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Biochemistry & Molecular Biology > L33-34: Nucleotide Metabolism I-II > Flashcards

L33-34: Nucleotide Metabolism I-II Flashcards

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1
Q

What are purines? Pyrimidines? Nucleosides? Nucleotides?

A
  • Purines = double-ringed structures = adenine and guanine, also hypoxanthine, xanthine, inosine - Pyrimidines = single-ringed structures = uridine, cytosine and thymine - Nucleosides = base (purine, pyrmidine) with sugar (oxy or deoxy) - Nucleotide = base, sugar and phosphate
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2
Q

Describe de novo synthesis of purines

A
  • PRPP = 5 phosphoribosyl 1 pyrophosphate - Ribose 5 phosphate + ATP = PRPP (ez: PRPP synthetase) - PRPP + gln = PRA (phosphoribosylamine) + PPi (ez: amidophosphoribosyltransferase) - 9 step process to convert PRA to IMP (4 reactions require ATP, C and N donated from gly, gln, asp, CO2 and N10-formyl THF). IMP = inosine monophosphate - IMP precursor for AMP and GMP via following rxns: - IMP + Asp + GTP = adenylosuccinate + GDP + Pi (ez: adenylosuccinate synthetase) - Adenylosuccinate = AMP + fumarate (ez: adenylosuccinase) - IMP + NAD = xanthosine5monophosphate (ez: IMP dehydrogenase) - XMP + Gln + ATP = GMP + glu + AMP (ez: GMP synthase) - Specific Nucleoside monophosphate kinases (convert XMP to XDP) and diphosphate kinases (XDP to XTP)
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3
Q

From what compound is PRPP synthesized? What enzyme catalyzes this reaction

A
  • Ribose 5 phosphate - Ez: PRPP synthetase
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4
Q

What enzyme catalyzes the committed step of purine synthesis and what is its product?

A
  • Formation of PRA is committed step of purine synthesis - PRPP + gln = PRA + glu (ez: amidophosphoribosyltransferase)
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5
Q

In general, where doe Cs and Ns of purine ring come from?

A
  • Amino acids - CO2 - N10-formyl THF
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6
Q

How much ATP input is required to synthesize IMP?

A
  • 6
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7
Q

Describe allosteric regulation of purine synthesis: what enzymes are regulated? Which allosteric modulators are responsible for this regulation?

A
  • PRPP synthetase (inhibited by ADP and GDP) - Amidophosphoribosyltransferase (inhibited by AMP, GMP; activated by PRPP) - Adenylosuccinate synthetase (inhibited by AMP) - IMP dehydrogenase (inhibited by GMP)
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8
Q

Roles of nucleoside 5 monophosphate and nucleoside disphosphate kinases?

A
  • Nucleoside 5 monophophate kinases: XMP + XTP = 2 XDP - Nucleoside disphosphate kinases: XDP + XTP = XTP + XDP
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9
Q

Organ responsible for purine nucleotide degradation

A
  • LIver
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10
Q

Describe degradation of GMP vs degradation of AMP to their constituent parts

A
  • General theme is to remove phosphate, then ribose, leaving you with base a.) GMP: - GMP = Guanosine + Pi (ez: 5-nucleotidase) - Guanosine + Pi = Guanine + Ribose-1-P (ez: purine nucleoside phosphorylase) b.) AMP pathway 1: - AMP = IMP + NH4+ (ez: AMP deaminase) - IMP = Inosine + Pi (ez: 5-nucleotidase) - Insoine + Pi = hypoxanthine + Ribose-1-P (ez: purine nucleoside phosphorylase) c.) AMP pathway 2: - AMP = Adenosine + Pi (ez: 5-nucleotidase) - Adenosine = inosine + NH4+ (ez: adenosine deaminase) - Insoine + Pi = hypoxanthine + Ribose-1-P (ez: purine nucleoside phosphorylase)
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11
Q

Describe degradation of bases?

A
  • Hypoxanthine + o2 = xanthine + H2o2 (ez: xanthine oxidase) - Guanine + H2o = xanthine + NH4+ (ez: guanine deaminase) - Xanthine + o2 = uric acid + H2o2 (ez: xanthine oxidase) - Uric acid eliminated in urine
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12
Q

Why does accumulation of uric acid lead to development of gout and kidney stones?

