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Purine de novo synthesis, in LIVER, large energy expenditure (more than pyr de novo)

1. Start with activated ribose (PRPP)


2. Build on nitrogen base using simpler starting materials (aa/ATP/CO2/FH4) to synth nts
SALVAGE: reattach nitrogenous base to PRPP to synth nts
Reactant Enzyme
Product
Notes
1. ribose- PRPP synthase (55-phosphoribosyl-1- ATPAMP
5phosphoribosylpyroph pyrophosphate
MG+2 cofactor
phosphat osphate synthase)
(PRPPP)
Deficiency leads to Arts Syndrome in kids
e
Activated by Pi
Inactivated by purine nts (AMP, GMP, IMP)
1 high E bond (HEB)
2. PRPP
PRPP glutamyl
5-phosphoribosyl-1- *******COMMITTED STEP
amidotransferase
amine (PRA, III)
glutamine (amide grp = Nu)glutamate
(stopped in lrg amts of
PPi2Pi via pyrophosphatase (1 HEB)
AMP/GMP) (inhib by
AMP/IMP/GMP,
activated by PRPP)
3. PRA
Glycinamide riboside
Glycinamide ribosyl- ATPADP+Pi (1 HEB)
synthetase
5-phosphate (GAR,
Glycine (-COO reacts with amino of PRA, III)
IV)
PRPP pyrophosphate displaced by Gly amide N
Purine atome C4, C5, N7 from Gly
4. GAR
Formyl transferase
Formylglycinamide
Formyl grp of N10-formyl FH4 transferred to amino grp of Gly
ribosyl 5-phosphate res of GAR, IV
(FGAR, V)
N10-formyl FH4tetrafolate(FH4) forming pur C8
Inhibited by PABA analogs (sulfonamides): affect bacteria, not
humans
5. FGAR
VI Vynthetase
Formylglycinamidin 2nd Glutamine N donor, carbonyl O of FGAR replaced with NH2
e ribosyl 5amide of glutamine
phosphate (FGAM,
ATP, Mg2+ cofactor
VI)
1 HEB
6. FGAM VII Synthetase
Aminoinidazole
ATP
ribosyl-5-phosphate H2O removed
(AIR, VII)
1 HEB
7. AIR
VII carboxylase
Aminoinidazole
C6 from CO2, used as HCO3
carboxylate ribosyl5-phosphate (CAIR,
VIII)
8. CAIR
IX synthetase
Aminoimidazole
ATPADP+Pi
succinyl
Purine N1 from Asp

9.
SAICAR

Adenylosuccinase

10.
AICAR

Formyl transferase v

11.
FAICAR

IMP DH (inhib by
mycophenolic acid,
tiazofurin)

carboxamide
ribosyl-5-phosphate
(SAICAR, IX)
Aminoimidazole
carboxamide ribosyl
5-phosphate
(AICAR, X)
Formimidoimidazole
carboxamide ribsyl
5-phosphate
(FAICAR, XI)
Inosine
monophosphate

AMP Synthesis (7 HEB from ribose


1. IMP
Adenylosuccinate
synthetase (inhib by
AMP)
2.
Adenylsuccinase
adenylsuccinat
e
GMP Synthesis (8 HEB from ribose
1. IMP
IMP DH (inhib by
GMP)
2. XMP
GMP synthase

1 HEB
C atoms of Asp are released as fumarate
N1 from Asp joins with the imidazole ring
Final purine C2 removed
N10-formyl FH4FH4
Inhibited by folic acid analogs (methotrexate: inhibits reduction
of FH2FH4, trimethoprim: selectively inhibits dihydrofolate
reductase)
2nd ring closure
H2O removed from formyl, carboxamide grp
IMP rapidly converted to AMP & GMP
Joins base hypoxathine joined by a glycosidic bond N9-C1

5-PAMP)
Adenylosuccinate
Adenosine monophosphate
(AMP)
5-PGMP)
Xanthine monophosphate
(NAD dependent) (XMP)
Guanosine monophosphate
(GMP)

ATP + AMP
ATP + GMP
ATP + G/CDP

Adenylate kinase
Guanylate kinase
Nucleoside diphosphate kinase

Purine bases
(xanthine,

Hypoxanthine-guanine
phosphoribosyl transferase (HGPRT)

C^ carbonyl O if IMP is substituted by amino grp of


aspartate
GTP
Asp: N source
GTP: energy

Glu donates its amino N to the carbonyl O at C2 of


XMP
NAD+NADH (reduction)
Ppi2Pi via pyrophosphatase
Insufficient ATP leads to IMPGMP
ATP: energy, can be hydrolyzed further

