrimidine-like molecule formed is orotate; this is subsequently attached to a ribose ring using PRPP as the activated form of ribose. This produces orotidylate.

46
Q

Once orotidylate has been formed, what happens to it and what is then formed?

A

It undergoes a decarboxylation to form uridylate (UMP), which in turn is phosphorylated twice with 2ATP to form UTP.

47
Q

Once UTP is formed, what happens to it? What acts as the amino group donor?

A

UTP is converted to CTP using glutamine as an amino group donor.

48
Q

The first committed step in pyrimidine synthesis is catalyzed by _____.

A

Aspartate transcarbamoylase (ATCase).

49
Q

Aspartate transcarbamoylase (ATCase) is allosterically inhibited by what?

A

CTP, the final product of this pathway.

50
Q

Nucleoside monophosphates (NMP’s) are converted to nucleoside diphosphates (NDPs) by which enzymes? What do they use as a phosphate group donor?

A

Nucleoside monophosphate kinases, which use ATP as the source of the phosphate group.

51
Q

Each nucleoside monophosphate kinase is _____ for which base is in the NMP. Knowing this, what would the enzyme that catalyzes the conversion from GMP to GDP be called?

A

​Specific. The enzyme that catalyzes the conversion of GMP to GDP is called guanylate kinase.

52
Q

Are the nucleoside monophosphate kinases specific to the sugar?

A

No.

53
Q

The nucleoside diphosphate produced by the nucleoside monophosphate kinases are next acted on by which enzyme? How many types are there? What is used as the phosphate donor?

A

Nucleoside diphosphate kinase. One type. ATP is the phosphate donor.

54
Q

Where does the ATP that converts NMPs → NDPs → NTPs come from?

A

It is derived primarily from oxidative phosphorylation in the mitochondria, although some ATP is produced in glycolysis via substrate-level phosphorylation.

55
Q

Deoxyribonucleotides are synthesized from _____ by a _____ reaction carried out by the enzyme _____.

A

Nucleoside diphosphate molecules (NDPs), reduction, ribonucleotide reductase

56
Q

What are the 4 substrates for ribonucleotide reductase? How are these substrates altered by the enzyme?

A

The substrates for this enzyme are ADP, GDP, CDP, and UDP. The 2’-OH position of the ribose ring becomes reduced to a hydrogen group to form deoxyribose

57
Q

How does ribonucleotide reductase provide the reducing equivalents for the reaction?

A

The enzyme itself provides the reducing equivalents through two cysteine residues and becomes oxidized as a result.

58
Q

After ribonucleotide reductase has acted, how is it regenerated?

A

After the reaction, the reduced form of the enzyme is regenerated using NADPH and a series of electron carriers.

59
Q

The ultimate source of reducing equivalents for the synthesis of deoxyribonucleotides comes from _____, which is produced in the _____.

A

NADPH, pentose phosphate pathway

60
Q

What are the 5 steps of how the reducing equivalents from NADPH are transferred to ribonucleotide reductase?

A
  1. NADPH initially reduces FAD to FADH2 which is a coenzyme for thioredoxin reductase.
  2. FADH2 is used to reduce a disulfide bond in the enzyme so that two free sulfhydryl groups (-SH) are produced.
  3. The reducing equivalents from these two sulfhydryl groups are used to reduce a disulfide bond in thioredoxin, which in turn are used to reduce a disulfide bond in ribonucleotide reductase.
  4. When the reduced form of ribonucleotide reductase passes its reducing equivalents to a ribose unit, deoxyribose results.
  5. The oxidized form of ribonucleotide reductase is converted back to the active reduced form by more NADPH.
61
Q

Ribonucleotide reductase is a (symmetrical/asymmetrical), (single/multi)-subunit enzyme that is allosterically regulated in a unique fashion.

A
62
Q

The two R1 subunits of ribonucleotide reductase each have what two sites? What is the third site of the enzyme and what is it formed by?

A
  1. Primary regulation site
  2. Substrate specificity site

A third site is the active site, which is a pocket formed when the R1 and R2 subunits come together.

63
Q

The primary regulation site of ribonucleotide reductase is bound by _____ and _____. How do each of these effect the enzyme?

A

ATP (activates), dATP (deactivates)

64
Q

The cell might need more of one than the other at any given time, so there must be some way to adjust the substrate binding activity of ribonucleotide reductase. What does this job and how?

A

The substrate specificity site, which can bind ATP, dATP, dGTP, and dTTP. Depending on which of these bind to the site, the substrate specificity of the active site is altered.

