Nucleotides Flashcards
(83 cards)
1
Q
Purine salvage pathway is mediated by how many enzymes , name them
A
2 ,
APRTase HGPRTase
2
Q
Committed step of de novo purine synthesis in
A
Reaction catalyzed by amidotransferase
3
Q
What is xanthine oxidase
A
A metalloflavoprotein containing FAD , molybdenum,iron
4
Q
Allopurinol inhibits what
A
Xantine oxidase
5
Q
Allopurinol inhibiting xanthine oxidase is example of
A
Suicide inhibitoion
6
Q
End product of purine catabolism is , and it’s normal level in the serum
A
Uric acid , 3-7mg/dL
7
Q
A condition when serum level of uri acid is not normal
A
Gout (increased)
8
Q
What causes tophi
A
Uric acid acid crystals accumulated in the cooler parts of the body
9
Q
What’s tophi
A
A deposit if crystalline uric acid or substances , at the surface of skin , joint ,cartilage
10
Q
Lesh -Nyhan syndrome is
A
x linked inherited
disorder Of purine metabolism
Due to deficiency of HGPRTase
Characterized by self-mutilation tendency
11
Q
Adenosine deaminase deficiency has been treated by
A
gene replacement therapy
12
Q
Why’s can we consider that Salvage and de novo are closely related
A
Substrate /starting material is the same , PRPP
13
Q
Free purines are salvaged by how many enzymes , name then
A
- : APRTase
HGPRTase
14
Q
Tissues where only salvage and no denovo takes place
A
Brain , RBCs
15
Q
The salvage pathway economize
A
Intercellular energy expenditure
16
Q
The step one in de novo synthesis is catalyzed by what and inhibited by what
A
Catalyzed by amino-transferase
Inhibited by AMP , GMP
17
Q
In the regulation on purine synthesis what acts as allosteric modifiers and how
A
AMP , GMP
binds to the enzyme converts monomeric active form to dimeric inactive form
AMP , GMP bind to same molecule at different sites ,act synergistically
18
Q
Which molecules inhibit their own formation and how
A
AMP & GMP
By feedback inhibition of adenylsuccinate synthetase and IMP dehydrogenase
19
Q
How is AMP formed
A
From IMP requiring GTP
GTP formation requires ATP
20
Q
How are GTP& ATP , Made available in sufficient quantities
A
AMP formation requires GTP
GMP requires ATP
21
Q
Another regulatory factor in purine synthesis
A
Availability of PRPP
Activity of PRPP synthetase is regulated by negative modifiers , purine and pyrimidine nucleotides
22
Q
Conversion of IMP to GMP enzymes involved
A
IMP dehydrogenase
Amino transferase
23
Q
Specific clinical syndromes are produced in salvage pathway when
A
Absence of enzymes
24
Q
What is step 0 or preparatory step in de novo synthesis
A
PRPP synthesis
25
What is the function of PRPP in de novo
Ribose-5-phosphate donor
26
Ribose -5-phosphate +ATP ——->
prpp +ADP
27
Other functions of prpp, other than de novo
Salvage , synthesis of pyrimidines nucleotides , nucleotide coenzymes
28
Why is prpp synthesis no considered a step in de novo synthesis
Common for synthesis of pyrimidine nucleotides , nucleotide coenzymes and salvage pathway
29
The number of ATP required for the synthesis of one molecule of purine nucleotide
6 ATP
30
Rate limiting step in de novo synthesis
First step
31
What inhibits step 4 of de novo
Azaserine , a anti cancer drug
32
What is inhibited by 6- mercaptopurine , an anti cancer drug
IMP to AMP
33
How is AMP produced .?
Amination of IMP
34
Number of steps to convert IMP to GMP
Two
35
Explain the steps to convert IMP - GMP
1.oxidation of IMP to XMP (Xanthosine monophosphate / xanthylic acid ).
By NAD+ dependent dehydrogenase
2. An amino transferase transfers NH2 group from glutamine to XMP to form GMP
ATP is hydrolysed to AMP in this level
Both AMP &GMP can be converted to di-, triphisphates
36
No.of steps in de novo synthesis pathway
10
37
How are the enzymes in denovo arranged
Multi enzyme complex in eukaryotic cells
Arrangement increases efficiency
38
Different sources involved in the formation of Purine ring
Glycine
Methenyl THFA
Formyl THFA
Amide N of glutamine
Amino group of aspartate
39
Why are humans called prototrophs
Synthesize purine and pyrimidine bases de novo
40
Which tissues does purine synthesis occur in and which organelle
Most tissues , major site is liver .
