Purine and Pyrimidine Metabolism Flashcards
The reactions catalyzed by HGPRT
HGPRT defeciency
In general: Synthesis of Nucleotides from Free bases
HGPRT an enzyme required for the synthesis of IMP and GMP
IMP free base is hypoxanthine
GMP free base is guanine
Defeciency can result in Lesch-Nyhan Synd.
Name the enzyme and the by-product
Guanosine E1→ Guanine + X
Inosine E2→ Hypoxanthine + X
In both rxns:
nucleoside → Free base
Both E1 & E2 :
Purine nucleo_side_ Phosphory_lase-_ PNP
Phosphoribosyl transferase
Major Pathway
Rxns catalyzed by this enzyme
Purine Salvg Pthwy
- Addition of Ribose-5P to a Basefree
- PRPP + Basefree → Nuctide** + PPi**
The enzyme that catalyzes the phosphorolysis of N-glycosidic bond:
Phosphorolysis of N-glycosidic bond is catalyzed by purine nucleoside phosphorylase (PNP)
Guanosine PNP→ guanine + R-1P
Inosine PNP→ hypoxanthine + R-1P
- Ribose 1-posphate can be isomerized to ribose 5-phosphate (R1P ⇔ R5P )
- Free bases (Bf or Basefree) can be salvaged ordegraded
- The reactions are part of purine Salvage Pathway (PuSP)
Three groups of enzymes that participate in Pu.SPs
- Deaminase (DAs): AMP-DA and Adenosine Deaminase (ADA)
Pt. w/ Ø ADA1- SCID & 1st Increased [dA] → [ATP] inc.
- PhosphoRibosyl Transferease (PRT): HGPRT and APRT
Pt. w/ Ø HGPRT - Inc. [UA] bc . exc. degrd . Purines (free bases) since they cnt b rcycld
- Purine nucleoside Phosphorylase (PNP)
ADA1 Ø
Possible causes of delay in SCID detection (1/100 K live births
In N/H. (normal and healthy) indiv:
- Adenosine ADA1→ Inosine
- dAdenosine ADA1→ dInosine <span>Deoxyinosine is found in DNA while inosine is found in RNA.)</span>
In ADA1Ø indiv:
dA builds up (dA convrts to dATP) leads to dATP accumulation.
dATP accumulation leads to reduced doxynucleotides, which impairs lymphocyte proliferaiton. ADA-deficient are SCID and are unable to produce significant numbers of mature T or B lymphocytes.
ADA1 Ø & _ribonucleotide diphosphate reductase (rNDP)_
ADA1 Ø causes an increase in dA and dATP conc.
Accumulated dATP inhibits rNDP.
rNDP substrates
ADP, GDP, UDP, CDP
Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase (rNDP), is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides
The portion of salvage pathway that is important for muscle tissue
Brief discription
Purine Nucleotide Cycle
Fumarate production as a result of AMP build-up, and its conversion to IMP in excercising muscle.
AMP also activates PFK-1 and glycogen phosphorylase b (glycolysis and glycogenolysis activation)
AMP deaminase Ø
Deficiency of AMP deaminase results in muscle fatigue during exercises (from 1 in 50 to 1 in 40,000 people).
Generation of ATP
(high intensity exercise)
During high intensity exercise cytosolic ATP is rapidly converted to ADP.
Direct generation of ATP from ADP by:
myokinase (adenylate kinase)
2ADP ⇔ ATP + AMP
Note: removing AMP causes right shift. One possible way, removing AMP by AMP deaminase
The reason for ammonia accumulation in exercising muscles
Because of the increased levels of AMP and IMP.
Degradation of purines is linked to the generation of ATP. During high intensity exercise cytosolic ATP is rapidly converted to ADP. ATP can be generated directly from ADP by myokinase (adenylate kinase):
2ADP⇔ ATP + AMP
The reaction is driven to the right by AMP deaminase (high conc. in skeletal muscle)
AMP + H2O → IMP + NH3
muscle AMP deaminase deficiency
Defective gene (inheritance pattern)
Sx
Exacerbation of the Sx
- AMPD1 gene
- fatigue, muscle weakness, cramps, pain and other muscle prob.
- Statins exacerbate the symptoms
Synthesis of pyrimidines
Base synthesized first
Produced from Asp and carbamoyl phosphate (from CO2 and Gln by CPSII)
The first three enzymes: CAD
CPSII analogous
Analogous to urea cycle CPS I
Unlike its analogous, CPSII uses Gln as source of N and occurs in cytosol
The first three enzymes of pyrimidine synthesis
CAD
- Carbamoyl phosphate synthetase II
- Asp transcarbamoylase
- Dihydro-orotase
Regulated Step of Pyrimidine Synthesis
production of carbamoyl phosphate catalized by CPS II.
CPS II activity: + PRPP, - UTP
[CPS II-P] made by MAP kinase increases CPSII responsiveness to PRPP (inc the prob. of activation)- During S-phase.
Folate deficiency can result in anemia (macrocytic or megaloblastic) because of limited dTMP syn.
An activator of CPSII
PRPP
Orotic acid (orotate) conversion to UMP
2 enzymes, 1 polypeptide, UMP synthase
UMP synthase Ø
leads to:
Hereditary orotic aciduria, megaloblastic anemia and growth retardation (red. Py.Synth.)
Treatment:
Oral uridine ( Uridine is converted to UMP bypassing metabolic block)
Causes of Orotic Aciduria
1- UMP synthase deficiency
2- Ornithine transcarbomylase def. (Urea Cycle)- leads to carbomyl phosphate accuml. in Mt. which leaks to the cytoplasm (bypasses the rxn catalyzed by CPSII)
Synthesis of deoxyribonucleotides occurs at—————- level.
diphosphate
CTP and dCTP production
CTP is produced by an addition of amino group from Gln to C4 of UTP
UTP and CTP are precursors of for RNA synthesis
CDP RR→ dCDP
Ribonucleotide reductase (RR)
dUDP synthesis
UDP RR→ dUDP
Ribonucleotide reductase (RR)
RR also syntheses dCTP