A
  • Uric acid is normally excreted in urine - It and salts have limited solubility, they are typically close to saturation in normal healthy individuals. Common salt = sodium urate - Deposition of sodium urate in kidney = kidney stone - Deposition of sodium urate in joints = gout (triggers inflammatory response)
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13
Q

Mechanism by which allopurinol reduces uric acid levels

A
  • Allopurinol and its metabolite oxypurinol (made by xanthine oxidase) are analogs of hypoxanthine - They inhibit xanthine oxidase and reduce uric acid formation - Intermediates such as hypoxanthine and xanthine are more soluble than uric acid and are eliminated in urine
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14
Q

Describe de novo synthesis of pyrimidines

A

1.) Synthesis of uridine nucleotides (three* enzymes below are part of CAD multifunctional protein) - Gln + bicarb + ATP = carbomyl phosphate + ADP + glu (ez: *carbomyl phosphate synthetase II) - Carbomyl phosphate + Asp = N-carbamoyl aspartate + Pi (ez: *asp transcarbamoylase) - N-carbamoyl aspartate = dihydroorotate (ez: *dihydroorotase) - Dihydroorotate + NAD = orotate + NADH (ez: dihydroorotate DH) - Orotate + PRPP = OMP + Pi (ez: ^orotate phosphoribosyltransferase) - OMP = UMP + Co2 (ez: ^OMP decarboxylase) Notes: three beginning ezs are part of *CAD multifunctional enzyme, last two are part of ^UMP synthase multifunctional enzyme 2.) Synthesis of cytosine nucleotides - UMP is converted to UTP via nucleoside-5-monophosphate kinases and nucleoside diphosphate kinases - UTP + glut + ATP = CTP + gln + ADP + Pi (ez: CTP synthase) 3.) Synthesis thymine nucleotides - Note: TMP, TDP or TTP are never synthesized (never get ribose forms), only make dTMP, dTDP and dTTP - dUMP + N5,N10-methylene THF = dTMP + THF

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15
Q

What is the clinical correlation of deficiency in uridine nucleotide synthesis?

A
  • UMP synthase mutation = orotic aciduria - Crystalluria, hypochromic megaloblastic anemia, growth retardation, neurologic abnormalities - Anemia is unresponsive to B12 and folic acid - Treatment with uridine
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16
Q

Describe orotic aciduria

A
  • Rare hereditary condition resulting in UMP synthase mutation - Crystalluria, hypochromic megaloblastic anemia, growth retardation, neurologic abnormalities - Anemia is unresponsive to B12 and folic acid - Treatment with uridine
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17
Q

Distinguish between carbomyl phosphate synthetase I and carbomyl phosphate synthetase II? Clarify what their substrates are and where each activity is found in the cell?

A

1.) CPS I: - Found in mitochondria of liver, synthesizes carbomyl phosphate for urea cycle - Substrates: bicarb, 2ATP, ammonium; Products: carbomyl phosphate, ADP, phosphate 2.) CPS II: - Found in cytosol of liver, synthesizes UMP - Substrates: bicarb, 2ATP, gln; Products: carbomyl phosphate, ADP, glu

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18
Q

How does thymine nucleotide synthesis differ from the other pyrimidines?

A
  • Only make deoxyribose nucleotide forms
19
Q

Regulation of pyrimidine synthesis

A

1.) UTP and CTP - Carbomyl phosphate synthetase II (inhibited by UTP, activated by PRPP) - CTP synthase (inhibited by CTP, activated by UTP) 2.) dTTP - thymidylate synthase (unknown)

20
Q

How are ribonucleotides converted into deoxyribonucleotides?

A
  • Ribonucleotides must be in diphosphate form - Enzymes needed : ribonucleotide reductase and thioredoxin reductase. - Cofactors: thioredoxin - Thioredoxin reductase uses NADPH to generate reduced thioredoxin for another rxn to occur
21
Q

Regulation of ribonucleotide reductase

A
  • Allosteric: NTPs and dNTPs activate and inhibit (dATP inhibits) - Transcriptional
22
Q

Why does the drug hydroxyurea block cell proliferation?

A
  • Inhibits ribonucleotide reductase and prevents dNTP synthesis, blocking cell division
23
Q

What is SCID? Causes?

A
  • Group of immune disorders impacting B and T cell proliferation - ~15% of cases due to adenosine deaminase (in degradation of AMP) where adenine metabolites build up - Model: accumulation of dATP inhibits ribonucleotide reductase blocking DNA replication and preventing proliferation OR adenine metabolites are toxic to lymphocytes
24
Q

What inhibits thymidylate synthase?

