10.2. Nucleotide metabolism

MET ABOLISM:
Str uctur e and Metabolism of Nucleotide
USMAN SUMO FRIEND T AMBUNAN
ARLI ADIT YA PARIKESIT
RIDO UT OMO

Departemen Kimia FMIPA UI // B202 // 13 May 2008

Nucleotide Function
Building blocks for DNA and RNA
Intr acellular sour ce of ener gy - Adenosine
tr iphosphate (AT P)
Second messenger s - Involved in intr acellular
signaling (e.g. cy clic adenosine monophosphate
[cAMP])
Intr acellular signaling switches (e.g. G-pr oteins)

Departemen Kimia FMIPA UI // B202 // 13 May 2008

Str uctur e of a Nucleotide
Despite the complex ity and diver sity of life the

str uctur e of DNA is dependent on only 4
differ ent nucleotides
Diver sity is dependent on the nucleotide
sequence
All nucleotides ar e 2 r ing str uctur es composed of:
5-carbon sugar :

-D-ribose (RNA)
-D-deoxyribose (DNA)

Base

Purine
Pyrimidine
A nucleotide WITHOUT a phosphate group
is a NUCLEOSIDE

Phosphate group

Departemen Kimia FMIPA UI // B202 // 13 May 2008

Str uctur e of a Nucleotide:
Sugar
5’

A nucleotide is made of
3 components:

1’

Ri
bo

se

3’

2’

se

Departemen Kimia FMIPA UI // B202 // 13 May 2008

4’

bo
yri
ox
De

A Pentose sugar
T his is a 5 car bon sugar
T he sugar in DNA is
deox y r ibose (lacks a 2’
–OH gr oup)
T he sugar in RNA is
r ibose

HOCH2 O

HOCH2 O

OH

OH

OH

HOCH2 O

OH H

OH

Str uctur e of a Nucleotide:
Bases - Purines

NH2

N

N

A

Adenine
N

N

6

7

5

1N

9

4

2

H

8

N

N
O

3

N

N

NH

Guanine

G
N
H

Departemen Kimia FMIPA UI // B202 // 13 May 2008

N

NH2

Nucleotide Str uctur e - 2
Bases - Pyr imidines

O

H3C

NH

T
Thymine

2

O

H

4
3

N

5

N

NH2

6
1

N

N

Sytosine

C
N
H

Departemen Kimia FMIPA UI // B202 // 13 May 2008

O

Nucleotide Str uctur e:

Bases - Pyr imidines
• T hy mine is found ONLY in DNA.
• In RNA, thy mine is r eplaced by ur acil
• Ur acil and T hy mine ar e str uctur ally similar
O
H3C

O
NH

NH

T
N

O

H
Departemen Kimia FMIPA UI // B202 // 13 May 2008

U
N
H

O

Phosphate Gr oups
• Phosphate gr oups ar e what makes a nucleoside a
nucleotide
• Phosphate gr oups ar e essential for nucleotide
poly mer ization
O
O

P

O

X

O

Basic structure
Departemen Kimia FMIPA UI // B202 // 13 May 2008

Phosphate Gr oups
Number of phosphate gr oups deter mines nomenclatur e
O
O

Monophosphate

P

O

CH2

O
O

O
O

Diphosphate

P

O

P
O

O
O

O

T r iphosphate

O

P
O

Departemen Kimia FMIPA UI // B202 // 13 May 2008

CH2

O

O

P
O

O
O

P
O

O

CH2

Base-Sugar -PO42Monophosphate

4

O

3

5

2

6
1

N
O

P

O

O

Phosphate

5’

C

O
4’

1’
3’

OH

Departemen Kimia FMIPA UI // B202 // 13 May 2008

2’

Sugar

N

Base

Sugar Phosphate
“backbone”

Nucleic Acid
Str uctur e
Poly mer ization
Departemen Kimia FMIPA UI // B202 // 13 May 2008

