Purine synthesis
Clinical implications
Pyrimidine synthesis
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Clinical implications2
Clinical case-1
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A 46-year-old male presents to the emergency department withsevere right toe pain.The patient was in usual state of health until early
in the morning when he woke up with severe pain in his right big toe.
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The patient denies any trauma to the toe and no previous history ofsuch pain in other joints. He did say that he had a "few too many" beers
with the guys last night. On examination, he was found to have a
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temperature of 38.2?C (100.8?F) and in moderate distress secondary
to the pain in his right toe.The right big toe was swollen, warm, red,
and exquisitely tender. The remainder of the examination was normal.
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Synovial fluid was obtained and revealed rod- or needle-shaped
crystals that were negatively birefringent under polarizing microscopy.
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3What is the likely diagnosis?
H ow would you make a definite
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diagnosis?What is the pathophysiology of this
disorder?
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4
Clinical case 2
In January 2000 a 2 year old boy was referred to a paediatric dental
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office in Landshut, Germany, because of severe and repeated lip
chewing and aggressive tongue biting. A medical history revealed a
normal pregnancy with no complications but a diagnosis of
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muscular hypotonia was made at four months of age. At 18 monthsa diagnosis was established through biochemical analysis and
molecular examinations.The child displayed self-destructive
behaviour ( biting) since 10 months of his age. Shortly thereafter
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the patient was supplied with arm cuffs for self-protection whichwere not tolerated and the self-mutilation continued. Eventually the
extraction of all primary teeth was deemed necessary to prevent
additional medical problems for this child.
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FOLLOW-UP:One year after the dental extractions the patient presented with
no bite injuries but was now using his fingers to injure himself
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5Fig. 1: Patient's extraoral appearance
Fig. 2: Mutilated thumb of left hand
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Fig. 3: Bandaged thumb on right hand
Fig. 4: Severely injured lower lip
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6What is the likely diagnosis?
H ow would you make a definite
diagnosis?
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What is the pathophysiology of this
disorder?
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7Clinical Case 3
A 4 year old girl presented to the clinic with Megaloblastic anaemia,
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growth failure and mental retardation. History revealed that the
child was born normally. The RBC count was 2.55 million /cmm
and Hb was 6 g/dl, She was given antibiotics and transfusion.
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Despite that the anaemia worsened.There was no responsefollowing treatment with B12, Folic acid and , or Pyridoxine.
A prominent feature of the child's urine was a crystalline sediment,
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which was found to be orotic acid. Orotic acid in amounts as
high as 1500 mg (9.6 mmol) was excreted daily
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(Normal 1.4mg/day, 9?mol).8
What is the likely diagnosis?
H ow would you make a definite
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diagnosis?
What is the pathophysiology of this
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disorder?What could be the treatment?
9
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Purine nucleotide biosynthesis
De novo synthesis
Phosphoribosylation of purines
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Phosphorylation of purine nucleoside10
De n ovo synthesis of Purines
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11Purine and pyrimidine. The atoms are numbered
according to the international system.
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12
Sources of individual atoms in the purine ring
13
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Synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP)
14
Synthesis of purine nucleotides
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15
16
17
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18
Clinical Importance/ Therapeutic
implications
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19
20
Conversion of IMP to AMP and GMP
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21
Conversion of IMP to AMP and GMP
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22Regulatory mechanisms
in the biosynthesis
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of adenineand guanine nucleotides
23
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Conversion of nucleoside monophosphates to nucleoside
diphosphates and triphosphates
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24Conversion of ribonucleotides
to deoxyribonucleotides
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25Ribonucleotide reductase
26
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Conversion of ribonucleotides todeoxyribonucleotides
27
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Reduction of ribonucleotidesto deoxyribonucleotides
by ribonucleotide reductase
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Generation of active site radicalMechanism for
ribonucleotide
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reductase
29
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mechanism for the ribonucleotide reductase reactionStep 1:The 3'-ribonucleotide radical formation
Step 2 and 3: cation formation at the 2' carbon after the loss of H2O
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Step 4: Two one-electron transfers accompanied by oxidation of the dithiol reduce
the radical cation
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Step 5: (reverse of 1): regenerating the active site radical (ultimately, the tyrosyl radical)and forming the deoxy product
Step 6:The oxidized dithiol is reduced to complete the cycle
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The tyrosyl radical functions to generate the active-site radical (OX),
which is used in the mechanism
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30Pyrimidine Synthesis
31
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32The biosynthetic pathway
for pyrimidine nucleotides
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33Orotic aciduria
Megaloblastic anaemia not responsive to Fe and folic acid
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Deficiency of Orotate phosphoribosyl transferase
Deficiency of OMP decarboxylase
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TypeITypeII
34
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UMP35
Thymidylate synthesis and folate metabolism
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as targets of chemotherapy.