A
  • 5-fluorouracil - Methotrexate
25
Q

How does 5-fluorouracil function?

A
  • Inhibits thymidylate synthase, which blocks de novo dTMP synthesis, ultimately blocking cell proliferation - It is converted into FUMP by phosphoribosyltransferase in the cell - FUMP is phosphorylated by a kinase and converted into FUDP/FUTP - Ribonucleotide reductase converts it into FdUDP, with kinase converting it into FdUTP - FdUTP can be incorporated into DNA - FUTP can be incorporated into RNA - Biggest effect is FdUDP is acted on by phosphatase and product, FdUMP, inhibits thymidylate synthase
26
Q

What are the products of UMP, CMP, dCMP and dTMP degradation?

A
  • UMP, CMP, dCMP: beta-alanine (beta-amino acid) - dTMP: beta-aminoisobutyrate
27
Q

What are the products of pyrimidine degradation? How are these secreted?

A
  • Beta-alanine and beta-aminoisobutyrate - Water soluble and eliminated in urine
28
Q

Which pyrimidine degradation product is unique to pyrimidine metabolism? How is this important?

A
  • Beta-aminoisobutyrate - Found in urine of cancer pts undergoing radiation or chemotherapy
29
Q

How does methotrexate function to inhibit thymidylate synthase?

A
  • Methotrexate is an antifolate medication - Remember, N5-N10-methylene THF is needed to convert dUMP to dTMP
30
Q

What is meant by term ‘salvage pathways’? What are the sources of substrates for these pathways?

A
  • Conversion of free bases and nucleosides to nucleotides - Sources are: diet, purine/pyrmidine nt degradation products
31
Q

What happens to DNA and RNA from food we ingest?

A
  • DNA and RNA are acted on by pancreatic nucleases in small intestine - Free nucleotides are acted on by phosphatases - Free nucleosides are taken up by intestinal epithelial cells and mostly metabolized by them - Some free bases and nucleosides circulate in blood - Trafficked to tissues in RBCs
32
Q

Where do salvage reactions occur?

A
  • In liver
33
Q

Outline salvage of purine bases

A
  • Hypoxanthine + guanine + PRPP = IMP / GMP (ez: HGPRtase) - Adenine + PRPP = AMP (ez: APRtase)
34
Q

Outline salvage of purine nucleosides

A
  • Adenosine + ATP = AMP + ADP (ez: adenosine kinase) - No salvage of guanosine
35
Q

Role of HGPRtase?

A
  • Hypoxanthine + guanine + PRPP = IMP / GMP
36
Q

Role of APRtase?

A
  • Adenine + PRPP = AMP
37
Q

Regulation of purine salvage?

A
  • PRPP consumed by HGPRtase and APRtase - Less available for amidophosphoribosyltransfer, therefore less PRA formed therefore less de novo synthesis
38
Q

Which is the only purine nucleoside that can be salvaged to a nucleotide?

A
  • Adenosine
39
Q

What is Lesch-Nyan syndrome?

A
  • Hereditary syndrome with severe or complete deficiency of HGPRtase activity - Hyperuricemia, uric acid stones, intellectual disability and self-injurious behavior
40
Q

Outline salvage of pyrimidine bases

A
  • Orotate/uracil and thymine + PRPP = XMP + PPi (ez: pyrmidine phosphoribosyltransferase) - No cytosine salvage
41
Q

What pyrimidine bases cannot be salvaged?

A
  • Cytosine
42
Q

Implication of pyrimidine salvage pathway?

A
  • PRPP consumptions means less PRPP available to stimulate CPS II, orotate phosphoribosyltransferase, therefore de novo pyrmidine synthesis is decreased
43
Q

Outline salvage of pyrimidine nucleosides.

A
  • Uridine / cytidine + ATP = UMP / CMP + ADP (ez: uridine-cytidine kinase)
44
Q

What is flucytosine?

A
  • Antifungal agent. It is an analog of cytosine. - Flucytosine = 5 FU (ez: cytosine deaminase) - 5FU becomes FUMP and inhibits thymidylate synthase in fungi. Humans don’t have cytosine deaminase, so don’t make 5FU or FUMP

Biochemistry & Molecular Biology (47 decks)

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