2 ADP
GDP + ADP
GTP or CTP +
ADP
IMP, GMP

PRPP: sourece of ribose 5-phosphate


Deficiency: Lesch-Nyhan Syndrome

guanine)
Adenine
Adenosine +
ATP

(competitive inhib IMP/GMP)


Adenine phosphoribosyl transferase
(APRTase) (compet inhib: adenine)
Adenosine kinase (5phosphotranferase)

Degradation of Purine Bases


AMP
AMP deaminase
AMP/GMP/IMP
5nucleotidase
Adenosine

Adenosine deaminase

Guanine
Hypoxanthine

Guanase/guanine deaminase
Xanthine oxidase (inhib by
allopurinoloxypurinol)
Xanthine oxidase

Xanthine

AMP

PRPP: sourece of ribose 5-phosphate

AMP

IMP
Adenosine/guanosine/inosin
e
Inosine
Xanthine
Xanthine

Def of adenosine deaminase =


severe combined immunodeficiency
(SCID)
O2H2O2 (reduced)
H2O2H2O+O2 via catalase

Uric acid

Pyrimidine De Novo Synthesis (less energy expenditure)


1. Build nitrogen base using simpler starting materials (aa/ATP/CO2/FH4)
2. Add PRPP to synth nts
1. HCO3Carbamoyl phosphate synthase (CPSII)
Carboxyphosphate
(activated by PRPP, inhib by ATP/UTP/CTP)
1a.
Carbamic acid
carboxyphosph
ate
1b. carbamic
********CSPII, ATCase, dihyrdoorotase are
Carbamoyl
acid
domains of a sungle multycatalytic peptide
phosphate
chain
2. carbamoyl
phosphate

Aspartate transcarbomylase (ATCase)


(activated by ATP/GTP, inhib by CTP)

Carbomoyl aspartic
acid (CAA)

3. CAA

Dihydroorolase

Dihydroorotic acid
(DHOA)

ATPADP
NH3 (ammonia) from Glu side
chain
ATP
*********REGULARE STEP
CO2 provides C2
Glu N3
2 HEB
-amino Asp condenses donates
C4, C5, C6, N1
*******COMMITTED STEP
no E input
Closed hydrolytically
H2oO released btw middle amide
grp of carbomoyl & -carboxyl

Asp
4. DHOA

Dihyroorotate DH (DHODH) (inhib by


Leflunomide-immunosuppresive for
rheumatoid arth)
Orotate phosphoribosyl transferase
******OPT & OAD belong to domains of a
single multicatalytic polypep chain, def
causes type I orotic acid aciduria, both inhib
by allopurinol

Orotic acid (OA,


orotate)

6. OMP

Orotidylic acid decarboxylase (inhib by UMP)


def causes type II orotic acid aciduria

7. UMP

Nucleotide monophosphate kinase (UMP


kinase)
Nucleotide diphosphate kinase

Uridine
monophosphate
(UMP) (RNA
precursor)
Uridine diphosphate
(UDP)
Uridine triphosphate
(UTP)
Cytidine
triphosphate (CTP)

5. OA

8. UDP
9. UTP

CTP synthase (activated by ATP/GTP, inhib by


CTP)

10. UDP

NADPH-dependent ribonucleotide reducatase


(2 subunits, regulated by dTTP, inhib by dATP,
6-azaruridine: anticancer, hydroxyurea) (in
presence of thioredoxin: red agent w/2 free
sulfhydryl (-SH2) grps to facilitate easy
forming of DISULFIDE BOND,
thioreductasedisulfide via oxidation,
thioredoxin reductase regenerates red
thioredoxin))
Nucleotidase
Thymidylate synthase (activated by ATP/GTP,
inhib by CTP, 5-fluorouracil: anticancer)
5-fluorouridine triphosphate (FUMPdFUMP

11. dUDP
12. dUMP

Orotidine 5monophosphate
(OMP)

Deoxyuridine
diphosphate (dUDP)
(can be
phosphorylated to
triphosphate to
make dUTPs for
DNA synth)
dUMP
dTMP

