Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.
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Transcript of Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.
![Page 1: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/1.jpg)
Anabolism of Nitrogen Compounds
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Nitrogen CycleFig. 22-1 Lehninger POB 4th Ed.
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Nitrogenase is a Very Important Enzyme
• Fe:S complexes as seen before• Mo:Fe complexes• Mg2+ cofactor• doesn’t occur in aerobic environment: plant produces
leghemoglobin
N N 2 NH4
Nitrogenase Complex
16 ATP16 ADP+ 16 Pi
2 H+H2
4 CoA4 Pyr 4 Acetyl CoA
4 CO2
.
.
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Movement of NH4+
• Just like catabolism, distribution is through Glu and Gln
• Glu not synthesized de novo in mammals, instead KG is aminated via glutamate dehydrogenase, a mitochondrial enzyme.
H3N C
CO2
CH2
H
CH2
CO2
C
CO2
CH2
CH2
CO2
O
NH4
Glutamate dehydrogenase
H2O
NADPH
+ H+NADP+
.
.
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Glutamine Synthetase is Control Point for Nitrogen Anabolism
Heavily regulated: allosteric inhibition by carbamoyl phosphate, Trp, AMP, CTP, His, Gly, Ala, glucosamine-6-phosphate
H3N C
CO2
CH2
H
CH2
CO2
+ NH4
H3N C
CO2
CH2
H
CH2
CO NH2
Gln Synthetase
Mg2+
ATP ADP+ Pi
+ H2O
.
.
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2nd Mechanism of Glutamine Synthetase Regulation Unique: AMP Attached to Tyr
Fig. 22-7(a) Lehninger POB 4th Ed.
• Adenylated form is inactive form• Cascade leads to adenylation as shown in 22-
7(b)
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Essential Amino Acids
• PVT TIM HALL
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Number of Enzymes Required to Synthesize Amino Acids
Table 30-2, Harper’s ROB, 24th Ed.
EssentialPhe 10Val 1 (7shared)Trp 5 (8 shared)Thr 6Ile 8 (6 shared)Met 5 (4 shared)His 6Arg 7Lys 8Leu 3 (7 shared)Total 59
NonessentialAla 1Asp 1Asn 1Glu 1Gln 1Pro 3Ser 3Gly 1Cys 2Tyr 1Total 15
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Semiessential Amino Acid
CO2
C H
CH2
H3N
CO2
C H
CH2
H3N
OH
Phe Hydroxylase
O2 H2O
NADNADH+ H
.
.
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Cys Synthesis
CH
NH3
CH2CH2SCO2 CH CO2CH2
NH3
Cystathionine
CH
NH3
CH2CH2SHCO2
Homocysteine
CH CO2HOCH2
NH3
Serine
H2O
cystathionineß-synthase
.
.
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Cys Synthesis
CH
NH3
CH2CH2SCO2 CH CO2CH2
NH3
Cystathionine
-ketobutyrate
C CH2CH3CO2
OCys
CH CO2CH2
NH3
HS
H2O
NH4
PLPcystathionine
-lyase
.
.
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Cys SynthesisHomocysteine Generation
Met SAM SAH
SAH
H2O Adenosine
homocysteine
ATP PPi+ Pi
methylacceptor
methylatedacceptor
methyltransferaseadenylyltransferase
hydrolase
.
.
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Creatine Synthesis
Gly Ornithine
Arg-Gly Transaminidase(Kidney) Glycocyamine
CNH2
NH2
HN CH2CO2
.
.
H3N C
H
CH2
CO2
CH2
CH2
NH
CH2N NH2
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Creatine Synthesis
Glycocyamine
CNH2
NH2
HN CH2CO2
Guanidoacetate Methyltransferase(Liver)
SAM SAH
Mg2+
ATP ADP
Creatine phosphate
CNHNH~
N CH2CO2
CH3
Pi
.
.
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Creatine Function
ADP ATP
Creatine Phosphate Creatine
Creatinephosphokinase
.
.
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Creatine Degradation
Nonenzymatic(Muscle)
Pi + H2O
Creatine phosphate
CNHNH~
N CH2CO2
CH3
Pi
CN CH2
CNO
CH3
H
NH
Creatinine
.
.
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Serotonin (5HT)
N
CO2
C H
CH2
H3N
H
N
C H
CH2
H3N
H
HO
H
Serotonin(5-hydroxytryptamine)
PLP
5 hydroxytryptophandecarboxylase
CO2
N
CO2
C H
CH2
H3N
H
HO
5-hydroxytryptophan
Trp hydroxylase
THF DHFO2 H2O
.