Nucleotide

Nucleic Acid Str uctur e:
“Base Pair ing”
• RNA [nor mally ] ex ists as a single str anded
poly mer
• DNA ex ists as a double str anded poly mer
• DNA double str and is cr eated by hy dr ogen
bonds between nucleotides
• Nucleotides alway s bind to complementar y
nucleotides

A

T

(2 H-bonds)

G

C

(3 H-bonds)

Departemen Kimia FMIPA UI // B202 // 13 May 2008

Nucleic Acid Str uctur e
“Base Pair ing”

hydrogen
bonds

Departemen Kimia FMIPA UI // B202 // 13 May 2008

Sy nthesis Pathways
For both pur ines and py r imidines ther e ar e
two means of sy nthesis (often r egulate one
another )

• de novo (fr om bits and par ts)
• salvage (r ecy cle fr om pr e-ex isting
nucleotides)

Departemen Kimia FMIPA UI // B202 // 13 May 2008

Many Steps Requir e an Activated
Ribose Sugar (PRPP)

5’

Departemen Kimia FMIPA UI // B202 // 13 May 2008

de novo Synthesis
• Committed step: T his is the point of no r etur n
• Occur s ear ly in the biosy nthetic pathway
• Often r egulated by final pr oduct (feedback inhibition)

X
Departemen Kimia FMIPA UI // B202 // 13 May 2008

Pur ine Biosynthesis (de novo)
Feedback inhibitor s: AMP, ADP, GMP, GDP, IMP

AMP
R-5-P

PRPP

PRA

AT P

IMP
GMP

PRA: 5-phosphor ibosy l-1-amine .

Departemen Kimia FMIPA UI // B202 // 13 May 2008

ADP

activation

GDP

GT P

inhibition

Salvage Pathway for Pur ines
Hypoxanthine + PRPP
IMP + PPi
Guanine + PRPP
GMP + PPi
Hypoxanthineguanosylphosphoribosyl transferase
(HGPRTase)

Adenine + PRPP

AMP + PPi

Adeninephosphoribosyl transferase
(APRTase)

Departemen Kimia FMIPA UI // B202 // 13 May 2008

Regulation of py r imidine nucleotide sy nthesis
CO2 + Gln + AT P

-

Inhibited by UMP

Car bamoy l phosphate

-

Inhibited by CTP

N-Car bamoy laspar tate

UMP

Departemen Kimia FMIPA UI // B202 // 13 May 2008

Salvage pathway for py r imidine nucleotide
biosy nthesis
PRPP

PPi

Py r imidine
Pyrimidine
r ibonucleoside Phosphoribosyl
transferase

PRPP
Or otate
UMP

PPi

Orotate
Phosphoribosyl
transferase

Departemen Kimia FMIPA UI // B202 // 13 May 2008

Py r imidine
monophosphate
H+

CO2

Or otidy lateOrotidylate

decarboxylase

Conclusion
• Nucleotides ar e composed of 5-car bon sugar ,
Base, and Phosphate gr oup

• For both pur ines and py r imidines ther e ar e
two means of sy nthesis:

 de novo
 salvage

Refer ences
• Fr y M. 2011, Essential Biochemistr y for Medicine
Wiley
• Gar r ett R.H. et al. 2012 Biochemistr y Br ooks Cole
Publishing Company
• Har v ey R.A. et al. 2011 Biochemistr y Wolter s Kluwer
Health/L ippincott Williams & Wilkins
• Laemmer hofer M. et al. 2013 Metabolomics in
Pr actice: Successful Str ategies to Gener ate and
Analy ze Metabolic Data Wiley
• Mathews C.K. et al. 2000 Biochemistr y Benjamin
Cummings
• Mur r ay R.K. et al. 2012. Har per ’s Illustr ated
Biochemistr y . 29th edition. McGr aw Hill Medical.
• Nelson D.L and Cox M.S. 2008. L ehninger Pr inciples of
th