????? Nucleotide metabolism

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?????Nucleotide metabolism
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????????

• ???????synthesis materials for nucleic acid
• ??Nucleotides Carry Chemical Energy in Cells
• ??????Some Nucleotides Are Intermediates in
  Cellular Communication
• ????Nucleotides Are Components of Many Enzyme
  Cofactors
• ??????? UDPG

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Energy in Nucleotides
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???

• The phosphate ester and phosphoric acid anhydride
  bonds of ATP. Hydrolysis of an anhydride bond
  yields more energy than hydrolysis of the ester.
  A carbon anhydride and ester are shown for
  comparison

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?????

• cAMP
• cGMP

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Intermediates in Cellular Communication

• ???????
• ppGpp ?????????????rRNA?tRNA??????

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For protein modification

• ??ADP-?????ADP-?????????,
• ??????????????????ADP-??,
• ??????????NAD????????????eEF-2?,???

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Nuclear protein digestion

• peptic acid proteins
• nuclear protein
• from food nucleic acids
• pancreas nuclease
• nucleotides
• pancreas,bowel nucleotase
  base
• phosphate
  nucleoside
• 
  nucleosidase
• 
  
  pentose

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????
??

• ????? ?????

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???????
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Metabolism of purine nucleotides

• De novo synthesis
• liver
• Anabolism
• Salvage pathway
• brain,bone marrow

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De novo synthesis

• ??????????(IMP)
• IMP???????????(AMP)???????(GMP)
• ATP,GTP????

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???????
????
???
???
????
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IMP??? 1
???????
PRPP???
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IMP??? 2
1-??-5-????
?????
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IMP??? 2-5
Stage 1 Formation of 5-aminoimidazole
ribonucleotide from PRPP 2. Addition of
glycine 3. Formylation 4. Adding of amino group
from Gln. 5. Imidazole ring closure.
???
????
??FH4
????
????
AIR???
GAR???
?????
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IMP??? 6-10
Second stage of purine biosynthesis Formation of
inosinate from 5-aminoimidazole ribonucleotide 6.
Carboxylation 7.Addition of aspartate 8.Eliminaton
fumarate(leaving the amino group) 9.Formylation
by N10-formylterahydrofolate 10.Dehydration and
ring closure
????
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???????????

• ??????????????????,???????????????????????
• ????????????????? ?
• ???????????????????,???????????
• ???IMP,???AMP,GMP?

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??AMP?GMP???
????? ?????
Aspartate ?????? ???? GTP
???
IMP???
IMP??? NAD
GMP??? ATP
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??ATP?GTP???

• ???????,?ATP?????
• AMP ? ADP ? ATP
• GMP ? GDP ? GTP

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Regulation of purine biosynthesis
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Regulation of purine biosynthesis
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??????????
?????????? ????-??? ???????
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Salvage pathway of purine

• Adenine PRPP APRT AMP PPi
• Hypoxanthine PRPP HGPRT IMP PPi
• Guanine PRPP HGPRT GMP PPi
• Adenonine adenosine kinase AMP
• ATP ADP

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????????

• Conserve energy???????????,????
• Decrease consumption of amino acid ????????

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????????

• There is no de novo synthesis in some organs such
  as brain and bone marrow.
• ????????,???????????,?????????,???????????????

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??????????
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Production of deoxynucleotides
2???
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Purine analogs
-SH??

• 6-????(6MP)?
• 6-??????
• ?????
• ????-??????????
• ????
• PRPP?????

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??????Purine analogs

• 8-?????

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???????
HN
H
N
H2N
H
O C
H N 10
H
5N H
HN
CH2
N -L-Glu H
C
O

• ???????

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??????
????????CH3
N
N
H2N
C
O C
H N 10
5N
N
CH2
N -L-Glu H
C
NH2
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Aminioterin and Methotrexate
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???????
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Amino acid analogs

• ?????azaserine ?6-??-5-?????,
• ??????????
• ???????????????

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????????????
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Degradation of purine
????
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Pyridine de novo synthesis
????HCO3-
2ATP
?????????II
2ADPPi
?????? ??????
??????
???????
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UMP???
???????
???
???
??????
??????
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UMP??UTP
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CTP???
dUDP
dUMP
TMP
UDP
TMP???
dCMP
???
CTP???
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Production of dTMP
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Regulation of pyrimidine Synthesis

• ATP CO2 aspartic acid
• aminoformylphosphate
• Carbamoyl aspartate purine
  nucleosides
• PRPP
  ATP5-phosphoribose
• UMP
• 
  pyrimidine nucleotide
• UTP CTP

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?????????????
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Salvage pathway of pyrimidine

• pyrimidine PRPP
  phosphoribosyl transferase
• PyrimidinePRPP PMP
  PPi
• UridineATP uridine kinase UMPADP
• Thymidine ATP thymidime kinase TMPADP

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??????????

• ?????Pyrimidine analogs
• 5-????5-FU
• ??????Amino acid analogs azaserine
• ?????
• Pyrimidine nucleoside analogs
• AC-1075, cyclo-c, Ara-C

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Some analogs
??
??
OH????? Ara-C
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