In cytoplasm
41
Steps in de novo synthesis that require atp
Steps 1 ,3 ,5 ,6, 7, 8
42
Endproduct of purine nucleotide metabolism .
This degrading takes place mainly in the
Uric acid (urate)
In liver
43
Most common abnormality of elevation of Utica acid level in blood
Hyperuricemia
44
The relation between gout and alcohol
Alcohol contains purine and it also increase the metabolism of purine to uric acid .
Alcohol lead to accumulation of alcohol
45
The main metabolic abnormality in patients with gout
An increased cellular pool of PRPP, substrate for rate limiting step
46
Gout is due to a defect in
PRPP synthetase
HGPRT
glucose 6 phosphatase
47
Most common abnormality caused by a disorder of purine metabolism
Hyperuricemia
Elevation of Uric acid level in blood . Serum Uric acid concentration exceeding 7mg/dL in male , 6 in female .
May or not be associated with uricosuria
48
Reason for manifestation of Hyperuricemia
Low solubility of Uric acid in water . At 30°C solubility is lowered to 4.5 mg/d
L
Therefore Uric acid is deposited in cooler areas of the body to cause tophi .
Tophi is seen in distal joints of foot .
49
The main metabolic abnormality in patients with gout
is an increased cellular pool of PRPP. The resultant activity of amino transferase lead to excess production of nucleotides resulting in Hyperuricemia
50
What is gout due to
Accumulation of urate crystals in the synovial fluid resulting in the inflammation leading to acute arthritis .
51
Causes of primary gout
5-phosphoribosyl amido transferase
Abnormal PRPP synthetase - higher Vmax which leads to increased production of PRPP
Deficiency of enzymes of salvage pathway
G6Pase deficiency
52
von Gierke’s disease
Glycogen storage disease due to G6Pase enzyme deficiency .
G6P cannot be converted to glucose .
More glucose is channeled into pentose phosphate shunt pathway ,
increased availability of ribose 5 phosphate .
Increased formation of PRPP
It causes primary gout
53
How does deficiency of enzymes in salvage pathway cause primary gout
Reactions which consume PRPP and produce more nucleotides which inhibit the enzyme (salvage pathway )
54
Causes of secondary Hyperuricemia
*Increased production of Uric acid
*reduced excretion rate
55
When can increased production of Uric acid be seen (leading to 2°) Hyperuricemia ?
i. Rapidly growing malignant tissues (leukaemia , lymphomas , polycythemia )
ii.also in cancer patients on radiotherapy or chemotherapy (tumour lysis syndrome )due to increased cell turnover .
Patients are given allopurinol to decrease Uric acid levels . Rasburicase (urate oxidase ) is also found effective .
iii.increased tissue damage due to trauma and raised rate of catabolism as in starvation
56
Reduced excretion rate leading to 2° Hyperuricemia
1. Renal failure
2.Treatment with thiazide diuretics which inhibit tubular secretion of Uric acid
3. Lactic acidosis and keto acidosis due to inference with tubular secretion
57
Gouty attacks maybe precipitated by
A high purine diet and increased intake of alcohol
Alcohol lead to accumulation of lactic acid .
58
A typical gouty arthritis affects the
first metatarsophalangeal joint (big toe) , may affect other joints . Joints in general painful .
Synovial fluid show birefringent urate crystals .
59
The total urate pool in normal , gout with tophi and without is
Normal - 1200 mg
Without tophi - 3000 mg
With tophi - 30000 mg
60
Chronic cases of gout , the swellings are composed of what ?
Sodium urate
UA get deposited around joints causing swelling composed of
61
Where else do urate crystals deposit in chronic gout
In renal medulla , progresses to urolithiasis and renal damage .
