CH. 32 Nucleotide Syn I

Pyrimidine synthesis is a   processes

Purine synthesis is a process

While  are easy for the body to metabolize and excrete,   are not

Purine synthesis involves intermediates that are  to some cells.

The final product of purine synthesis is  

At brush border there are cells that break down nuceleotides in the   and 

Enzymes that break down nucleotides are  ,  ,  , and  

First,   and  
dissociate nucleotides from the
phosphodiester backbones

Then   dissociate the Phosphate
(--P) from the nucleoside

Finally,   further break down
the nucleosides into   and
 .

Membrane transport proteins carry the products of nucleotide digestion into epithelial cells from the lumen via   and   transport

The products are transported into the   and then into the  .

The products are transported to the   and other tissues wherethey undergo further metabolic processes

Nucleotides are the building blocks for what 3 important things?

NADP+ (used in   processes -> high energy) is a phosphorylated form of NAD+ (used in   processes)

Coenzyme A, which feeds the TCA and is a cofactor in   and 

The salvage pathway involves activated ribose  . The denovo pathway involves activated ribose  

If you ingest substances that have nitrogenous bases, then you can use those as building blocks for your nucleotides via   pathway (saves energy).

If you do not have enough nitrogenous bases around, you can build your own nucleotides from scratch using very simple molecules ( ).

Ribose 5-phosphate (R5P)-> Produced as an
intermediate of the   and
 

PRPP is produced by the   of
ribose 5-phosphate by enzyme   It involves the addition of   that come from ATP

PRPP is allosterically controlled. It is activated by   and  as  . It is inhibited by   and   feedback inhibition.

PRPP is used in   purine and pyrimidine synthesis in   salvage and de novo pathways.

  are synthesized one at a time (or few at a time) directly onto the ring. Enzymes are present in larges complexes or  

The intermediate of purine synthesis is  

In the synthesis of pyrimidines, the ring is synthesized as  and gets attached to ribose phosphate. It the gets converted to the pyrimidine nucleotides.

The  is the primary organ that
produces nucleic acids.

The liver manages , which is a key
component of purine biosynthesis

For de-novo purine synthesis, you need:
 ,  ,  ,  ,
 .

TEST QUESTION!!!! Starting with PRPP, the first committed step
in the production of IMP is the addition of
an amino group from   by the enzyme
  to make
 .

There are   steps from PRPP to formation of IMP

After attachment of amino group from  ,   is committed to go forward towards de novosynthesis of purines

PRPP glutamine amidotransferase ->  controlled and   regulated

PRPP is an allosteric FEED-FORWARD activator of  

PRPP is an allosteric   activator of PRPP glutamine amidotransferase.

PRPP glutamine amidotransferase is allosterically inhibited by end-products -> ,   and 

A chemotherapeutic drug,  , also inhibits PRPP amidotransferase. It blocks purine synthesisand DNA synthesis.

Once   is formed, the path is committed to purine synthesis and there are 9 morereactions to form  .

The catalzying process of purine biosynthesis in by channeling to increase   and  

In the first step of the formation of IMP, ribose phosphate pyrophosphokinase converts ribose 5 phosphate to PRPP. This process is inhibited by 

In the second step of the formation of IMP, glutamine-PRPP-amidotransferase converts PRPP into 5-phosphoribosylamine. This process is activated by   (feed-forward) and inhibited by  ,  , and  .

5-phosphoribosylamine is converted to IMP in 9 steps using  ,  ,  , and   as carbon donor

From IMP,   and   can be formed

IMP is converted to andeylosuccinate and then to AMP using an amino group from  . Process is inhibited by   (feedback)

IMP is converted to XMP and then to GMP using an amino group from  . Process is inhibited by   (feedback).

In purine synthesis,  and   are used via  
to start building the   ring on the ribose.

With GAR synthetase, reactions use charged to deliver  
groups to the structure. That is a one-carbon transfer with a carbonyl group at   and another at  .

The synthesis of AMP requires  

In AMP synthesis, the carbonyl group is replaced by an  

The synthesis of GMP requires  

In GMP synthesis, the H in the  is replaced by an   group

The formation of AMP   energy! If you want to make AMP and you’re low in energy levels, it’s not a good idea to use up  !

First, the carbonyl oxygen is activated by using energy of GTP and plugging in an   -> makes  .

GTP is a  for Adenylosuccinate Synthetase -> pushes the reaction forward. Second, the carbon skeleton of aspartate is cut off, releasing   and forming 

The formation of   process uses energy! If you want to make GMP and you’re low in energy levels, it’s not a good idea to
use-up  

In the first step of GMP synthesis, the enzyme  oxidizes IMP to form  . This reaction is coupled with the reduction of  

In the second step of GMP synthesis, the carbonyl just created is activated by   and there’s the transfer of an amino group from .

Cannot be stressed enough! AMP uses  , GMP uses   (what AA?)

The need of one type of   to   the other type is important for maintaining a proper balance

GTP is a positive effector of  

  is an essential water-soluble vitamin (absorbed in duodenum))

Folate mainly comes from  , nuts, meats

What is the precursor for vit B9 synth?

 is a biproduct of methanol (toxic), so folate can
help to detoxify from methanol poisoning

B9 is needed for   and   synthesis. It is also involved in amino acid snthesis, nuceloprotein synthesis, catecholamine synthesis, and formic acid.

Microorganisms convert pteridine precursors and para-aminobenzoic acid into folic acid. Folic acid
synthesis is inhibited by  

Folate is converted to dihydrofolate (DHF) by  

The antibiotic trimethoprim inhibits   Perfers bacterial   to human.

  groups carried by THF

THF is a 6-methylpterin derivative linked in sequence to  and  
residues (n= 1 –6)

Sufonamides (sulfa drugs) are antibiotics that are analogs to   and competitively inhibit bacterial
synthesis of THF at the PABA incorporation step.

THF is important in the transfer of  units.

THF is derived from , a doubly oxidized form
that must be enzymatically reduced before it becomes an
active coenzyme.

Both reactions that form tetrahydrolate from folate are catalyzed by  

C1 units are covalently attached to THF at positions ,
  or both   and .

Folate is involved in   and is sometimes called  

Deficiency in   can result in megaloblastic anemia, cardiovascular disease, and birth defects

IMP biosynthesis is an energetically consuming process that
requires the hydrolysis of  ATPs.

  in purine rings are from glutamine

Everything starts with  
Metabolic contribution of  
to the purine biosynthesis and
other anabolic pathways

The activity of PRPP synthetase varies with the
concentrations of several metabolites, including   and
 , which are activators, and   and  , which
are inhibitors.

***Test Question
The pathways synthesizing  ,  , and   are
regulated in most cells -> control the total amounts of
purines produced and also coordinate the relative
amounts of   and  .

-Gln-PRPP-amidotransferase is controlled by feedback
inhibition ( ,  ,  ).

-The branched portion of the pathway from IMP:  inhibition
- High   inhibits adenylosuccinatesynthase;
- Similarly, high   inhibits IMP
dehydrogenase.

Reciprocal regulation via GTP and ATP:
-  stimulates adenylosuccinate
synthase.
-  stimulates XMP-glutamine
amidotransferase.

The monophosphates are converted to
  using respective specific
kinases (Adenylate kinase, Guanylate
kinase)

Purine diphosphates are converted
to triphosphates in reactions
catalyzed by  

  catalyzes conversion of all
nucleoside diphosphates to
nucleoside triphosphates.