Copyright to Lehning 36
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erThymidylate Is Derived from dCDP and dUMP
37
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Clinical Case 3A 4 year old girl presented to the clinic with Megaloblastic anaemia,
growth failure and mental retardation. History revealed that the
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child was born normally. The RBC count was 2.55 million /cmm
and Hb was 6 g/dl, She was given antibiotics and transfusion.
Despite that the anaemia worsened.There was no response
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following treatment with B12, Folic acid and , or Pyridoxine.A prominent feature of the child's urine was a crystalline sediment,
which was found to be orotic acid. Orotic acid in amounts as
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high as 1500 mg (9.6 mmol) was excreted daily
(Normal 1.4mg/day, 9?mol).
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38What is the likely diagnosis?
H ow would you make a definite
diagnosis?
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What is the pathophysiology of this
disorder?
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What could be the treatment?39
Secondary Orotic aciduria?
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Ornithine transcarbamylase deficiency
40
MCQ
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Methotrexate a dihydrofolate reductase
inhibitor used for the treatment of rapidly
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growing cancer, incorporation of which ofthe ring carbons in the generic purine
structure would most likely be affected by
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methotrexate?
A. 2
B. 4
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C.6D.8
41
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Difference between De novo pathway andsalvage pathway
What is the Requirement of salvage
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pathway
Brain---Low levelof PRPP glutamyl transferase
RBC, PMN-lack 5 phospho ribosyl amine
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42
Salvage pathway
Adenosine and hypoxanthine-phosphoribosyl transferases
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Pu + PR-PP Pu-RP + PPi
Adenosine kinase
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Pu-R + ATP PuR-P + ADP43
Salvage pathways of purine nucleotide synthesis
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44
Lesions on the lips of Lesch-Nyhan patients
caused by self-mutilation.
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X linked recessive disorder
Gouty arthritis
Urolithiasis
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Motor dysfunctionCognitive defects
Behavioural disturbances
45
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Clinical case
A one-and-a-half-year-old male child born to a
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consanguineously married couple was brought to theDepartment of Pedodontics, Sinhgad Dental College, for
dermatological assessment of failure to thrive and lacerations
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over lower lip, thumbs, and index finger due to self-biting (Fig.
1). After recording the history from the parents, it was
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revealed that the child had developed the habit of self-biting at10 months of age. He was the only child born to the parents
after a normal gestation/pregnancy. He was unable to hold his
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head yet. He measured 58 cm (50th centile 74.6 cm) in height,
weighed 6.3 kg (50th centile 9.08 kg), and had occipitofrontal
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circumference of 44.9 cm (50th centile 45.3 cm). His bone agewas consistent with his chronological age and mental age was 8
months. On examination, welldefined ulcers/lacerations with
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crusting and scarring at places involving the left thumb and left
index finger were observed (Fig. 2). Also a gauze piece was
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seen rapped around the child's right thumb46
, with the parents giving the history of ulcer wound
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healing spontaneously after bandaging but recurrencewithin a day after removal (Fig. 3). Nails of the involved
fingers were dystrophic. A single, well-defined, deep
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ulcer with ragged margins and some scarring was
present over the lower lip (Fig. 4). Chorea,
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hyperreflexia, and positive Babinski's sign were evidenton neurological examination. All deep tendon reflexes
were brisk and plantar reflex were extensor on either
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side. The systemic examination and laboratory
investigations (blood cell counts, hepatorenal
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functions, urinalysis, and chest radiograph) werenormal.The serum uric acid levels were 6.5 mg/dl
(normal 1.7?5.8 mg/dl), and the urine uric acid:
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Creatinine ratio was 3:4 (normal 2:5?3:5).