.
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DOPA/Dopamine
CO2
C H
CH2
H3N
OH
CO2
C H
CH2
H3N
OH
HO
C H
CH2
H3N
OH
HO
H
Dopamine
Dopadecarboxylase
CO2
PLP
DopaTyr
.
.
Tyr hydroxylase
THF DHFO2 H2O
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Questions from last time
N
C H
CH2
H3N
H
HO
H
Serotonin(5-hydroxytryptamine)
serotonin N-acetylase
acetyl CoACoASH
N
CH2
CH2
H
HO
NH
C O
CH3
N-acetylserotonin
N
CH2
CH2
H
CH3O
NH
C O
CH3
melatonin
methyl transferase
SAM SAH
.
.
monoamineoxidase(MAO)
O2
NH4
N
C O
CH2
H
HO
H
5-hydroxyindole-3-acetate
excreted as conjugates
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Epinephrine
C H
CH2
H3N
OH
HO
H
C H
CH
H3N
OH
HO
H
OH
norepinephrine
phenylethanolamineN-methyltransferase
SAM SAH
CH2
CH
H2N
OH
HO
OH
CH3
epinephrine .
.
Dopamineß-hydroxylase
O2
Cu+2
vitamin CH2O
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Histamine
CO2
C H
CH2
H3N
N NH
PLP
CO2
Histidinedecarboxylase
NH3
CH2
CH2
N NH
.
.
![Page 22: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/22.jpg)
Polyamines
H3N C
H
CH2
CO2
CH2
CH2
NH3
ornithinedecarboxylase
CO2
putrescine
CH2
NH3
CH2
CH2
CH2
NH3
ornithine
.
.
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Polyamines
decarboxylatedSAM
putrescine
spermidinesynthase
CH3-S-A
NH2
CH2
CH2
NH3
NH3
(
( )4
)3
.
.
![Page 24: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/24.jpg)
Polyamines
H3N C
H
CH2
CO2
CH2
S
CH3
Met
ATP PPi+ Pi
Mg2+
H3N C
H
CH2
CO2
CH2
S
CH3
A
SAM
SAMDecarboxylase
CO2
PLP
H3N C
H
CH2
H
CH2
S
CH3
A
decarboxylatedSAM
.
.
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Polyamines
decarboxylatedSAM
spermidine
sperminesynthase
CH3-S-A
NH2
CH2
CH2
NH2
NH3
CH2)3
NH3
(
( )3
)4
(
spermine .
.
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Glutathione Synthase
H3N C
CO2
CH2
H
CH2
CO2
+H3N C
CO2
CH2
H
CH2
C
C
CO2
CH2SH
HNH
O
CO2
C H
CH2SH
H3N
CO2
C H
H
H3N
H3N C
CO2
CH2
H
CH2
C
C
CO2
CH2SH
HNH
O
+
Mg2+
ATP ADP+ Pi
-glutamylcysteinesynthetase
Mg2+
ATP ADP+ Pi
glutathionesynthetase
H3N C
CO2
CH2
H
CH2
C
C
CH2SH
HNH
O C
O CO2
C H
H
N
H
Glutathione(GSH)
.
.
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Heme Metabolism(Liver Mitochondria)
CH2
C
CH2
O
CO2
S-CoA
CH2
NH3
CO2 CoASH
-aminolevulinatesynthase
CH2
C
CH2
CO2
O
CH
CO2
NH3
-aminolevulinatesynthase
CO2
CH2
C
CH2
CO2
O
CH2
NH3
-aminolevulinate-amino-ß-ketoadipate
PyrP
Heme
.
.
Liver Mitochondria
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Heme Metabolism(Liver Cytoplasm)
NH
CHCH2
NH3
CH2 CH2
CO2 CH2
CO2
Porphobilinogen
CH2
C
CH2
CO2
O
CH2
NH3
2
Liver Cytoplasm
2 H2O
porphobininogensynthase, AKA
ALA dehydratase
.
.
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Heme Metabolism
CN
CH
CN
CH
C
HN
HC
NH
C
HC
CH3 CH
CH3
CH2
CH CH2
CH3
CH2
CH3CH2
CH2
CO2
CH2
CO2
Protoporhyrin
2. uroporphyrinogenIII cosynthase
3. uroporphyrinogendecarboxylase
CO2
4. coporphyrinogenoxidase (Mw)
CO2
1. uroporphyrinogensynthase
NH4
NH
CHCH2
NH3
CH2 CH2
CO2 CH2
CO2
4
Fe2+ added in mitochondria (Mw)to form porphyrin
.
