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MHS-Unit 4 > Purine and Pyrimidine Metabolism > Flashcards

Purine and Pyrimidine Metabolism Flashcards

1
Q

The reactions catalyzed by HGPRT

HGPRT defeciency

A

In general: Synthesis of Nucleotides from Free bases

HGPRT an enzyme required for the synthesis of IMP and GMP

IMP free base is hypoxanthine

GMP free base is guanine

Defeciency can result in Lesch-Nyhan Synd.

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2
Q

Name the enzyme and the by-product

Guanosine E1→ Guanine + X

Inosine E2→ Hypoxanthine + X

A

In both rxns:

nucleoside → Free base

Both E1 & E2 :

Purine nucleo_side_ Phosphory_lase-_ PNP

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3
Q

Phosphoribosyl transferase

Major Pathway

Rxns catalyzed by this enzyme

A

Purine Salvg Pthwy

  1. Addition of Ribose-5P to a Basefree
  2. PRPP + Basefree → Nuctide** + PPi**
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4
Q

The enzyme that catalyzes the phosphorolysis of N-glycosidic bond:

A

Phosphorolysis of N-glycosidic bond is catalyzed by purine nucleoside phosphorylase (PNP)

Guanosine PNP→ guanine + R-1P

Inosine PNP→ hypoxanthine + R-1P

  • Ribose 1-posphate can be isomerized to ribose 5-phosphate (R1P ⇔ R5P )
  • Free bases (Bf or Basefree) can be salvaged ordegraded
  • The reactions are part of purine Salvage Pathway (PuSP)
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5
Q

Three groups of enzymes that participate in Pu.SPs

A
  • Deaminase (DAs): AMP-DA and Adenosine Deaminase (ADA)

Pt. w/ Ø ADA1- SCID & 1st Increased [dA] → [ATP] inc.

  • PhosphoRibosyl Transferease (PRT): HGPRT and APRT

Pt. w/ Ø HGPRT - Inc. [UA] bc . exc. degrd . Purines (free bases) since they cnt b rcycld

  • Purine nucleoside Phosphorylase (PNP)
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6
Q

ADA1 Ø

Possible causes of delay in SCID detection (1/100 K live births

A

In N/H. (normal and healthy) indiv:

  1. Adenosine ADA1→ Inosine
  2. dAdenosine ADA1→ dInosine <span>Deoxyinosine is found in DNA while inosine is found in RNA.)</span>

In ADA1Ø indiv:

dA builds up (dA convrts to dATP) leads to dATP accumulation.

dATP accumulation leads to reduced doxynucleotides, which impairs lymphocyte proliferaiton. ADA-deficient are SCID and are unable to produce significant numbers of mature T or B lymphocytes.

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7
Q

ADA1 Ø & _ribonucleotide diphosphate reductase (rNDP)_

A

ADA1 Ø causes an increase in dA and dATP conc.

Accumulated dATP inhibits rNDP.

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8
Q

rNDP substrates

A

ADP, GDP, UDP, CDP

Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase (rNDP), is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides

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9
Q

The portion of salvage pathway that is important for muscle tissue

Brief discription

A

Purine Nucleotide Cycle

Fumarate production as a result of AMP build-up, and its conversion to IMP in excercising muscle.

AMP also activates PFK-1 and glycogen phosphorylase b (glycolysis and glycogenolysis activation)

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10
Q

AMP deaminase Ø

A

Deficiency of AMP deaminase results in muscle fatigue during exercises (from 1 in 50 to 1 in 40,000 people).

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11
Q

Generation of ATP

(high intensity exercise)

A

During high intensity exercise cytosolic ATP is rapidly converted to ADP.

Direct generation of ATP from ADP by:

myokinase (adenylate kinase)

2ADP ⇔ ATP + AMP

Note: removing AMP causes right shift. One possible way, removing AMP by AMP deaminase

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12
Q

The reason for ammonia accumulation in exercising muscles

A

Because of the increased levels of AMP and IMP.

Degradation of purines is linked to the generation of ATP. During high intensity exercise cytosolic ATP is rapidly converted to ADP. ATP can be generated directly from ADP by myokinase (adenylate kinase):

2ADP⇔ ATP + AMP

The reaction is driven to the right by AMP deaminase (high conc. in skeletal muscle)

AMP + H2O → IMP + NH3

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13
Q

muscle AMP deaminase deficiency

Defective gene (inheritance pattern)

Sx

Exacerbation of the Sx

A
  • AMPD1 gene
  • fatigue, muscle weakness, cramps, pain and other muscle prob.
  • Statins exacerbate the symptoms
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14
Q

Synthesis of pyrimidines

A

Base synthesized first

Produced from Asp and carbamoyl phosphate (from CO2 and Gln by CPSII)

The first three enzymes: CAD

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15
Q

CPSII analogous

A

Analogous to urea cycle CPS I

Unlike its analogous, CPSII uses Gln as source of N and occurs in cytosol

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16
Q

The first three enzymes of pyrimidine synthesis

A

CAD

  1. Carbamoyl phosphate synthetase II
  2. Asp transcarbamoylase
  3. Dihydro-orotase
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17
Q

Regulated Step of Pyrimidine Synthesis

A

production of carbamoyl phosphate catalized by CPS II.