47
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Fig. 1: Patient's extraoral appearanceFig. 2: Mutilated thumb of left hand
Fig. 3: Bandaged thumb on right hand
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Fig. 4: Severely injured lower lip
48
What is the likely diagnosis?
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H ow would you make a definitediagnosis?
What is the pathophysiology of this
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disorder?
49
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Causes of Hyperuricemia in LNSIncreased availability of PRPP
Loss of feed back inhibition by AMP and
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GMPIncreased degradation of Hypoxanthine
and Guanine
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50
Regulatory aspects of the biosynthesis of
purine and pyrimidine ribonucleotides
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51
Digestion of dietary
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nucleic acids52
53
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5455
Clinical conditions
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5657
Tophaceous gout
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Analysis of joint fluid58
Negatively birefringent monosodium urate crystals
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within polymorphonuclear leukocytes in aspiratedsynovial fluid examined by polarized-light microscopy.
59
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Causes of hyperuricemia
Under excretion
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Defects in the excretory systemLactic acidosis
Drugs
Lead poisoning--Basophilic stippling
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---Saturnine gout
Over production
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PRPP synthetase mutationLeschnyhan syndrome
Myeloproliferative disorder
Vo n Gierkes disease
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Fructose intolerance60
Clinical case-1
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A 46-year-old male presents to the emergency department withsevere right toe pain.The patient was in usual state of health until early
in the morning when he woke up with severe pain in his right big toe.
--- Content provided by FirstRanker.com ---
The patient denies any trauma to the toe and no previous history ofsuch pain in other joints. He did say that he had a "few too many" beers
with the guys last night. On examination, he was found to have a
--- Content provided by FirstRanker.com ---
temperature of 38.2?C (100.8?F) and in moderate distress secondary
to the pain in his right toe.The right big toe was swollen, warm, red,
and exquisitely tender. The remainder of the examination was normal.
--- Content provided by FirstRanker.com ---
Synovial fluid was obtained and revealed rod- or needle-shaped
crystals that were negatively birefringent under polarizing microscopy.
--- Content provided by FirstRanker.com ---
61What is the likely diagnosis?
H ow would you make a definite
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diagnosis?What is the pathophysiology of this
disorder?
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62
Why Alcohol precipitates gout
63
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Alcohol precipitates gout
64
Treatment of GOUT
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Acute attack
Colchicine
Steroids
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Indomethacin
Longterm therapeutic strategy
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AllopurinolFebuxostat--Nonpurine inhibitor of Xanthine oxidase
Diet: Avoid diet rich in nucleic acid
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65
Allopurinol, an inhibitor
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of xanthine oxidase66
Antioxidant effect of uric acid
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67Pro-oxidant effect of uric acid
68
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What is pseudogout?Pseudogout is a type of inflammation of joints (arthritis) that
is caused by deposits of crystals, called calcium
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pyrophosphate, in and around the joints. Pseudogout literally
means "false gout." It derives its name from its similarity
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to gout.Pseudogout is clearly related to aging
is associated with degenerative arthritis.
Acute attacks of the arthritis of pseudogout can be caused
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by dehydration
Pseudogout can also be caused by the hormonal effects on
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calcium metabolism from hyperparathyroidism.abnormal calcifications seen in the cartilage of joints on X-
rays
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weakly positively birefringent rhomboid crystals under
polarizing microscope
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69Adenosine deaminase and
Purine nucleoside phosphorylase deficiencey
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Toxic effects due to
2' dATP
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S adenosyl homocysteinTreatment
Bonemarrow transplantattion
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Enzyme replacement therapy
70
Catabolism of pyrimidines
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71
Catabolism of pyrimidines contd
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72Summary
Purines and pyrimidines are formed from amphibolic
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intermediates and thus are dietarily nonessential.Ingested nucleic acids are degraded to purines and
pyrimidines
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Several reactions of IMP biosynthesis require folate
derivatives and glutamine. Consequently, antifolate drugs
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and glutamine analogs inhibit purine biosynthesis.IMP is a precursor both of AMP and of GMP. Glutamine
provides the 2-amino group of GMP, and aspartate the
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6-amino group of AMP.
Phosphoryl transfer from AT P converts AMP and GMP
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to ADP and GDP. A second phosphoryl transfer fromAT P forms GTP, but ADP is converted to ATP primarily
by oxidative phosphorylation.
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73
Summary contd
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Hepatic purine nucleotide biosynthesis is stringently regulated bythe pool size of PRPP and by feedback inhibition of PRPP glutamyl
amidotransferase by AMP and GMP
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Coordinated regulation of purine and pyrimidine nucleotide
biosynthesis ensures their presence in proportions appropriate for
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nucleic acid biosynthesis and other metabolic needsHumans catabolize purines to uric acid (pKa 5.8), present as the
relatively insoluble acid at acidic pH or as its more soluble sodium
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urate salt at a pH near neutrality.
Urate crystals are diagnostic of gout. Other disorders of purine
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catabolism include Lesch-Nyhan syndrome, von Gierke disease, andhypouricemias
Since pyrimidine catabolites are water-soluble, their
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overproduction does not result in clinical abnormalities
Excretion of pyrimidine precursors can, however, result from a
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deficiency of ornithine transcarbamoylase because excesscarbamoyl phosphate is available for pyrimidine biosynthesis.
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MCQ 1A 42-year-old male patient undergoing
radiation therapy for prostate cancer
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develops severe pain in the metatarsal
phalangeal joint of his right big toe.
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Monosodium urate crystals are detected bypolarized light microscopy in fluid obtained
from this joint by arthrocentesis. Uric acid
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crystals are present in his urine. This
patient's pain is directly caused by the
overproduction of the end product of which
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of the following metabolic pathways?
75
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A. De novo pyrimidine biosynthesis.B. Pyrimidine degradation.
C. De novo purine biosynthesis.
D. Purine salvage.
E. Purine degradation
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76
MCQ 2
A 1-year-old female patient is lethargic,
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weak, and anemic. Her height and weight
are both low for her age. Her urine
contains an elevated level of orotic acid.
The administration of which of the
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following compounds is most likely toalleviate her symptoms?
77
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A. Adenine.B. Guanine.
C. Hypoxanthine.
D. Thymidine.
E. Uridine.
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78
MCQ 3
The rate of DNA synthesis in a culture of
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cells could be most accurately
determined by measuring the
incorporation of which of the following
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radiolabeled compounds?79
A. Adenine.
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B. Guanine.C. Phosphate.
D. Thymidine.
.
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80
MCQ 4
A 44-year-old woman who recently lost her job because of
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absenteeism, presents to her physician complaining of
loss of appetite, fatigue, muscle weakness, and
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emotional depression. The physical examination revealsa somewhat enlarged liver that feels firm and nodular,
and there is a hint of jaundice in the sclerae and a hint of
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alcohol on her breath. The initial laboratory profile
included a hematological analysis that showed that she
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had an anemia with enlarged red blood cells(macrocytic). A bone marrow aspirate confirmed the
suspicion that she has a megaloblastic anemia because it
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showed a greater than normal number of red and white
blood cell precursors, most of which were larger than
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normal. Further analyses revealed that her serum folicacid level was 2.9 ng/mL (normal = 6 to 15), her serum
B12 level was 153 pg/mL (normal = 150 to 750), and
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her serum iron level was normal.
81
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The patient's megaloblastic anemia is mostlikely caused by which of the following?
A.A decreased synthesis of methionine
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B. A decreased conversion of dUMP todTMP
C.A decrease in the synthesis of
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phosphatidyl choline
D.A decrease in the levels of succinyl CoA
E.A decreased synthesis of dUTP
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82
MCQ 5
Leukemia patients are often given the compound
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Leucovorin (N5-formyl THF) fol owing treatment
with the drug methotrexate.Why is Leucovorin
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useful as part of this treatment protocol?A. It facilitates the uptake of methotrexate by
cel s
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B. It can be converted to THF by bypassing DHFR
C. It acts as an activator of thymidylate synthase
D. It prevents the uptake of methotrexate by
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normal cel sE. It stimulates cel s of the immune system
83
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What laboratory test would help in
distinguishing an orotic aciduria caused by
ornithine transcarbamylase deficiency
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from that caused by UMP synthasedeficiency?
84
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