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Molecules to Cells > Nucleotide Metabolism 8.24 > Flashcards

Nucleotide Metabolism 8.24 Flashcards

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Organic Chemistry 101 flashcards
1
Q

differentiate between a free base, nucleoside, and nucleotide

A

free base - just the purine or pyrimadine base
nucleoside - base and pentose sugar
nucleotide - base, pentose sugar, and phosphate group

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2
Q

describe nitrogenous base numbering

A
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3
Q

name the positions at which purines differ

name the positions at which pyrimadines

A
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4
Q

Where is the glycosidic linkage formed in nucleotides

A

for purines - 9’ Nitrogen

for pyrimadines - 1’ Nitrogen

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5
Q

Describe the naming of purine and pyrimidine nucleotide derivatives

A
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6
Q

Give the structure of PRPP (phosphoribosylpyrophosphate)

A
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7
Q

Describe the linear synthesis portion of purine de novo synthesis

Note donation order/sources, energy requirements, points of regulation and how they are regulated

A

ribose-5-phosphate to inosine-5-phosphate

ribose-5-phosphate -> PRPP via PRPP synthetase

PRPP -> phosphoribosylamine via ATase = committed step and rate limiting step - allostericaly controlled - high [purine nucleotides] closes dimer - high [PRPP] opens dimer

donation order: 9’N glutamine -> 4’C, 5’C, 7’N glycine -> 8’C formyl -> 3’N glutamine -> 6’ CO2 -> 1’N aspartate -> 2’C formyl

10 steps, 5 ATP

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8
Q

Describe the branch point synthesis portion of purine de novo synthesis

Note important points of regulation and how they are regulated

A

IMP ends up as G-nucleotides or A-nucleotides

A-nucleotide pathway – (IMP->Adenylosuccinate via adenylosuccinate synthetase)(Adenylosuccinate->AMP via adenylosuccinate lyase)(AMP->ADP via adenylate kinase)(ADP->ATP via nucleoside diphosphate kinase) - high [AMP] downregulates adenylosuccinate synthetase

G-nucleotide pathway – (IMP->XMP via IMP dehydrogenase)(XMP->GMP via GMP synthase)(GMP->GDP via guanylate kinase)(GDP->GTP via nucleoside diphosphate kinase) - high [GMP] downregulates IMP dehydrogenase

cross-regulation - high ATP upregulates GMP synthase - high GTP upregulates adenylosuccinate synthetase

monophosphate->diphosphate is base specific

high [purine nucleotides] downregulates both ATase and PRPP synthetase in linear synthesis pathway

diphosphate->triphosphate has broad specificity

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9
Q

describe steady state behavior of adenylate kinase

A

maintains a specific ratio of A-nucleotides

100X ATP, 10X ADP, 1X AMP

this is important for maintaining the metabolic capability of the body

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10
Q

summary of Purine de novo synthesis

A
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11
Q

summary of purine degredation and excretion

A

three steps - dephosphorylation, deamination, phosphorolysis (removal of sugar)

AMP
option 1: (AMP->Adenosine via nucleotidase)(Adenosine->Inosine via adenosine deaminase)(Inosine->Hypoxanthine via purine nucleoside phosphorylase)(hypoxanthine-> xanthine via xanthine oxidase or xanthine dehydrogenase)(xanthine->uric acid via xanthine or xanthine dehydrogenase)
option 2: (AMP->IMP via AMP deaminase)(IMP->Inosine via nucleotidase)(Inosine->Hypoxanthine via purine nucleoside phosphorylase)(hypoxanthine-> xanthine via xanthine oxidase or xanthine dehydrogenase)(xanthine->uric acid via xanthine or xanthine dehydrogenase)

GMP
(GMP->Guanosine via nucleotidase)(Guanosine->Guanine via purine nucleotide phosphorylase)(Guanine->Xanthine via Guanase)(Xanthine-Uric acid via xanthine oxidase or xanthine dehydrogenase)

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12
Q

Xanthine dehydrogenase vs Xanthine Oxidase

A

Xanthine dehydrogenase is converted to Xanthine oxidase in low oxygen environment

XDH uses NAD+ as electron acceptor

XO uses water as electron acceptor (produces H2O2 in the process) - can be harmful - in heart attack, low O2 in heart muscle can lead to XO buildup. When O2 is restored, free radicals can be produced

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13
Q

Describe the purine salvage pathway for free bases and nucleosides

A

free base - requires PRPP
Adenine+PRPP = AMP+PPi via adenine phosphoribosyltransferase (APRT)
Guanine+PRPP = GMP+PPi via hypoxanthine-guanine phosphoribosyltransferase (HPRT)
Hypoxanthine+PRPP = IMP+PPi via HPRT

nucleoside - requires ATP
Adenosine+ATP = AMP+ADP via adenosine kinase
guanosine+ATP = GMP+ADP via guanosine kinase