May cause deposition in UT leading to calculi or stone formation with renal damage
62
Treatment of gout / reduce urate
1.reduce purine intake , alcohol
2. Increase renal excretion by URICOSURIC DRUGS,
3. Reduce production by allopurinol hypoxanthine analog .
4. Colchicine , an anti inflammatory agent very useful to arrest arthritis in gout
5. Use of PEG (Polyethylene glycol ) uricase and conversion of Uric acid to allatonin ( more water soluble ) easily excreted .
Also tried as therapeutic measure to reduce body uric acid pool .
63
Function of uricosuric drugs
Decrease the reabsorption of Uric acid from kidney tubules . Eg: probenecid
64
Allopurinol and it’s use I’m reducing urate production
*An analog of hypoxanthine.
*Competitive inhibitor of xanthine oxidase , decrease formation of Uric acid .
*xanthine and hypoxanthine are more soluble - excreted more easily
* xanthine oxidase converts allopurinol to alloxanthine(more effective inhibitor of xaox
Suicide inhibition
65
Allopurinol was synthesised by
Ellion and hitchings
66
Lesch nyhan syndrome
* X linked inherited disorder of purine metabolism
* different mutations in HGPRTase gene identified
*Incidence 1 in 10k
* deficiency of HGPRTase
* rate of salvage decreased resulting in accumulation of PRPP , decreased level of inhibitory purine nucleotides .
Allopurinol is used in treatment , since salvage in deficient , effective only to inhibit xanthine oxidase
67
Lesch x nyhan syndrome is characterised by
Self mutilation
Mental retardation
Excessive Uric acid
Nephrolithiasis ( kidney stone )
68
What does the neurological manifestations of lesch-nyhan suggest
Brain depends on salvage pathway for the requirements of IMP , GMP
69
Name a hypouricemic condition
ADA adenosine deaminase deficiency
70
ADA Deficiency
*Severe immunodeficiency,both T and B cells deficient
*inherited autosomal recessive
* ADA deficiency leads to accumulation of
Adenosine and dATP - - inhibit further production of precursors of precursor for DNA synthesis especially dCTP
* lymphocytes usually contain high levels of ADA
Reduced lymphocytes-common manifestation
*this leads to impaired C i and hum oral immunity
71
Xanthine oxidase deficiency
Genetic defect
Characterised by hypouricemia, increased excretion of hypoxanthine , xanthine and liver damage .
72
Treatment ADA
Antibiotics and periodic injections of immunoglobulin - live saving
Weekly intra muscular injections of bovine ADA = beneficial
Bone marrow stem cells will increase both B and T cells
First successful gene replacement therapy tried in this
73
Purine nucleotide phosphorylase deficiency produces
immune deficiency but only B cell function in affected
74
Other functions of ADA
* rapid diagnosis of tuberculosis
*ADA estimation csf is used for diagnosis of TB meningitis
* ADA levels estimated in various body fluids like blood , CSF , pleural fluid , pericardial fluid , ascitic fluid
Cut off value for CSF is 10.0 U/L , other fluids 60 U/L
*EXTRA pulmonary TB diagnose by pleural or as it’s fluid
75
Normal blood level of Uric acid ranges
2-5 mg/dL in females
3-7 mg/dL in males
UA is sparingly soluble in water , an antioxidant .
Nucleic acid content is more in non-veg diet
76
Normal daily excretion of Uric acid
500- 700 mg
77
First enzyme in purine synthesis by de novo
Phospho ribosyl amido transferase
78
What would affect the reactions involving one carbon group transfers
Folate antagonists (methotrexate)
79
Other synthetic nucleotide analogs used as anti cancer agents
6-thio guanine and 8- aza guanine
80
A glutamine antagonist that inhibits reactions involving glutamine ( step 1 and 4)
Azaserine ( diazoacetyl-L- serine )
81
Useful anti cancer drugs that are analogs as purine synthesis inhibitors
Competitive inhibitors of naturally occurring nucleotides ,
Utilized to synthesise DNA , such DNA functionally inactive , cell division arrested
*mercaptopurine
*folate antagonists (methotrexate)
*azserine (diazoacetyl-L- serine)
* 6-thio guanine, 8- aza guanine
82
Caffeine
*trimethyl derivative of xanthine
* inhibits phosphodiesterase causes prolonged action of cyclic AMP and increases the activity of hormone sensitive lipase
* enhances the effect of epinephrine on glycogenolysis
83
Degradation of purine nucleotides take solace mainly in
Liver