.
![Page 30: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/30.jpg)
Heme Metabolism
CN
CH
CN
CH
C
N
HC
N
C
HC
CH3 CH
CH3
CH2
CH CH2
CH3
CH2
CH3CH2
CH2
CO2-
CH2
CO2-
Fe3+
CN
CH
CN
CH
C
N
HC
N
C
HC
CH3 CH
CH3
CH2
CH CH2
CH3
CH2
CH3CH2
CH2
CO2-
CH2
CO2-
Fe2+heme oxygenase
(microsomal)
NADPH+ H+
NADP+
heme oxygenase(microsomal)
NADPH
+ H+ +O2
NADP+
+ H2O
CN
CH
CN
C
C
N
HC
N
C
HC
CH3 CH
CH3
CH2
CH CH2
CH3
CH2
CH3CH2
CH2
CO2-
CH2
CO2-
OH
Fe3+
.
.
![Page 31: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/31.jpg)
Heme Metabolism
O2 Fe3+
CO
HN
O
HNP
CHCH2
N
P
HN
CHCH2
OBiliverdin IX-
biliverdin reductase
NADPH+H+
NADP+
HN
O
HNP
CHCH2
N
P
HN
CHCH2
O
H
H
Bilirubin IX-(yellow)("green")
Conjugation
.
.
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Conjugation
• Bilirubin diglucuronide– Glucuronic acid– Added in open chain form– Added to propyl groups– Increases water solubility
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De novo Purine Synthesis 1
O
OHHO
2-O3POH2C
OH
-D-ribose-5-phosphate
AMP, GMP, IMP
O
OHHO
2-O3POH2C
O P O
O
P
O
O
O
O
PRPP
PRPP synthetase
Mg2+
ATP AMP
.
.
![Page 34: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/34.jpg)
De novo Purine Synthesis 2
AMP, GMP, IMP
O
OHHO
2-O3POH2C NH3
Note changein conformation
5'-phospho-ß-D-ribosylamine
H2O PPiGln Glu
Gln:PRPP amidotransferase
O
OHHO
2-O3POH2C
O P O
O
P
O
O
O
O
PRPP
.
.
![Page 35: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/35.jpg)
De novo Purine Synthesis 3
glycinamideribosyl-5'-phosphate
O
OHHO
2-O3POH2C NH
CO
CH2
NH3
5'-phosphoribosylglycinamide synthetase
ADP+ Pi
ATPMg2+
H2O
CH2
CO2
H3N
O
OHHO
2-O3POH2C NH3
5'-phospho-ß-D-ribosylamine
.
.
![Page 36: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/36.jpg)
De novo Purine Synthesis 4
glycinamideribosyl-5'-phosphate
O
OHHO
2-O3POH2C NH
CO
CH2
NH3
R5P
NH
CO
CH2
NC
H
H
O
formylglycinamideribosyl-5'-phosphate
formyltransferase
N10-formyl-THF
THF
.
.
![Page 37: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/37.jpg)
De novo Purine Synthesis 5
R5P
NH
CO
CH2
NC
H
H
O
formylglycinamideribosyl-5'-phosphate
Mg2+
ATP ADP+ Pi
formylglycinamidine ribosyl-5'-phosphate synthetase
Gln Glu R5P
NH
CHN
CH2
NC
H
H
O
.
.
![Page 38: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/38.jpg)
De novo Purine Synthesis 6
R5P
NH
CHN
CH2
NC
H
H
O
aminoimidazole ribosyl-5'-phosphate synthetase
H2OADP+ Pi
ATP
Mg2+
N
N
R5PNH2
aminoimidazoleribosyl-5'-phosphate
.
.
![Page 39: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/39.jpg)
De novo Purine Synthesis 7
N
N
R5PNH2
aminoimidazoleribosyl-5'-phosphate
N
N
R5PNH2
CO2
aminoimidazole carboxylateribose-5'-phosphate
aminoimidazoleribosyl-5'-phosphate
carboxylase
CO2
Note: no biotin, no ATP
.
.
![Page 40: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/40.jpg)
De novo Purine Synthesis 8
N
N
R5PNH2
CO2
aminoimidazole carboxylateribose-5'-phosphate
N
N
R5PNH2
CNCH
CH2
CO2
CO2
O
aminoimidazole succinyl carboxamideribosyl-5'-phosphate
succinyl carboxamideribosyl-5'-phosphate synthetase
H2OAspADP+ Pi
ATPMg2+
.
.
