CH. 33 Nucleotide Syn 2

Metabolism -> incudes   and  

When cells proliferate,  nucleotide
synthesisis needed for DNA replication and
RNA transcription to make proteins.

**** TEST QUESTION
Glutamine is precursor for   and   biosynthesis

De novo synthesis -> primary in the  

Done using phosphoribosyl pyrophosphate (PRPP, a ribose sugar with
pyrophosphates attached) with  

De novo synthesis is catalyzed by  enzyme and is an   reaction

Denovo synthesis is activated by   of PRPP. Low levels   rate of synthesis.

PRPP is both  and  

PRPP is produced by pyrophosphorylation of ribose 5-phosphate by  

Ribose 5-phosphate (R5P)
• Produced by intermediate of the   and  

High PRPP leads to higher plasma  concentrations

Regulation of PRPP synthetase by   and   feedback inhibition

In the salavge pathway,  
enzyme phosphorylates and ribosylates dietary adenine and
guanine forming the purine nucleotides (ATP and GTP) used
for DNA and RNA synthesis

In the salvage pathway, the nitrogenous bases of degraded nucleic acids are available for  .   is needed here too!

What are the two important enzymes of the salavge pathway?
- Hypoxanthine+PRPP->IMP
Guanine+PRPP-> GMP
- ) Adenine+PRPP->AMP

HGPRT:This enzyme is exceptionally important,and it is inhibited by both   and   (feed back inhibition).

What are the two functions of HGPRT?

Thermodynamically, the reactions are pushed forward by removal of PPi product by the enzyme:  

Salvage pathway ->  
•   can add adenine to PRPP to make   and  

Degradation converts purines and purine nucleotides to
 

******TEST QUESTION   converts hypoxanthine to xanthine
and ultimately to uric acid.

Degradation of Purines

1. Degradation starts with the  , so the nucleotides become nucleosides (adenosine or inosine) by the action of nucleotidases.

2. Adenosine is converted to inosine by adenosine deaminase (ADA) with the removal  .

3. Purine nucleoside phosphorylase (PNP) can then
remove ribose from inosine as  . This the reaction that yields  .

For AMP degradation the important enzyme from AMP side
 

For GMP degradation, the important enzyme is  

Both AMP and GMP degradation need   and  

Increase in salvage pathway depletes   levels and
  de novo synthesis

Salvage pathway leads to more   and   production

De novo generates more   breakdown products

High de novo activity increases   turnover, resulting in
higher  concentrations

Higher salvage pathway activity leads to  de novo
synthesis and reduces plasma uric acid

Increased plasma   levels leads disease; gout

Plasma becomes saturated if urate levels exceed 6.8 mg/dL.
• Levels over   for men or   for women is considered
hyperuricemia. (too much uric acid in the blood)

High plasma levels of uric acid can lead to deposition of uric acid crystals in
joints
• Crystals of uric acid gather in areas with slow blood flow (  and
 ) and higher gravitational pull ( )

In gout, synovial fluid favors the  

Secondary gout
• Increased uric acid associated with   turnover
• From leukemias, lymphomas, and after chemotherapy.

In secondary gout, increase in  can lead to overproduction of uric acid
• occurs in  storage diseases and tissue hypoxia

In secondary gout,  intake can cause accelerated ATP catabolism and decreased renal excretion of uric acid.

Saturnine gout; from   exposure
• 18th-century England, prevalent among the upper classes with  
• The Romans because they drank from vessels containing  .
• Caused lead  

  of uric acid gather in areas with slow blood flow joints and kidney tubules
• occurs when your kidneys don't eliminate uric acid efficiently
• Uric acid crystals can form   in some people.

What are the 3 causes of hyperuricemia?

Overproduction of purines -> increased  degradation
• Consumption of  foods (animal origin)

Von Gierke disease
• Can’t break down   -> leads to lactic acidosis. Lactic acid competes for excretion with  
-> build- up of 

Causes 8 of underexcretion by uric acid in kidneys

What are the 4 things to be avoided on a low purine diet?

 inhibits xanthine oxidase.
-xanthine oxidase converts hypoxanthine to
xanthine and ultimately to  
-Inhibition stops   formation.

Alluprinol causes   of hypoxanthine, but that's okay because it gets recycled back into the purine salavge pathway by  

Decrease in   activity results in increased levels of  in Lesch-Nyhan syndrome
. • Self- mutilation
• Mental retardation
• Hyperuricemia

With Lesch-Nyhan syndrome, polymorphisms in HGPRT lead to decreased enzyme activity and   ( )

In Lesh-Nyhan syndrome Decreased nucleotide production
→   dopamine production
→   in striatal dopaminergic pathways

SCID: Adenosine Deaminase (ADA) -> one of the key enzymes of  metabolism

SCID: Primarily,   is involved in the development and maintenance of the  , although isozymes are also in the brain, gastrointestinal tract and extracellularly.

SCID: Adenosine Deaminase Deficiency ->   (autosomal recessive) that causes
 .

SCID is characterized by the lack of both  and  function, thereby allowing multiple
infections (bacterial, viral and fungal) to take place.

The pyrimidine ring is formed from simple molecules
•  , , , 

What are the 4 steps of pyrimidine biosynthesis?
Part 1:Formation of  
Part 2:  conversion to  
Part 3:   combination with   to form  
Part 4: Formation of  

Part 1 Pyramidine Synth: Formation of   de novo synthesis of a pyrimidine
•Requires->  , and  [derived from   hydrolysis].

Nucleotide production happens in the liver because it is best able to handle   formation

From the formation of Carbamoylphosphate
•  and a   are released in the reaction.
•Carbamoyl phosphate synthetase II catalyzes the reaction
(in the  ).
(CPSI acts within  )

Part 2: Carbamoyl conversion to  
•   joins through aspartate transcarbamoylase
(ATCase)to make carbamoylaspartate
• After a couple of reactions   makes-> Orotate,
which has the basic pyrimidine ring shape.

Clinical correlation:Oroticaciduria
• Autosomal recessive condition characterized by excessive
excretion of orotic acid in urine (deficiency of  ) in the presence of normal levels of  

Part 3: Orotate combination with PRPP to form orotidylate(OMP)
• in the combination, the   is released and
 is formed.

Part 4: Formation of  
• Orotidylateis decarboxylated via orotidylatedecarboxylase
to form  . Without this enzyme, this reaction would take
~ 78 M years for this reaction to occur.

The main product of pyrimidine synthesis is  

In the conversion of UMP to dTMP, three important
enzymes are  , , and  .

 is required for the formation of
the deoxyribonucleotides for DNA synthesis.