Download MBBS Biochemistry PPT 19 Nucleotide Metab Lecture Notes

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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