CPS II activity: + PRPP, - UTP

[CPS II-P] made by MAP kinase increases CPSII responsiveness to PRPP (inc the prob. of activation)- During S-phase.

Folate deficiency can result in anemia (macrocytic or megaloblastic) because of limited dTMP syn.

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18
Q

An activator of CPSII

A

PRPP

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19
Q

Orotic acid (orotate) conversion to UMP

A

2 enzymes, 1 polypeptide, UMP synthase

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20
Q

UMP synthase Ø

A

leads to:

Hereditary orotic aciduria, megaloblastic anemia and growth retardation (red. Py.Synth.)

Treatment:

Oral uridine ( Uridine is converted to UMP bypassing metabolic block)

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21
Q

Causes of Orotic Aciduria

A

1- UMP synthase deficiency

2- Ornithine transcarbomylase def. (Urea Cycle)- leads to carbomyl phosphate accuml. in Mt. which leaks to the cytoplasm (bypasses the rxn catalyzed by CPSII)

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22
Q

Synthesis of deoxyribonucleotides occurs at—————- level.

A

diphosphate

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23
Q

CTP and dCTP production

A

CTP is produced by an addition of amino group from Gln to C4 of UTP

UTP and CTP are precursors of for RNA synthesis

CDP RR→ dCDP

Ribonucleotide reductase (RR)

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24
Q

dUDP synthesis

A

UDP RR→ dUDP

Ribonucleotide reductase (RR)

RR also syntheses dCTP

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25
Q

Ribonucleotide reductase (RR)

A

UDP/CDP RR→ dUDP/dCDP

Synthesis of dUDP and dCDP

26
Q

dTTP Synthesis

A

dTTP is produced by methylation of dUMP

thymidylate synthase from N5,N10-methylene-THF

27
Q

Synthesis of CTP, dCTP, and dTTP

A

CTP is produced by an addition of amino group from Gln to C4 of UTP

dCTP and dUDP synthesised by RR

dTTP is produced by methylation of dUMP ( catalyzed thymidylate synthase from N5,N10-methylene-THF).

28
Q

Inhibitor of thymidylate synthase

(aticancer)

A

5-fluorouracil

No dTMP synthesis – arrest of cell division

29
Q

Inhibitor of dihydrofolate reductase

(anticancer)

A

Methotrexate (antifolate drug)

30
Q

Anticancer drugs

(target enzymes of pyrimidine synthesis)

A

5-fluorouracil inhibits thymidylate synthase (No dTMP)

Methotrexate inhibits dihydrofolate reductase (blocks recycling of 5,10-methylese-FH4.

Antifolate drug)

31
Q

mechanism of methotrexate action

Conditions treated by it

A
  1. An inhibition of purine and pyrimidine synthesis.
  2. Reduction of antigen-dependent T-cell proliferation.
  3. Promotion of adenosine release with adenosine-mediated suppression of inflammation.

antiintlammatory effects

  • cancer, severe Psoriasis, RA, Systemic Lupus Erythematosus
32
Q

The enzymes of the Py. Salv. Pth

A

nucleoside phosphorylases (base ⇔ nucleoside)

nucleoside + P ⇔ Base + R1-P

nucleoside kinases

33
Q

Pyrimidine Salvage Pathway

A

Pyrimidine bases are salvaged by two-step route:

Nucleoside phosphorylase adds deoxyribose residue.

Thymine phosphorylases uses deoxyribose 1-phosphate as a substrate.

Nucleoside phosphorylase can catalyze the reversible reaction:

nucleoside + phosphate ⇔ base +ribose 1-phosphate

A specific nucleoside kinases convert nucleosides to nucleotides.

34
Q

b-aminoisobutyrate & b-alanine

A

Found in urine- pyrimidine degradation

  1. nucleoside formation- remove P from pyrimidine nucleotides
  2. nucleoside cleavage (R1P and base)
  3. degrade bases
  • Cytosine deamination →B-alanine
  • Thymine → B-aminoisobutyrate
35
Q

ribonucleotide reductase

A

NDPs are substrates to make dNDPs

Reduction of ribose to deoxyribose:

Occurs on the diphosphate level

The reaction is catalyzed by ribonucleotide reductase

36
Q

Regulation of ribonucleotide reductase

Allosteric regulation

Coenzyme/cofactors

A

A- two allosteric sides:

1- activity

ATP activates

dATP inhibits

2- specificity

B- thioredoxin and NADPH

37
Q

Regulation of Specificity

ribonucleotide reductase

A

Binding of ATP, dTTP, or dGTP to substrate specificity site determines what substrate can binds to the active site.

