Pyrimidine Biosynthesis

1
Pyrimidine Biosynthesis
NOTABLES
Carbamoyl Phosphate Synthetase II
Aspartate Transcarbamylase (ACTase)
2 components to make ring
PRPP (to add ribose)
5-UMP is the product
2
Carbamoyl-PO4 Synthetase II
2ADP PO4
L-Glutamine
3
L-Aspartate

Carbamoyl-PO4
Aspartate Transcarbamylase
Dihydroorotate
4
Dihydroorotate
Orotate
(Looks like uracil with a -COO- group)
5
Orotate
Orotate monophosphate
PRPP
6
CO2
5-OMP
Uridine 5-monophosphate
(5-UMP)
7
ODDS AND ENDS
Nucleoside Monophosphate Kinase
5-UMP ATP
UDP ADP
Adenylate kinase
ADP ADP
5-AMP ATP
Guanylate kinase
GDP ADP
GMP ATP
Nucleoside Diphosphate Kinase
UDP ATP
UTP ADP
GDP ATP
GTP ADP
?
dADP ATP
dATP ADP
ADP ATP
ATP ADP
8
Summary of Pyrimidine Nucleotide Biosynthesis
UTP CTP TTP dCTP dTTP
5-UMP
UDP
UTP
CDP
CTP
dUDP
There is no TMP, TDP, TTP
dUTP
dCDP
dCMP
Rapid
dCTP
dUMP
dTDP
dTTP
dTMP
9
Post Synthesis modifications
5-UMP
UDP
UTP
Glutamine
Deoxy Thymidine synthesis requires THF
Glutamate
dUDP
CTP
dUMP
R
5,10-Methylene THF
Dihydrofolate
dTMP
Thymine
R
10
SALVAGING
Can Purine and Pyrimidine nucleotides be
synthesized by joining ribose to a free ring?
Yes
Why is this possible?
Because some tissues like brain lack the ability
to synthesize the purine ring from scratch.
How is this accomplished?
Synthase enzymes called ribosyltransferases
combine the base with PRPP producing a nucleoside
mono- phosphate.
11
Hypoxanthine-Guanine Phosphoribosyl Transferase
(HGPRT)
PPi
PRPP
Guanine
Lesch-Nyhan Syndrome
12
Adenosine
Hypoxanthine
Nucleotidase
Adenine
Adenine deaminase
Xanthine Oxidase
Xanthine
Uric Acid
PURINE DEGRADATION
Fully oxidized Purine
13
CO2
Allantoin (other vertebrates)
Uric Acid (primates, birds, reptiles, insects)
Allantoic Acid (bony fishes)
2
(marine invertebrates)

Urea
Glyoxylate
(amphibians, cartilag. fish)
14
Pyrimidine Catabolism
Uridine or deoxythymidine
CMP
Cytidine
Uracil (Thymine)
Dihydrouracil (Dihydrothymine)
Ureidopropionate (Ureidoisobutyrate)
15
CO2 NH4
H2
(Methyl)malonyl semialdehyde
Malonyl-CoA (Methylmalonyl-CoA)
Succinyl-CoA
16
Quiz 4
BIOSYNTHESIS of Nucleotides
Take a sheet of paper. Put your name on it.
Your task is to determine the minimum number of
compounds required to make UTP.
I
The compounds that you select must be. (1) two
amino acids that are closest to UTP in the
pathway (2) one high energy source (3) one
carbohydrate that is closest to UTP in the
pathway
Show how it is possible to synthesize UTP with
only two of the compounds named above.
II
Part I is worth 1 points or 4 points total
Part II is worth 4 points
17
I Answers
1. Amino acids glutamine, aspartate
2. Energy source ATP
3. Carbohydrate Ribose or Ribose-5-PO4