Completed pyr ring attached to


ribose 5-P from PRPP (also
precursor for His and Trp)
PPi released (irreversible) PPi2Pi
via pyrophosphatase (1 HEB)
3 HEB in OMP synth from Glu &
CO2
3 HEB in UMP formation from Asp
& CO2
ATPADP+Pi
ATPADP+Pi
Glutamine amine donor (NH4 can
also be donor) replaces carbonyl
of UTP
Cannot occur at monophosphate
level
Glutamineglutamate
ATPADP+Pi
Reduced to deoxyribose occurs at
DIphosphate level
UDP reduced at 2 C (OH
becomes H)

Dephosphorylation
dUMP methylated @C5
methyl grp source: N5-N10methylene FH4 (1C grp transfer)

substrate inhibitor of dUMP at thymidylate


synthase active site, form fFUM-FH4,
dTMP/dTTP

13. dTMP
14. dTDP

Nucleotide monophosphate kinase


Nucleotide diphosphate kinase

dTDP
dTTP (precursor dor
DNA synth,
regulates
ribonucleotide
reductase)

methylene grp reduced to methyl


grp by FH4
FH2FH4 via dihydrofolate
reductase (inhib by
methotrexate) w/NADPH as
reductant (reduced)
Must regen FH4 to synth more
thymydilate
ATP
ATP

Degradation of pyrimidine in LIVER, leads to H2O soluble compounds (-alanine, BAIB)


Phase 1
1. Pyrimidine nts
Nonspecific phosphatases
Nucleosides
dephosphorylation
2. nucleosides
Cleavage enz
Free pyr bases (cytosine,
uracil, thymine)
Phase 2
2a. Cytosine
NADPH-dependent DH
Dihydrouracil
Reduced
Dihydrouracil
Dihydropyrimidinase or
-ureidopropionate
Hydrated
hydratase
-ureidopropionate
-ureidopropionase
CO2, NH3, -alanine
2b. Thymine
NADPH-dependent DH
Dihydrouracil
Reduced
Dihydrouracil
Dihydropyrimidinase or
-ureidopropionate
Hydrated
hydratase
-ureidopropionate
-ureidopropionase
CO2, NH3, aminoisobutyrate (BAIB)
Phase 3
3a. -alanine (from cytosine) Transaminase (+activation)
Malonyl CoACO2/de novo
synth of FA/synth of CoEnz

3b. -aminoisobutyrate
(BAIB) (from thymine)
NAD Synthesis
1. Nicotinamide (derive of
niacin-Vit B3)

Transamincase (+activation)
Nicotinamide phsophoribosyl
transferase

2. nicotinamide
NAD-pyrophosphorylase
mononucleotide
3. NAD
Phosphorylating enz
FMN/FAD Synthesis (for reversible redox rxns)
1. Riboflavin (from Vit B2)
Riboflavin kinase
2. FMN

FAD-pyrophosphorylase

CoEnz A Synthesis (component of acetyl CoA)


1. Panthothenate (Vit B5)
Panthothenate kinase
2. 4-phosphopanthothenate
(ATP dep)
+ Cys
phosphopanthothenoylcysteine
synthetase
3. 4phosphopanthothenoylcysteine
phosphopanthenoylcysteine decarboxylase
4. 4-phosphopantotheine
Dephospho-CoA
pyrophosphorylase
5. dephosphocoenzyme A
(ATP dep) dephospho-CoA
kinase

A/carnosine
Methylmalonyl CoAsuccinyl
CoA to Krebs
Nicotinamide mononucleotide Nicotinamide condenses
with PRPP (ribose 5-P
donor)
PPi released
Nicotinamide adenine
P of ATP of nicotinamide
dinucleotide (NAD)
mononucleotide
NADP
P by ATP
Riboflavin phosphate (flavin
mononucleotide, FMN)
Flavin adenine dinucleotide
(FAD)

ATP

4-phosphopanthothenate
4phosphopanthenoylcysteine

ATP
ATP

4-phosphopantotheine

decarboxylation

Dephosphoconezyme A

CoEnz A

ATP

Folic acid analogs: methotrexate (MTX), trimethoprim


Dihydrofolate analog: amethopterin
Purine analogs: 1,6-mercaptopurine, acyclovir (acylcloguanosine), adenine arabinoside (Ara-A), 2-3-dideoxyinosine
Hypoxanthine analog: allopurinol
Pyrimidine nucleoside analogs: 5-fluorouracil, 6-azuradine, arabinosyl cytosine (Ara-C) cytosine arabinoside 5triphosphate interferes with DNA rep, 3-azido-5deoxythymidine (azothymidine, AZT)
Glutamine analogs: azaserine, acividin
Degradation products of pyrimidine: -alanine, -aminoisobutyrate