65
Q

When dTTP binds to the substrate specificity site of ribonucleotide reductase, _____ is the favoured substrate.

A

GDP

66
Q

Through the use of the _____ site and _____ site, the proper balance of deoxyribonucleotides is obtained.

A

Regulation, substrate specificity

67
Q

Thymine nucleotides are derived from _____ and _____, which can be converted to _____ and _____ by which enzyme?

A

CDP and UDP, dCDP and dUDP by ribonucleotide reductase

68
Q

dCDP and dUDP can then be phosphorylated using _____ to form _____ and _____. _____ can be used straight away in DNA synthesis, but some of it can also undergo deamination to produce _____.

A

ATP, dCTP and dUTP. dCTP, dUTP.

69
Q

dUTP can be converted to dUMP through what mechanism? Why is this an important step?

A

By hydrolysis of two of the three phosphate groups. It is only dUMP which is a substrate for the enzyme thymidylate synthase.

70
Q

If you compare the structures of uracil and thymine, you will note that they are almost identical with the exception of what?

A

Thymine has a methyl group on carbon 5 of the pyrimidine ring.

71
Q

The reaction catalyzed by thymidylate synthase is a _____ reaction.

A

methylation

72
Q

Methyl groups are donated in the thymidylate synthase reaction by which molecule? When this molecule donates it’s methyl group, what is produced?

A

In the case of thymidylate synthase, a specific form of tetrahydrofolate is used called N5,N10-methylene-tetrahydrofolate. Dihydrofolate is produced.

73
Q

In order for dihydrofolate to be reutilized, what must happen? What enzyme catalyzes this? What is produced in this reaction and what subsequently happens to it?

A

it needs to be reduced to tetrahydrofolate using NADPH. This is catalyzed by dihydrofolate reductase. The dTMP produced by this reaction is subsequently converted to dTTP.

74
Q

What is dTTP the substrate for? It is produced from dNTP by the sequential action of what two enzymes?

A

The substrate for DNA polymerases, by the sequential action of a nucleoside monophosphate kinase followed by nucleoside diphosphate kinase

75
Q

Herpes simplex and herpes zoster both have an enzyme called _____, which humans have as well, which is responsible for converting the nucleoside thymidine to dTMP, and then eventually to dTTP.

A

thymidine kinase

76
Q

What is a key difference between the thymidine kinase enzyme in herpes virus and in humans? What drug does this difference take advantage of?

A

The enzyme in herpes virus has significantly less stringent substrate specificity, and will use other somewhat similar molecules, unlike the human enzyme.

Acyclovir

77
Q

The structure of Acyclovir is similar to a _____, and because of its loose specificity, viral thymidine kinase phosphorylates it and it becomes converted to a _____ form. The herpes virus then does what with this form?

A

Purine, triphosphate. The virus incorporates the drug into its growing DNA as it is trying to copy its DNA to produce more viruses.

78
Q

When herpes adds Acyclovir to its genome what happens? Why?

A

Acyclovir causes viral DNA synthesis to come to a complete stop and thus halts the infection cycle and the production of new virus. This is because there is no ribose ring on it, so no more nucleotides can be added to it.

79
Q

HIV is a retrovirus, and thus has a RNA genome which it uses as a template to produce a double-stranded DNA copy using the enzyme _____. This enzyme has a very _____ substrate specificity.

A

Reverse transcriptase. Loose.

80
Q

What drug is used to treat HIV? How?

A

Zidovudine, a thymine-based nucleotide analog, which like Acyclovir in herpes also cause termination of DNA synthesis because no more nucleotides can be added to it

81
Q

A well-established feature of cancers is _____. What does this require?

A

Uncontrolled cell proliferation. This requires massive amounts of DNA to be produced, and thus lots of purine and pyrimidine nucleotides.

82
Q

Because _____ is specific for DNA, its synthesis in particular has been a popular target for the development of cancer therapeutics

A

Thymine

83
Q

What enzymes are the two targets of anti-cancer drugs? What drug(s) is primarily used for each and how does it work?

A
  1. Thymidylate synthase
    • 5-fluorouracil (similar structure to dUMP, the normal substrate for thymidylate synthase) binds to the enzyme and inactivates it, which blocks the production of thymine-based nucleotides and thus slows DNA synthesis dramatically.
  2. Dihydrofolate reductase
    • ​​Methotrexate,aminopterin, andtrimethoprim are all structural analogues of dihydrofolate and inhibit the dihydrofolate reductase when they bind the enzyme.
84
Q
A

Metabolic Pathways (BMSC 230) (19 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions