Neuclitide
Neuclitide
Neuclitide
Nucleotide Metabolism
Noor Ullah
M.Phil Biochemistry& Molecular Biology
Lecturer IPMS, KMU
1
11/5/2023
Historical resume
• The nucleic acids have been the subject of biochemical investigations since 1869
when Friedrich Miescher, a 25-year old Swiss chemist, isolated nuclei from pus
cells- contained a hitherto unknown phosphate rich substance- named nuclein.
• These nuclei were then analyzed and found to have different composition from
any cellular component- was called nuclein.
• When all the proteins was completely removed, it became clear that the new
material was an acid- nucleic acid.
2
11/5/2023
• They are the macromolecules present in most living cells either in the free
state or protein bound- nucleoproteins.
3
11/5/2023
4
11/5/2023
10
5
11/5/2023
Nucleosides
• Result from linking one of the sugars with a purine or pyrimidine
base through an N-glycosidic linkage
• Purines bond to the C1’ carbon of the sugar at their N9 atoms
• Therefore, the purine nucleosides are N-9 glycosides and the pyrimidine
nucleosides are N-1 glycosides.
11
12
6
11/5/2023
Nucleotides
• Nucleotides are the
phosphoric acid esters of
nucleosides.
13
Nucleotides- Functions
• Functions of Nucleotides:
1. As carriers of chemical energy.
• Nucleotides may have one, two or three phosphate groups covalently
linked at 5′-OH of ribose- nucleoside mono-, di- and tri phosphates-
NMPs, NDPs and NTPs, respectively.
• The 3 phosphate groups called- α, β and γ, starting from the ribose.
• NTPs are used as a source of chemical energy- Adenosine triphosphate
(ATP) is by far, the most widely used.
• The hydrolysis of ATP and other nucleoside triphosphates is an exergonic
reaction.
• The bond between the ribose and the α-phosphate is an ester linkage. On
hydrolysis yields about 14 kJ/mol.
• The α-β and β-γ linkages are phosphoric acid anhydrides. On hydrolysis
each anhydride bond yields about 30 kJ/mol.
14
7
11/5/2023
ATP
15
Nucleotides- Functions
2. As components of enzyme factors:
• Many enzyme cofactors and coenzymes (such as coenzyme A, NAD+ and FAD) contain
adenosine as part of their structure.
3. As chemical messengers:
• The cells respond to their environment by chemical signals in the surrounding medium-
these chemical signals (first messengers) with receptors on the cell surface often leads
to the formation of second messengers inside the cell- lead to adaptive changes inside
the cell.
• One of the most common second messengers is the nucleotide adenosine cyclic
monophosphate (cyclic AMP or cAMP).
16
8
11/5/2023
17
18
9
11/5/2023
19
N10-
Formyltetrahydrofolate
N10-
Formyltetrahydrofolate
20
10
11/5/2023
21
kinase kinase
AMP ADP ATP
kinase kinase
GMP GDP GTP
22
11
11/5/2023
dADP dATP
dGDP dGTP
23
24
12
11/5/2023
25
26
13
11/5/2023
27
14
11/5/2023
29
PRPP PPi
O
O N N
N N 2 -O N
3P O H 2C
O
N
N h y p o x a n th in e -g u a n in e
N p h o s p h o rib o s y l tra n s fe ra s e
H y p o x a n t h in e (H G P R T ) HO OH
IM P
O O
PRPP PPi
N N N N
N N NH2 2 -O N
3P O H 2C
O
N NH2
G u a n in e
HO OH
GMP
.
Absence of activity of HGPRT leads to Lesch-Nyhan syndrome. 30
15
11/5/2023
Nucleoproteins (nucleic
acids + proteins)
Oligonucleotides
Phosphodiesterases
Mononucleotides
Phosphatases
phosphorylation;
ATP synthesis;
Phosphoric acid synthesis of phospholipids;
buffer systems;
constituent of bones, cartilages
32
16
11/5/2023
33
34
17
11/5/2023
NH2 O
Adenosine
C C
N Deaminase N Purine nucleoside
N C HN C
phosphorylase
CH CH
HC C HC C O
N N N
N
C N
Ribose-P Ribose-P
HN C
IMP CH
AMP
HC C
N N
Xanthine Oxidase H
Hypoxanthine
O O
C N C N
HN C HN C
C O CH
C C C C
O N N O N N
H H H H
GMP
Uric Acid Xanthine
36
18
11/5/2023
Gout
• Primary causes:
1. decreased excretion of uric acid by the kidney due to renal disease-
sometimes it is inherent.
2. Defect in purine metabolism: increased synthesis of purine nucleotides
which may be idiopathic or due to increased levels of PRPP that
stimulate synthetic pathway of purine nucleotides.
• Secondary causes: High intake of purine rich diet such as red meat, liver,
xanthine beverages like tea, coffee, cola or due to medication in radiation
injury, blood diseases, tumors, toxemia, kidney diseases
37
Gout
• Symptoms:
1. Hyperuricemia
2. Arthritis- inflammation of the joints
due to deposition of urate crystals-
hot red and swollen joints with
severe pain.
3. Redness and swelling of big toe.
4. It may also present as tophi
(masses of urate crystals deposited
under skin) appears after several
years.
5. It may lead to kidney stones,
38
19
11/5/2023
Gout
• Treatment:
39
O O
C C H
N C
HN C HN C
CH N
HC C HC C
N N N
N H H
Hypoxanthine Allopurinol
Xanthine oxidase
Xanthine oxidase
40
20
11/5/2023
21