To adjust the affinity for less abundant dNTPs

38
Q

Degradation of Purine Bases

A
39
Q

Degradation of Purine Bases

A

mainly in the liver.

Produces two free bases: guanine and hypoxanthine.

Hypoxanthine xanthine oxidase→xanthine

Guanine guanase→xanthine

Xanthine is converted to uric acid and excreted in urine.

Xanthine <strong>xanthine oxidase/dehydrogenase</strong> → Uric acid

Its increased activity has been associated with hypercholesterolemia.

40
Q

uric acid, urate (increased level)

A

Uric acid is a final product of purine degradation in humans. Uric acid forms urate at physiological pH.

Urate is not very soluble in aq. solutions.

Normal [urate]bld is very close to Ksp.

Increased [urate] (hyperuricemia) can lead to the formation and deposition of urate crystals in tissues and joint.

41
Q

Some disorders that causes overproduction of purines

A

PRPP synthetase overactivity

Glucose-6-phosphatase deficiency (vonGierke disease)

42
Q

Gout management

A
  1. Acute gout attack by NSAIDs (ibuprofen) or injection of glucocorticoids into joints to manage inflammation.
  2. Lowering uric acid level by using the inhibitors of xanthine oxidase (alluporinol or oxipurinol) or uricosuric drugs that increase excretion of uric acid in urine (should not be used in persons with already high urine concentration of uric acid).
  3. Dietary changes: by limiting consumption of alcohol (lactate production) and purine-rich food (meat, fish, spinach, and dry beans)

Alcohol promotes ATP turnover leading to an increased degradation of purines.

Lactate increases uric acid renal reabsorption.

43
Q

inhibitors of xanthine oxidase

A

alluporinol

oxipurinol

44
Q

uricosuric drugs

A

lowers uric acid conc. in urine

45
Q

obesity and hyperuricemia

A

Obese people tends to have high plasma level of urate

46
Q

Diet and hyperuricemia

A

subjects with high protein diet ,which is also rich in nucleic acids, and with high alcohol consumption have high levels of plasma urate

47
Q

alcohol consumption and hyperuricemia

A

Oxidation of alcohol generates acetate that is converted to acetyl-CoA, which increases adenine nucleotide turn over by increasing consumption of ATP.

ATP + Acetate + CoA ⇔ AMP + Pyrophosphate + Acetyl-CoA

48
Q

Xanthinuria

A

This is a rare hereditary disorder in which there is a mutations in liver xanthine dehydrogenase gene or the molybdenum cofactor gene.

The catabolism of purine stops at the xanthine and hypoxanthine compounds.

The blood uric acid is very low.

Increased excretion of urinary xanthine.

This may lead to the formation renal xanthine stones.

Reduced excretion of urinary uric acid.

49
Q

Diseases Associated with Reduced Uric Acid Levels

A
50
Q

Diseases Associated with Elevated Uric Acid Levels

A

Gout, CVD, hYPERtension(renal)

51
Q

Increasing Uric Acid Concentrations as a Treatment for:

A

SC injory, MS (other neurological cond.)

52
Q

Decreasing Uric Acid Concentrations as a Treatment for:

A

Gout, CVD, HyperTension

53
Q

Allopurinol and Xanthine

A

Allopurinol (a structural analogue of hypoxanthine) is a substrate for xanthine oxidase.

Converted to Oxypurionol (inhibits xanthine oxidase).

Redction in UA production

54
Q

Degraded purines are spread over three products

A

hypoxanthine, xanthine, and uric acid

55
Q

Rapid decrease in uric acid level

A

Rapid decrease in uric acid level can lead to quick dissolution of urate crystals, which would triggers proinflammatory cytokine production and development of inflammation

56
Q

Disorder of purine and pyrimidine metabolism: gount

Gene defect

Accumulated metabolite

Clinical Sx

A
57
Q

Disorder of purine and pyrimidine metabolism: SCID

Gene defect

Accumulated metabolite

Clinical Sx

A
58
Q

Disorder of purine and pyrimidine metabolism: immunodeficiency disease

Gene defect

Accumulated metabolite

Clinical Sx

A
59
Q

Disorder of purine and pyrimidine metabolism: lesh-nyhan syndrome

Gene defect

Accumulated metabolite

Clinical Sx

A
60
Q

Disorder of purine and pyrimidine metabolism: hereditary orotic aciduria

Gene defect

Accumulated metabolite

Clinical Sx

A
61
Q

Disorder of purine and pyrimidine metabolism: xanthinuria

Gene defect

Accumulated metabolite

Clinical Sx

A
62
Q

Disorder of purine and pyrimidine metabolism: Exercise induced myopathy

Gene defect

Accumulated metabolite

Clinical Sx

A

MHS-Unit 4 (11 decks)

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