Download 4-Catabolism of Purine Nucleotides

1. Regarding the reaction of dUMP------ dTMP
a)
Riboncucltidereductase is required to catalyze the reaction
b)
DHF (Dihydrofolate) is formed
c)
Ilydroxyurease inhibit the reaction
d)
N5 N10 methylinetctrahydrofolate is required
e)
Folate analog decreases the rate of the reaction
 2. Sulphur containing amino acid is
 (A) Methionine (B) Leucine
 (C) Valine (D) Asparagine
 Phosphorylation of adenosine to AMP is
 catalysed by
 (A) Adenosine kinase
 (B) Deoxycytidine kinase
 (C) Adenylosuccinase
 (D) Adenylosuccinate synthetase
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CATABOLISM OF PURINE
NUCLEOTIDES
2
Dr. Shumaila Asim
Lecture # 4
pentose phosphate
pathway
nucleotide
H2O
R-5-P
PRPP
nucleotidase
Pi
nucleoside
Pi
salvage
pathway
R-1-P
purine
nucleoside
phosphorylase
oxidation
uric acid
3
Utilization of ribose and deoxyribose
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DEGRADATION OF PURINES
PURINES

Uric acid is the end product in humans

Uric acid = alloxan + urea

Excreted mainly through kidneys (600-800 mg/day)

Some mammals contain uricase, which converts uric acid to a
highly water-soluble product, allantoin
5
6
O
NH2
C
N
C
N
C
HN
C
N
CH
CH
HC
C
HC
N
N
C
N
O
N
Ribose-P
Ribose-P
IMP
AMP
C
HN
CH
HC
C
C
N
HN
C
C
O
C
N
H
N
H
Hypoxanthine
O
C
HN
C
N
Xanthine Oxidase
O
C
N
N
H
Uric Acid
C
N
O
CH
C
O
C
N
H
N
H
Xanthine
GMP
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DISORDERS OF PURINE
METABOLISM
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PURINE RELATED DISORDERS

Gout

Other hyper-uricemias

Lesch – Nyhan Syndrome

Von Gierke’s disease

Hypo-uricemia

Adenosine deaminase and

Purine nucleoside phosphorylase deficiency
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GOUT


Uric Acid =
3 – 9 mg/dl
(Serum / plasma)
2.5 – 7.5 mg/dl or 0.15 – 0.45 mmol/L (Women)
or
0.18 – 0.54 mmol/L (Men)
A group of disorders of purine metabolism due to
over production & hence over-excretion of uric acid

PRPP synthetase is abnormal and is not responsive to feedback
inhibition by ADP & GDP
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GOUT

Characterized by
a.
Hyper-uricemia
b.
Recurrent inflammatory arthritis induced by deposits of crystals of
sodium urate (tophi) in and around joints
c.

Uric acid urolithiasis (urinary calculus or stone)
When serum level of uric acid (urate) exceeds the solubility
limit [>7mg/dl (men) & >6mg/dl (women)], it crystallizes in the soft
tissues and joints  inflammatory reaction
(Gouty arthritis)
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12
GOUT
Primary gout (metabolic & renal)

Predominantly in men

May be due to overproduction or
under-excretion of uric acid or both
Secondary gout

As a result of hyper-uricemia caused by another disorder (e.g.
leukemia, polycythemia) where there is rapid turnover of nucleic
acids
13
14
Allopurinol – a suicide inhibitor used to treat Gout
O
O
C
C
HN
C
N
HN
C
H
C
N
CH
HC
C
N
H
Hypoxanthine
N
HC
C
N
N
H
Allopurinol
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Diet and drugs that may promote gout
●
too much food, too rich in purines
●
excessive fructose or sucrose
●
alcoholic beverages
●
anorexia nervosa
●
drugs that interfere with uric acid secretion: pyrazinamide,
salicylic acid
●
drugs that contain purines: dideoxyadenosine
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ADVANCED GOUT
CLINICALLY APPARENT TOPHI
2
1
3
1
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1. Photos courtesy of Brian Mandell, MD, PhD, Cleveland Clinic.
2. Photo courtesy of N. Lawrence Edwards, MD, University of Florida.
3. ACR Clinical Slide Collection on the Rheumatic Diseases, 1998.
OTHER HYPER-URICEMIAS
Lesch-Nyhan Syndrome

A severe deficiency or complete absence of enzyme of salvage
pathway (hypo-xanthine-guanine phospho-ribosyl
transferase)

Purine bases cannot be salvaged

More hypo-xanthine available   uric acid

Severe gout, renal failure & neurological problems
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OTHER HYPER-URICEMIAS
Von Gierke’s Disease

Deficiency of Glucose-6-Phosphatase

Glucose-6-Phosphate cannot be converted to glucose

Glucose-6-Phosphate will enter HMP shunt   ribose-5-P
  PRPP   purines   uric acid

In addition, G-6-P  Lactic acid, which competes with
uric acid for excretion resulting in uric acid retention
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LESCH-NYHAN SYNDROME
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HYPO-URICEMIA

Xanthine oxidase deficiency

Decreased xanthine degradation  accumulation

Increased hypoxanthine excretion

Decreased uric acid formation and excretion
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Immunodeficiency Disorders
1. Adenosine deaminase deficiency

Due to this deficiency adenosine & deoxy-adenosine cannot be
degraded  concentration increases  converted into
nucleotides (ATP & dATP) in WBC

dATP inhibits ribonucleotide reductase thus inhibiting DNA
synthesis, therefore WBCs cannot proliferate
(T-Cell, B-Cell functions are defective)
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Immunodeficiency Disorders
2. Purine nucleoside phosphorylase (PNP) deficiency

Inability to metabolize guanosine and deoxy-guanosine 
Accumulation  Conversion to nucleotides (GTP & dGTP) 
which also inhibit ribonucleotide reductase (but not to the
degree of ATP & dATP)  only T-lymphocyte function is
affected (i.e. symptoms not so severe)
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Nucleotide antimetabolites as anticancer and antiviral drugs
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ANTI METABOLITES OF PURINE
NUCLEOTIDES
 Antimetabolites
of purine nucleotides are structural
analogs of purine, amino acids and folic acid.
 They
can interfere, inhibit or block synthesis
pathway of purine nucleotides and further block
synthesis of DNA, RNA, and proteins.
 Widely
used to control cancer.
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PURINE ANALOGS
 6-Mercaptopurine
(6-MP) is a analog of
hypoxanthine.
OH
SH
N
N
N
N
H
hypoxanthine
N
N
N
N
H
6-MP
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
6-MP nucleotide is a analog of IMP
de novo synthesis
-
amidotransferase
-
6-MP
IMP
6-MP nucleotide
-
AMP and GMP
-
HGPRT
salvage pathway
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AMINO ACID ANALOGS
 Azaserine
(AS) is a analog of Gln.
O
H2N
NH2
C
CH2
CH2
O
N
N
CH2
C
Gln
CH COOH
NH2
O
CH2
AS
CH COOH
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FOLIC ACID ANALOGS
 Aminopterin
(AP) and Methotrexate (MTX)
NH2
N
N
H2N
N
CH2
R
O
N
C NH C CH2
H
OH
H2N
H
N
N
CH2 COOH
N
MTX
R＝CH3： TXT
R＝H： AP
N
COOH
CH2 N
O
COOH
C NH
C
H
CH2 CH2
N
folic acid
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COOH
NADPH + H+
NADP+
folate
FH2 reductase
-
NADPH + H+
FH2
NADP+
FH2 reductase
FH4
-
AP or MTX
•The structural analogs of folic acid(e.g. MTX) are widely used
to control cancer (e.g. leukaemia).
•Notice: These inhibitors also affect the proliferation of
normally growing cells. This causes many side-effects
including anemia, baldness, scaly skin etc.
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QUESTIONS

Describe the reactions involved in catabolism of purine
nucleotides

Discuss the different disorders related to metabolism of purine
nucleotides
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