Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 19 Nucleotide Metab Notes. - biochemistry notes pdf, biochemistry mbbs 1st year notes pdf, biochemistry mbbs notes pdf, biochemistry lecture notes, paramedical biochemistry notes, medical biochemistry pdf, biochemistry lecture notes 2022 ppt, biochemistry pdf.
Nucleotide Metabolism
1
Objectives
Purine synthesis
Clinical implications
Pyrimidine synthesis
Clinical implications
2
Clinical case-1
A 46-year-old male presents to the emergency department with
severe 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.
The patient denies any trauma to the toe and no previous history of
such 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
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.
Synovial fluid was obtained and revealed rod- or needle-shaped
crystals that were negatively birefringent under polarizing microscopy.
3
What is the likely diagnosis?
H ow would you make a definite
diagnosis?
What is the pathophysiology of this
disorder?
4
Clinical case 2
In January 2000 a 2 year old boy was referred to a paediatric dental
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
muscular hypotonia was made at four months of age. At 18 months
a diagnosis was established through biochemical analysis and
molecular examinations.The child displayed self-destructive
behaviour ( biting) since 10 months of his age. Shortly thereafter
the patient was supplied with arm cuffs for self-protection which
were 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.
FOLLOW-UP:
One year after the dental extractions the patient presented with
no bite injuries but was now using his fingers to injure himself
5
Fig. 1: Patient's extraoral appearance
Fig. 2: Mutilated thumb of left hand
Fig. 3: Bandaged thumb on right hand
Fig. 4: Severely injured lower lip
6
What is the likely diagnosis?
H ow would you make a definite
diagnosis?
What is the pathophysiology of this
disorder?
7
Clinical Case 3
A 4 year old girl presented to the clinic with Megaloblastic anaemia,
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.
Despite that the anaemia worsened.There was no response
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
high as 1500 mg (9.6 mmol) was excreted daily
(Normal 1.4mg/day, 9?mol).
8
What is the likely diagnosis?
H ow would you make a definite
diagnosis?
What is the pathophysiology of this
disorder?
What could be the treatment?
9
Purine nucleotide biosynthesis
De novo synthesis
Phosphoribosylation of purines
Phosphorylation of purine nucleoside
10
De n ovo synthesis of Purines
11
Purine and pyrimidine. The atoms are numbered
according to the international system.
12
Sources of individual atoms in the purine ring
13
Synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP)
14
Synthesis of purine nucleotides
15
16
17
18
Clinical Importance/ Therapeutic
implications
19
20
Conversion of IMP to AMP and GMP
21
Conversion of IMP to AMP and GMP
22
Regulatory mechanisms
in the biosynthesis
of adenine
and guanine nucleotides
23
Conversion of nucleoside monophosphates to nucleoside
diphosphates and triphosphates
24
Conversion of ribonucleotides
to deoxyribonucleotides
25
Ribonucleotide reductase
26
Conversion of ribonucleotides to
deoxyribonucleotides
27
Reduction of ribonucleotides
to deoxyribonucleotides
by ribonucleotide reductase
Generation of active site radical
Mechanism for
ribonucleotide
reductase
29
mechanism for the ribonucleotide reductase reaction
Step 1:The 3'-ribonucleotide radical formation
Step 2 and 3: cation formation at the 2' carbon after the loss of H2O
Step 4: Two one-electron transfers accompanied by oxidation of the dithiol reduce
the radical cation
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
The tyrosyl radical functions to generate the active-site radical (OX),
which is used in the mechanism
30
Pyrimidine Synthesis
31
32
The biosynthetic pathway
for pyrimidine nucleotides
33
Orotic aciduria
Megaloblastic anaemia not responsive to Fe and folic acid
Deficiency of Orotate phosphoribosyl transferase
Deficiency of OMP decarboxylase
TypeI
TypeII
34
UMP
35
Thymidylate synthesis and folate metabolism
as targets of chemotherapy.
Copyright to Lehning 36
er
Thymidylate Is Derived from dCDP and dUMP
37
Clinical Case 3
A 4 year old girl presented to the clinic with Megaloblastic anaemia,
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.
Despite that the anaemia worsened.There was no response
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
high as 1500 mg (9.6 mmol) was excreted daily
(Normal 1.4mg/day, 9?mol).
38
What is the likely diagnosis?
H ow would you make a definite
diagnosis?
What is the pathophysiology of this
disorder?
What could be the treatment?
39
Secondary Orotic aciduria?
Ornithine transcarbamylase deficiency
40
MCQ
Methotrexate a dihydrofolate reductase
inhibitor used for the treatment of rapidly
growing cancer, incorporation of which of
the ring carbons in the generic purine
structure would most likely be affected by
methotrexate?
A. 2
B. 4
C.6
D.8
41
Difference between De novo pathway and
salvage pathway
What is the Requirement of salvage
pathway
Brain---Low levelof PRPP glutamyl transferase
RBC, PMN-lack 5 phospho ribosyl amine
42
Salvage pathway
Adenosine and hypoxanthine-phosphoribosyl transferases
Pu + PR-PP Pu-RP + PPi
Adenosine kinase
Pu-R + ATP PuR-P + ADP
43
Salvage pathways of purine nucleotide synthesis
44
Lesions on the lips of Lesch-Nyhan patients
caused by self-mutilation.
X linked recessive disorder
Gouty arthritis
Urolithiasis
Motor dysfunction
Cognitive defects
Behavioural disturbances
45
Clinical case
A one-and-a-half-year-old male child born to a
consanguineously married couple was brought to the
Department of Pedodontics, Sinhgad Dental College, for
dermatological assessment of failure to thrive and lacerations
over lower lip, thumbs, and index finger due to self-biting (Fig.
1). After recording the history from the parents, it was
revealed that the child had developed the habit of self-biting at
10 months of age. He was the only child born to the parents
after a normal gestation/pregnancy. He was unable to hold his
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
circumference of 44.9 cm (50th centile 45.3 cm). His bone age
was consistent with his chronological age and mental age was 8
months. On examination, welldefined ulcers/lacerations with
crusting and scarring at places involving the left thumb and left
index finger were observed (Fig. 2). Also a gauze piece was
seen rapped around the child's right thumb
46
, with the parents giving the history of ulcer wound
healing spontaneously after bandaging but recurrence
within a day after removal (Fig. 3). Nails of the involved
fingers were dystrophic. A single, well-defined, deep
ulcer with ragged margins and some scarring was
present over the lower lip (Fig. 4). Chorea,
hyperreflexia, and positive Babinski's sign were evident
on neurological examination. All deep tendon reflexes
were brisk and plantar reflex were extensor on either
side. The systemic examination and laboratory
investigations (blood cell counts, hepatorenal
functions, urinalysis, and chest radiograph) were
normal.The serum uric acid levels were 6.5 mg/dl
(normal 1.7?5.8 mg/dl), and the urine uric acid:
Creatinine ratio was 3:4 (normal 2:5?3:5).
47
Fig. 1: Patient's extraoral appearance
Fig. 2: Mutilated thumb of left hand
Fig. 3: Bandaged thumb on right hand
Fig. 4: Severely injured lower lip
48
What is the likely diagnosis?
H ow would you make a definite
diagnosis?
What is the pathophysiology of this
disorder?
49
Causes of Hyperuricemia in LNS
Increased availability of PRPP
Loss of feed back inhibition by AMP and
GMP
Increased degradation of Hypoxanthine
and Guanine
50
Regulatory aspects of the biosynthesis of
purine and pyrimidine ribonucleotides
51
Digestion of dietary
nucleic acids
52
53
54
55
Clinical conditions
56
57
Tophaceous gout
Analysis of joint fluid
58
Negatively birefringent monosodium urate crystals
within polymorphonuclear leukocytes in aspirated
synovial fluid examined by polarized-light microscopy.
59
Causes of hyperuricemia
Under excretion
Defects in the excretory system
Lactic acidosis
Drugs
Lead poisoning--Basophilic stippling
---Saturnine gout
Over production
PRPP synthetase mutation
Leschnyhan syndrome
Myeloproliferative disorder
Vo n Gierkes disease
Fructose intolerance
60
Clinical case-1
A 46-year-old male presents to the emergency department with
severe 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.
The patient denies any trauma to the toe and no previous history of
such 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
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.
Synovial fluid was obtained and revealed rod- or needle-shaped
crystals that were negatively birefringent under polarizing microscopy.
61
What is the likely diagnosis?
H ow would you make a definite
diagnosis?
What is the pathophysiology of this
disorder?
62
Why Alcohol precipitates gout
63
Alcohol precipitates gout
64
Treatment of GOUT
Acute attack
Colchicine
Steroids
Indomethacin
Longterm therapeutic strategy
Allopurinol
Febuxostat--Nonpurine inhibitor of Xanthine oxidase
Diet: Avoid diet rich in nucleic acid
65
Allopurinol, an inhibitor
of xanthine oxidase
66
Antioxidant effect of uric acid
67
Pro-oxidant effect of uric acid
68
What is pseudogout?
Pseudogout is a type of inflammation of joints (arthritis) that
is caused by deposits of crystals, called calcium
pyrophosphate, in and around the joints. Pseudogout literally
means "false gout." It derives its name from its similarity
to gout.
Pseudogout is clearly related to aging
is associated with degenerative arthritis.
Acute attacks of the arthritis of pseudogout can be caused
by dehydration
Pseudogout can also be caused by the hormonal effects on
calcium metabolism from hyperparathyroidism.
abnormal calcifications seen in the cartilage of joints on X-
rays
weakly positively birefringent rhomboid crystals under
polarizing microscope
69
Adenosine deaminase and
Purine nucleoside phosphorylase deficiencey
Toxic effects due to
2' dATP
S adenosyl homocystein
Treatment
Bonemarrow transplantattion
Enzyme replacement therapy
70
Catabolism of pyrimidines
71
Catabolism of pyrimidines contd
72
Summary
Purines and pyrimidines are formed from amphibolic
intermediates and thus are dietarily nonessential.
Ingested nucleic acids are degraded to purines and
pyrimidines
Several reactions of IMP biosynthesis require folate
derivatives and glutamine. Consequently, antifolate drugs
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
6-amino group of AMP.
Phosphoryl transfer from AT P converts AMP and GMP
to ADP and GDP. A second phosphoryl transfer from
AT P forms GTP, but ADP is converted to ATP primarily
by oxidative phosphorylation.
73
Summary contd
Hepatic purine nucleotide biosynthesis is stringently regulated by
the pool size of PRPP and by feedback inhibition of PRPP glutamyl
amidotransferase by AMP and GMP
Coordinated regulation of purine and pyrimidine nucleotide
biosynthesis ensures their presence in proportions appropriate for
nucleic acid biosynthesis and other metabolic needs
Humans catabolize purines to uric acid (pKa 5.8), present as the
relatively insoluble acid at acidic pH or as its more soluble sodium
urate salt at a pH near neutrality.
Urate crystals are diagnostic of gout. Other disorders of purine
catabolism include Lesch-Nyhan syndrome, von Gierke disease, and
hypouricemias
Since pyrimidine catabolites are water-soluble, their
overproduction does not result in clinical abnormalities
Excretion of pyrimidine precursors can, however, result from a
deficiency of ornithine transcarbamoylase because excess
carbamoyl phosphate is available for pyrimidine biosynthesis.
74
MCQ 1
A 42-year-old male patient undergoing
radiation therapy for prostate cancer
develops severe pain in the metatarsal
phalangeal joint of his right big toe.
Monosodium urate crystals are detected by
polarized light microscopy in fluid obtained
from this joint by arthrocentesis. Uric acid
crystals are present in his urine. This
patient's pain is directly caused by the
overproduction of the end product of which
of the following metabolic pathways?
75
A. De novo pyrimidine biosynthesis.
B. Pyrimidine degradation.
C. De novo purine biosynthesis.
D. Purine salvage.
E. Purine degradation
76
MCQ 2
A 1-year-old female patient is lethargic,
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
following compounds is most likely to
alleviate her symptoms?
77
A. Adenine.
B. Guanine.
C. Hypoxanthine.
D. Thymidine.
E. Uridine.
78
MCQ 3
The rate of DNA synthesis in a culture of
cells could be most accurately
determined by measuring the
incorporation of which of the following
radiolabeled compounds?
79
A. Adenine.
B. Guanine.
C. Phosphate.
D. Thymidine.
.
80
MCQ 4
A 44-year-old woman who recently lost her job because of
absenteeism, presents to her physician complaining of
loss of appetite, fatigue, muscle weakness, and
emotional depression. The physical examination reveals
a somewhat enlarged liver that feels firm and nodular,
and there is a hint of jaundice in the sclerae and a hint of
alcohol on her breath. The initial laboratory profile
included a hematological analysis that showed that she
had an anemia with enlarged red blood cells
(macrocytic). A bone marrow aspirate confirmed the
suspicion that she has a megaloblastic anemia because it
showed a greater than normal number of red and white
blood cell precursors, most of which were larger than
normal. Further analyses revealed that her serum folic
acid level was 2.9 ng/mL (normal = 6 to 15), her serum
B12 level was 153 pg/mL (normal = 150 to 750), and
her serum iron level was normal.
81
The patient's megaloblastic anemia is most
likely caused by which of the following?
A.A decreased synthesis of methionine
B. A decreased conversion of dUMP to
dTMP
C.A decrease in the synthesis of
phosphatidyl choline
D.A decrease in the levels of succinyl CoA
E.A decreased synthesis of dUTP
82
MCQ 5
Leukemia patients are often given the compound
Leucovorin (N5-formyl THF) fol owing treatment
with the drug methotrexate.Why is Leucovorin
useful as part of this treatment protocol?
A. It facilitates the uptake of methotrexate by
cel s
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
normal cel s
E. It stimulates cel s of the immune system
83
What laboratory test would help in
distinguishing an orotic aciduria caused by
ornithine transcarbamylase deficiency
from that caused by UMP synthase
deficiency?
84
This post was last modified on 05 April 2022