![Page 41: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/41.jpg)
De novo Purine Synthesis 9
N
N
R5PNH2
CNCH
CH2
CO2
CO2
O
aminoimidazole succinyl carboxamideribosyl-5'-phosphate
adenylosuccinase
H2O
CH
CH
CO2
CO2
N
N
R5PNH2
CNH2
O
aminoimidazole carboxamideribosyl-5'-phosphate
.
.
![Page 42: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/42.jpg)
De novo Purine Synthesis 10
N
N
R5PNH2
CNH2
O
aminoimidazole carboxamideribosyl-5'-phosphate
N
N
R5PNH
CNH2
O
CO
Hformimidoimidazole carboxamide
ribosyl-5'-phosphate
.
.
formyltransferase
THFN10-formyl-THF
![Page 43: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/43.jpg)
De novo Purine Synthesis 11
N
N
R5PNH
CNH2
O
CO
Hformimidoimidazole carboxamide
ribosyl-5'-phosphate
N
N
R5P
N
N
O
IMP
H2O
IMP synthase
.
.
![Page 44: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/44.jpg)
De novo Purine Synthesis 12a
N
N
R5P
HN
N
O
IMP N
N
R5P
N
N
N
C CO2
H
CH2CO2
Adenylosuccinate
adenylosuccinate synthetase
H2OAspGDP+ Pi
GTP
Mg2+
.
.
![Page 45: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/45.jpg)
De novo Purine Synthesis 13a
N
N
R5P
N
N
N
C CO2
H
CH2CO2
Adenylosuccinate
N
N
R5P
N
N
NH2
AMP
adenylosuccinase
H2O
CH
CH
CO2
CO2
.
.
![Page 46: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/46.jpg)
De novo Purine Synthesis 12b
N
N
R5P
HN
N
O
IMP
N
N
R5P
N
N
O
O
XMP
IMP D.H.H2O
NAD+NADH
+ H+
.
.
![Page 47: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/47.jpg)
De novo Purine Synthesis 13b
N
N
R5P
N
N
O
O
XMP
N
N
R5P
N
N
O
NH2
GMP
XMP:Gln amidotransferase
Gln Glu ATP AMP+ PPi
.
.
![Page 48: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/48.jpg)
De novo Pyrimidine Synthesis 1
carbamoylphosphate
C
O
NH3 OPO32-
Gln Glu2 ATP
2 ADP+ 1 Pi
carbamoyl phosphatesynthetase II
HCO3
.
.
![Page 49: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/49.jpg)
De novo Pyrimidine Synthesis 2
carbamoylphosphate
C
O
NH3 OPO32-
CTP
Asp Pi
N-carbamoyl aspartate
CO2
C H
CH2
N
CO2
H
C
O
NH3
aspartatetranscarbamoylase
.
.
![Page 50: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/50.jpg)
De novo Pyrimidine Synthesis 3
N-carbamoyl aspartate
CO2
C H
CH2
N
CO2
H
C
O
NH3 N
N
H
O
H
O
CO2H2O
dihydroorotase
dihydroorotate
.
.
![Page 51: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/51.jpg)
De novo Pyrimidine Synthesis 4
N
N
H
O
H
O
CO2NADH
+ H+
NAD+
dihydroorotate D.H.*N
N
H
O
H
O
CO2
dihydroorotate
.
.
![Page 52: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/52.jpg)
De novo Pyrimidine Synthesis 5
N
N
H
O
H
O
CO2
orotate:phosphoribosyltransferase
PRPP PPiO
OHHO
2-O3POH2C
N
NO
H
O
CO2
oritidylate(OMP)
orotate
.
.
.
.
![Page 53: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/53.jpg)
De novo Pyrimidine Synthesis 6
O
OHHO
2-O3POH2C
N
NO
H
O
UMP
oritidylatedecarboxylase
CO2
O
OHHO
2-O3POH2C
N
NO
H
O
CO2
oritidylate(OMP)
.
.
![Page 54: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/54.jpg)
De novo Pyrimidine Synthesis 7
O
OHHO
PPPOH2C
N
NO
H
O
UTP
O
OHHO
2-O3POH2C
N
NO
H
O
UMP
2 ADP2 ATP
1. NMPK2. NDPK
.
.
![Page 55: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/55.jpg)
De novo Pyrimidine Synthesis 8
O
OHHO
PPPOH2C
N
NO
H
O
UTP
O
OHHO
PPPOH2C
N
NO
H
NH2
CTP
cytidylate synthetase
Gln Glu ATP ADP+ Pi
.
.
