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Pyrimidine Biosynthesis
NOTABLES
Carbamoyl Phosphate Synthetase II
Aspartate Transcarbamylase (ACTase)
2 components to make ring
PRPP (to add ribose)
5’-UMP is the product
Carbamoyl-PO4 Synthetase II
COO+
H3N-C-H
CH2
CH2
C=O
NH2
L-Glutamine
O
+ CO2 + 2ATP
H2N-C~OPO3=
+ 2ADP + PO4=
O
H2N-C~OPO3=
COO+
H3N-C-H
CH2
+
Carbamoyl-PO4
COOO
HO
H2 N
C
C
N
O OPO H
3
Energy
L-Aspartate
Aspartate
Transcarbamylase
O
Pi
C
CH2
C
H
COO-
H
HN
C
C
C
O
N
H
H
H
COO-
Dihydroorotate
O
O
H
C
HN
C
C
C
O
N
H
H
H
COO-
Dihydroorotate
H
C
NAD+
NADH + H+
HN
C
C
C
O
N
H
COO-
Orotate
(Looks like uracil with a
-COO- group)
O
O
H
C
H
C
HN
C
HN
C
C
C
C
C
O
N
H
Orotate
COO-
CH2OPO3=
O
OPP
HO OH
PRPP
O
N
COO-
CH2OPO3=
O
HO OH
Orotate monophosphate
O
H
C
HN
O
O
C
C
N
C
C
COO-
HN
CH
C
CH
O
N
CH2OPO3=
O
CH2OPO3=
CO2
O
HO OH
HO OH
5’-OMP
Uridine 5’-monophosphate
(5’-UMP)
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
?
Summary of Pyrimidine
Nucleotide Biosynthesis
5’-UMP
There is
no TMP,
TDP, TTP
dTTP
UTP
CTP
TTP
dCTP
dTTP
UDP
UTP
dUDP
CTP
CDP
dUTP
dCMP
dCDP
dUMP
dCTP
Rapid
dTDP
dTMP
Post Synthesis modifications
5’-UMP
UDP
UTP
Glutamine
O
dUDP Glutamate
HN
O
Deoxy Thymidine
synthesis requires
THF
CTP
N
dUMP
R
5,10-Methylene THF
O
HN
O
HN
CH3
N
R
NH2
Dihydrofolate
dTMP
Thymine
O
N
Cytosine
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 monophosphate.
Hypoxanthine-Guanine Phosphoribosyl Transferase
(HGPRT)
O
O
N
HN
H2 N
H2N
N
N
H
N
HN
PRPP
Guanine
Lesch-Nyhan Syndrome
N
N
CH2OPO3=
O
HO OH
+ PPi
Adenosine
Nucleotidase
O
C
N
Hypoxanthine
HN
C
C
HC N C N
Adenine
H2O2
O2
H
H
Adenine deaminase
O
N
C
HN
C
Xanthine
C
Xanthine
C N C N
Oxidase
O
H
H
O
C
H
N
H2O2
HN
C
C=O
C N C N
Fully oxidized O
H
H
Purine
Uric Acid
O2
PURINE
DEGRADATION
O
H
N
C
H
N
O
H2 N
C
C=O
C N C N
O
+ CO2
H
H
HN
C
C=O
C N C N
O
H
H
Uric Acid
Allantoin
(primates, birds, reptiles,
insects)
(other vertebrates)
O
NH
C-O- C=O
C N C N
Allantoic Acid O
H
H
H2 N
(bony fishes)
+
4NH4 + 2CO2
(marine invertebrates)
2
H2N
Urea
O
C
O
NH2 +
(amphibians, cartilag. fish)
H
O
C-C
O-
Glyoxylate
Pyrimidine Catabolism
NH4+
PO4
CMP
NADP+
UMP
dTMP
NADPH
+
O
C
HN
O
Uridine or deoxythymidine
Cytidine
C
N
H
H(CH3)
C H
C
H
H
Dihydrouracil
(Dihydrothymine)
PO4
(d)Ribose-1-PO4
H+
Uracil (Thymine)
O
H(CH3)
-OC
H2 N
CH2
O
C
N
H
CH2
Ureidopropionate
(Ureidoisobutyrate)
O
-O-
C
H2N
O
C
N
H(CH3)
CH
C
H2N
C
O H2 N
H(CH3)
CH
+ CO2 + NH4+
CH2
O
CH-(CH3)
S-CoA
-O-
CH2
COOC=O
O
NAD+
HS-CoA
COO-
-O-
C
CH-(CH3)
NADH +
H+
Malonyl-CoA
(Methylmalonyl-CoA)
CH=O
(Methyl)malonyl
semialdehyde
H2 N
Succinyl-CoA
H(CH3)
CH
CH2
Quiz 4
BIOSYNTHESIS of Nucleotides
Take a sheet of paper. Put your name on it.
I
Your task is to determine the minimum number
of compounds required to make UTP.
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
II
Show how it is possible to synthesize UTP with only two
of the compounds named above.
Part I is worth 1 points or 4 points total
Part II is worth 4 points
I Answers:
1. Amino acids:
glutamine, aspartate
2. Energy source:
ATP
3. Carbohydrate:
Ribose or Ribose-5-PO4
II. Answer:
Select glutamine and ATP
Pathway: Gln -> Glu -> Kg -> OAA ->Aspartate
OAA -> PEP -> ->Glu-6P -> Ribose-5-P -> PRPP