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Medical Biochemistry > Purine and Pyrimidine Metabolism > Flashcards

Purine and Pyrimidine Metabolism Flashcards

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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
*Ribonucleotide reductase (RR)*
UDP/CDP RR→ dUDP/dCDP Synthesis of **dUDP** and **dCDP**
26
dTTP Synthesis
dTTP is produced by **methylation o**f dUMP ***_thymidylate synthase_*** from N5,N10-methylene-THF
27
Synthesis of CTP, dCTP, and dTTP
**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
Inhibitor of thymidylate synthase | (aticancer)
5-fluorouracil ## Footnote No dTMP synthesis – arrest of cell division
29
Inhibitor of dihydrofolate reductase | (anticancer)
Methotrexate (antifolate drug)
30
Anticancer drugs (target enzymes of pyrimidine synthesis)
5-fluorouracil inhibits thymidylate synthase (No dTMP) Methotrexate inhibits dihydrofolate reductase (blocks recycling of 5,10-methylese-FH4. Antifolate drug)
31
mechanism of methotrexate action Conditions treated by it
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
The enzymes of the Py. Salv. Pth
nucleoside phosphorylases (**base ⇔ nucleoside)** nucleo**side** + P ⇔ **Base** + R1-P nucleoside kinases
33
Pyrimidine Salvage Pathway
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
b-aminoisobutyrate & b-alanine
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
ribonucleotide reductase
NDPs are substrates to make dNDPs Reduction of ribose to deoxyribose: Occurs on the diphosphate level The reaction is catalyzed by ribonucleotide reductase
36
Regulation of ribonucleotide reductase Allosteric regulation Coenzyme/cofactors
A- two allosteric sides: 1- activity ATP activates dATP inhibits 2- specificity B- **thioredoxin** and **NADPH**
37
Regulation of Specificity ribonucleotide reductase
Binding of ATP, dTTP, or dGTP to substrate specificity site determines what substrate can binds to the active site. ## Footnote **To adjust the affinity for less abundant dNTPs**
38
Degradation of Purine Bases
39
Degradation of Purine Bases
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 *xanthine oxidase/dehydrogenase* → Uric acid Its increased activity has been associated with **_hypercholesterolemia_**.
40
uric acid, urate (increased level)
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 K**sp**. _Increased [urate]_ (**hyperuricemia**) can lead to the formation and deposition of urate crystals in tissues and joint.
41
Some disorders that causes overproduction of purines
PRPP synthetase overactivity Glucose-6-phosphatase deficiency (vonGierke disease)
42
Gout management
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
inhibitors of xanthine oxidase
alluporinol oxipurinol
44
uricosuric drugs
lowers uric acid conc. in urine
45
obesity and hyperuricemia
Obese people tends to have high plasma level of urate
46
Diet and hyperuricemia
subjects with high protein diet ,which is also rich in nucleic acids, and with high alcohol consumption have high levels of plasma urate
47
alcohol consumption and hyperuricemia
**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
Xanthinuria
This is a rare hereditary disorder in which there is a mutations in _liver_ **xanthine dehydrogenase gen**e 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
Diseases Associated with **Reduced Uric Acid Levels**
50
Diseases Associated with **Elevated Uric Acid Levels**
Gout, CVD, hYPERtension(renal)
51
**Increasing** Uric Acid Concentrations as a **Treatment for:**
SC injory, MS (other neurological cond.)
52
**Decreasing** Uric Acid Concentrations as a **Treatment** for:
Gout, CVD, HyperTension
53
Allopurinol and Xanthine
Allopurinol (a structural analogue of hypoxanthine) is a **_substrate_** for *xanthine oxidase*. Converted to Oxypurionol (inhibits xanthine oxidase). Redction in UA production
54
Degraded purines are spread over three products
hypoxanthine, xanthine, and uric acid
55
Rapid decrease in uric acid level
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
Disorder of purine and pyrimidine metabolism: gount Gene defect Accumulated metabolite Clinical Sx
57
Disorder of purine and pyrimidine metabolism: SCID Gene defect Accumulated metabolite Clinical Sx
58
Disorder of purine and pyrimidine metabolism: immunodeficiency disease Gene defect Accumulated metabolite Clinical Sx
59
Disorder of purine and pyrimidine metabolism: lesh-nyhan syndrome Gene defect Accumulated metabolite Clinical Sx
60
Disorder of purine and pyrimidine metabolism: hereditary orotic aciduria Gene defect Accumulated metabolite Clinical Sx
61
Disorder of purine and pyrimidine metabolism: xanthinuria Gene defect Accumulated metabolite Clinical Sx
62
Disorder of purine and pyrimidine metabolism: Exercise induced myopathy Gene defect Accumulated metabolite Clinical Sx

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