![Page 56: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/56.jpg)
Loose Ends: Ribonucleotide Reductase
NDP
ODP N
HO OH
dNDP
ODP N
HO H
Ribonucleotide reductase
reducedthioredoxin
oxidizedthioredoxin
thioredoxinreductase
FADH2FAD
NADPH
+ H+NADP+
.
.
![Page 57: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/57.jpg)
Loose Ends: T Synthesis
UDP dUDPRibonucleotide reductase
NADPH
+ H+NADP+
.
.
![Page 58: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/58.jpg)
Loose Ends: T Synthesis
dUMP dTMPdUDPPhosphatase
H2O Pi
Thymidylate synthase
N5,N10-methylene THFDHF
.
.
![Page 59: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/59.jpg)
Loose Ends: T Synthesis
dTTPdTMP
2 ADP2 ATP
1. NMPK2. NDPK
.
.
![Page 60: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/60.jpg)
Summary of Nucleotide Synthesis
• Purines built up on ribose– PRPP synthetase key step– 13 enzyme activities on 3 polypeptides (to IMP)
• Pyrimidine rings built, then ribose added– Carbamoyl phosphate synthetase II key step– Multifunctional enzyme (mammals): all but
dihydroorotate DH (CAD)
• Salvage is important—rapid turnover of mRNA
![Page 61: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/61.jpg)
Summary of Nucleotide SynthesisSource of Atoms
.
.
N
CN
C
CC
NH2
O
N
CN
C
CC
O
CH3
OCO2
NH4
Asp
Gln
N5,N10-methyleneTHF
N
CN
C
CC
O
O
N
C
NC
N
CC
CN
NH2
N
C
NC
N
CC
CN
O
NH2
Gln
N10-formylTHF
Gly
Asp
CO2
![Page 62: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/62.jpg)
Purine Salvage Occurs by Two Mechanisms: From Bases
N
NN
N
NH2
O
Guanine
N
N N
O
N
Hypoxanthine
O
OHHO
2-O3POH2C
N
N N
O
N
IMP
O
OHHO
2-O3POH2C
N
NN
N
NH2
O
GMP
.
.
Adenine AMP
PRPP PPi
adenine phosphoribosyl transferase
PRPP PPi
hypoxanthine-guaninephosphoribosyl transferase
(HGPRT)
![Page 63: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/63.jpg)
Purine Salvage Occurs by Two Mechanisms: From Nucleosides
AdenosineDeoxyadenosine
AMPdAMP
DeoxycytidineDeoxyadenosineDeoxyguanosine
Adenosine Kinase
ATP ADP
DeoxycytidineKinase
ATP ADP
dCMPdAMPdGMP
.
.
![Page 64: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/64.jpg)
Pyrimidine Salvage Occurs Only From the Nucleosides
ATP
Mg2+
ADP
Uridine-cytidinekinaseUridine
CytidineUMPCMP
ATP
Mg2+
ADP
deoxycytidinekinase
deoxycytidine dCMP
ATP
Mg2+
ADP
Thymidinekinase
thymidine TMP
.
.
![Page 65: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/65.jpg)
Regulation is Complex
• PRPP pool size is a major point of de novo synthesis
• PRPP stimulates pyrimidine synthesis
• TDP inhibits PRPP production
![Page 66: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/66.jpg)
AMP, GMP and IMP Feedback Inhibit Allosterically
R-5-P PRPP RibosylamineAMPAMP/ADP
GMP/GDPIMP IMP
GMP
.
.
![Page 67: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/67.jpg)
AMP and GMP Inhibit Their Own Synthesis From IMP
IMP
GMP
AMP ATP
GTP
.
.
![Page 68: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/68.jpg)
Ribonucleotide Reductase is Heavily Regulated
Fig. 22-40(a) Lehninger POB 4th Ed.
• Note dimeric protein• Complicated
mechanism involving free radicals
• Overall activity controlled by ATP/dATP
![Page 69: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/69.jpg)
Ribonucleotide Reductase is Heavily Regulated
Fig. 36-10, Harper’s ROB, 24th Ed.
• Note dimeric protein• Complicated
mechanism involving free radicals
• Overall activity controlled by ATP/dATP
• Allosteric control
![Page 70: Anabolism of Nitrogen Compounds. Nitrogen Cycle Fig. 22-1 Lehninger POB 4 th Ed.](https://reader035.fdocuments.us/reader035/viewer/2022062308/56649d485503460f94a23a6d/html5/thumbnails/70.jpg)
Pyrimidine Synthetic Enzyme Gene Expression is Also Regulated
• Multifunctional protein (dihydroorotate dehydrogenase separate)
• coordinate repression and derepression (will talk about later)