Nucleotide metabolism
De novo synthesis of purine
Salvage pathway for purine
Purine degradation
balance of purine
purine nucleotide cycle
in muscle
De novo synthesis of pyrimidine
Nucleotide biosynthesis
de novo biosynthesis pathway
salvage purines & pyrimidines
from diet & degradative pathways
好的抗癌、抗菌目標
ribose可代謝產能,
nitorgenous base不行
嘌呤環上N的來源
11 steps
ribose-5-P → IMP
N-1:aspartate (aspartic acid)
C-2、C-8:N10-formyl-THF
N-3、N-9:glutamine amide N
C-4、C-5、N-7:glycine
C-6:CO2
STEP 1
STEP 2
STEP 11
酵素
PRPP synthetase / ribose-5-phosphate pyrophosphokinase
反應
ribose-5-phosphate → PRPP
PRPP:5-phosphoribosyl-α-pyrophosphate
加 glutamine
反應
PRPP → phosphoribosyl-β-amine
酵素
Gln:PRPP amino-transferase
azaserine
很像glutamine→
抑制glutamine dependent酵素
反應
FAICAR →inosine monophosphate (IMP)
FAICAR:N-formylaminoimidazole-4-carboxamide ribonucleotide
酵素
IMP synthase
Rate-limiting step
First-committed step
purine & pyrimidine ribonucleotides
inhibit
click to edit
需要 6 ATP
multifunctional enzymes
A-1/A-2/A-3
STEP 3.4.6
B-1/B-2
STEP 7.8
C-1/C-2
STEP 10.11
tetrahydrofolate
folate
缺乏folic acid會導致核苷酸不足
→貧血anemia
acceptors & donors of
one-carbon units
active form of folate
for all oxidation level carbon
(除了CO2)
oxidation level
formate (2)
-CH=O
N10-formyl-THF
formaldehyde (0)
methanol (-2)
precursor
6-methyl pterin
PABA
glutamine
sulfonamides
磺胺類藥物
compete
click to edit
block folic acid formation
analogs
methotrexate
aminopterin
anti-cancer
in purine synthesis
STEP 4.10
IMP → AMP or GTP
AMP synthesis
GTP synthesis
STEP 1
反應
酵素
adenylsuccinate synthetase
STEP 2
IMP + aspartate → adenylsuccinate
反應
adenylsuccinate → AMP + fumerate
需要GTP
酵素
adenylsuccinase / adenylsuccinate lyase
STEP 1
反應
IMP → XMP
酵素
IMP dehydrogenase
STEP 2
反應
XMP → GMP
酵素
GMP synthetase
需要ATP
regulation
IMP synthesis
R-5-P pyrophosphokinase
AMP synthesis
ADP & GDP (-)
Gln:PRPP aminotransferase
AMP, ADP, ATP & GMP, GDP,GTP & IMP (-)
PRPP (+)
GMP synthesis
adenylsuccinate synthetase
AMP (-)
IMP dehydrogenase
GMP (-)
NMP → NDP & NTP
specific nucleoside monophosphate
AMP + ATP → 2ADP
酵素:adenylate kinase
GMP + ATP → GDP + ADP
酵素: guanylate kinase
nucleoside diphosphate kinase
all NDP + ATP → NTP + ADP
回收核酸分解出的purine:adenine, guanine, hypoxanthine
發生在extrahepatic tissues
發生在liver
佔嘌呤生物合成90%
不消耗ATP
adenine + PRPP ↔ AMP + PPi
酵素:adenine phosphoribosyl transferase (APRT)
hypoxanthine + PRPP ↔ IMP + PPi
guanine + PRPP ↔ GMP + PPi
酵素: hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
缺乏HGPRT
Lesch-Nyhan syndrome
purine synthesis 增加200-fold
血液中 uric acid 增加
(purine代謝產生尿酸)
severe arthritis
最終產物:uric acid
AMP
adenosine
adenosine deaminase (ADA)
inosine
AMP deaminase
IMP
purine nucleoside
phosphorylase (PNP)
nucleotidase
nucleotidase
hypoxanthine
XMP
nucleotidase
xanthosine
PNP
xanthine
xanthine oxidase
GMP
nucleotidase
guanosine
PNP
guanine
guanine deaminase
xanthine oxidase
uric acid
四肢累積過多尿酸
gout 痛風
allopurinol 可抑制 xanthine oxidase
de novo synthesis
(10%)
purine necleotides in use
uric acid
(10%)
recycling
(90%)
wastes
運動時,AMP deaminase 將AMP → IMP,釋放NH3
因為AMP量下降,促進adenylate kinase製造更多ATP
IMP 可再回收為AMP
嘧啶環的來源
3C、N:aspartate
N:glutamine
C:HCO3-
主要的嘧啶
cytosine
uracil
thymine
6 steps
glutamine → UMP
STEP 1
glutamine + HCO3- + 2ATP + H2O → carbamoyl phosphate + glutamate
酵素
carbamoyl phosphate synthase II (CPS II)
STEP 2
carbamoyl-P + aspartate → carbamoyl-Asp
activator:PRPP
inhibitor:UTP
酵素
aspartate transcarbamoylase (ATCase)
STEP 3
carbamoyl-Asp → dihydroorotate (DHO) + OH-
酵素
dihydroorotase
STEP 4
DHO → orotate (一種嘧啶)
酵素
DHO dehydrogenase
STEP 5
orotate + PRPP → orotidine 5'-monophosphate (OMP)
酵素
orotate phosphoribosyltransferase
PRPP 提供 ribose-P
STEP 6
OMP → UMP + CO2
酵素
OMP decarboxylase
multifinctional polypeptides
CPS II, ATCase, dihydroorotase,
orotate PRT, OMP decarboxylase
metabolic channeling more efficient
3 steps
UMP → CTP
STEP 1
STEP 2
STEP 3
UMP + ATP → UDP + ADP
酵素
nucleoside monophosphate kinase
UDP + ATP → UTP + ADP
酵素
nucleoside diphosphate kinase
UTP + glutamine + ATP → CTP + glutamate
酵素
CTP synthetase
regulation
animals
bacteria
CPS II
PRPP, IMP, ATP (+)
UDP, UTP (-)
ATCase
ATP (+)
CTP (-)
pyrimidine degradation
人類:free pyrimidines bases不會salvaged
(只有nucleotides中的會被回收)
cytosine, uracil
分解代謝產生
β-alanine, ammonium, CO2
β-alanine 可被回收合成coenzyme A
thymine
分解代謝產生
β-aminoisobutyric acid (BAIBA), ammonium, CO2
form deoxyribonucleotides
細胞中90%的核酸是RNA
NDP的2'C去氧→dNDP
酵素
ribonucleotide reductase
3 nucleotide binding sites
C:substrate (active site)
on R2
NDPs
α2β2
A:activity-determining (overall activity site)
on R1
ATP(+) & dATP(-)
S:specificity-determining (substrate specific site)
on R1
ATP
thioredoxin reductase & thioredoxin提供還原力
(reversible sulfide:sulfhydryl transition)
(S-S/SH HS 氧化還原循環)
Tyr122 free radical
1>> removal of Ha hydrogen(Cys439)
2>> creation of C-3' redical
disulfide formation between Cys225 & Cys462
1>> dehydration
2>> form dNTP
dTTP
dGTP
dATP
偏向反應
CDP, UDP
偏向反應
GDP, ADP
偏向反應
ADP
SCID:severe combined immunodeficiency
缺乏ADA >> deoxyadenosine 不能轉為deoxyinosine
nucleoside kinase 將其轉為dAMP → dATP
dATP 抑制 ribonucleotide reductase
無法合成dNTP, 無法複製DNA
Thymine nucleotides合成
dUDP, dCDP → dTMP
dUDP → dUTP →
dUTPase
→ dUMP → dTMP
dCDP → dCMP
dCMP deaminase
→ dUMP → dTMP
dUMP → dTMP
酵素:thymidylate synthase
methylate甲基化dUMP的5號位
甲基提供者: N5,N10-methylene-THF
reductive methylation