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14
Q

Summary of the purine pathways

A
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15
Q

function of adensine in the heart

A

coronary vasodilator

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16
Q

function of IMP in exercise

A

IMP is converted to ATP after exercise

17
Q

How is the purine pathway relevant to Lesch-Nyhan Syndrome

A

HPRT deficiency = deficient salvage system during DNA processing heavy periods of development - lack of allosteric inhibition of PRPP synthase and ATase leads to higher de novo-purine synthesis and purine metabolites

X-linked and thus affects mostly men, characterized by gout (high uric acid) and serious neurological complications

18
Q

What is xanthinuria

A

loss of XDH function leading to xanthine buildup

19
Q

How is severe combined immunodeficiency (SCID) related to purine pathways

A

deficiency of adenosine deaminase (ADA) and/or purine nucleoside phosphorylase (PNP) lead to T-cell dysfunction

loss of function in these enzymes results in adenosine and guanosine buildup which causes them to be salvaged and turned into dATP and dGTP - this then inhibits ribonucleotide reductase (RR) from producing other deoxy nucleotides

20
Q

How does gout arise? how is it treated

A

uric acid is the least soluble purine base - sits near saturation level at normal

gout is due to overproduction or underexcretion of uric acid which results in crystallization

Causes of primary gout (inherited): high [PRPP synthetase], low [HPRT], problem with renal urate transport protein

Causes of secondary gout (acquired): drug intake or diet

Treat by inhibiting XDH (side effect is that ATase function drops, XDH inhibition causes creater salvage of Guanine and thus makes more nucleotides which inhibit ATase)

21
Q

Describe de novo pyrimidine synthesis

note donors/positions, major enzymes and regulatory steps

A

Glutamine/HCO2 -> UMP

3’N Glutamine and 2’C CO2 -> 4’C, 5’C, 6’C, 1’N Aspartate

6 steps, 5 ATP

Carbamoyl-phosphate synthetase, Aspartate transcarbamoylase, and dihydro-orotase are located on one protein (CAD) and form the ring (steps 1-3) - rate limiting step - regulated allosterically and through phosphorylation

Dihydro-orotate dehydrogenase (DHODH) step 4

UMP synthase (step 5-6)

22
Q

describe synthesis of other pyrimidine nucleotides from UMP

A

must first convert UMP to either UDP or UTP

UMP + ATP = UDP + ADP via pyrimidine monophosphate kinase - high specificity
UDP + ATP = UTP + ADP via nucleoside diphosphate kinase (broad specificity)

UTP -> CTP via CTP synthetase

23
Q

describe pyrimidine catabolism

A

similar to purine catabolism (three phases) - dephosphorylation (nucleotidase), deamination (deaminase), phosphorolysis (phosphorylase)

24
Q

describe catabolism of uracil and thymine

A

each uses the same three enzymes - end products are amino acids

uracil -> alanine

thymine ->aminoisobutyrate

25
Q

describe pyrimidine salvage

A

occurs mainly at the nucleoside level (as opposed to purines where salvage is mostly at the free base level)

enzymes are base specific

26
Q

what is orotic aciduria? how is it related to the pyrimidine pathway? how is it treated?

A

UMP synthase deficiency which results in excessive orotic acid excretion (anemia is the main symptom)

not enough UMP being made (and thus deficient in the other pyrimidines

treat with uridine (can be salvaged by uridine kinase to make UMP) - uracil cannot be salvaged and thus isn’t much use here

27
Q

what is pyrimidine 5-nucleotidase deficiency? effects?

A

cannot breakdown nucleoside monophosphates (UMP, CMP, dTMP) in erythrocytes - especially high cytidine nucleotides

results in anemia

28
Q

what is dihydropyrimidine dehydrogenase deficiency? effects?

A

cannot breakdown pyrimidine nucleosides into amino acids - results in elevated serum uracil and thymine

leads to seizures and microencephaly

29
Q

what is dihydropyrimidinase deficiency?

A

cannot breakdown dihydropyrimidines

elevated serum dihydropyrimidines - neurological symptoms

30
Q

how are purine and pyrimidine ribonucleotides converted to deoxyribonucleotides

regulation?

A

ribonucleotide reductase (RR) - broad specificity - requires a ribonucleoside diphosphate substrate

uses NADPH as a reducer

RR is allosterically regulated by dNTP and is an important factor in ADA deficiency

31
Q

how is Thymidine monophosphate made?

A

dUMP -> dTMP via thymidylate synthase

Molecules to Cells (9 decks)

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