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Nucleotide Metabolism
10/12/11 First Lecture
20
Medical
Graduate
10/13/2011

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Term
What are the biological function of nucleotides?
Definition
1. Energy Metabolism - ATP synthesis
2. Information - DNA and RNA subunits
3. Physiological Mediators - cAMP, cGMP
4. Compoenents of coenzymes
5. Intermediates for small molecule group transfer
6. Allosteric effectors that bind to enzymes
Term
What are the three components of a nucleotide?
Definition
1. Nitrogenous base - purine or pyrimidine
2. Ribose or Deoxyribose sugar
3. Phosphate (that makes them acidic and negatively charged)
Term
What two organic components are the functional groups of nucleotides and where are they located on the compounds? What is the exception to this rule?
Definition
1. amino or a carbonyl group

2. 12 oclock and 8 oclock positions

3. The exception is a 2 oclock methyl group that differentiates thymine from uracil
Term
What is the difference between a nucleoside and a nucleotide?
Definition
Nucleoside = nitrogenous base + sugar

Nucleotide = nitrogenous base + sugar + phosphate
Term
What is the difference between a ribose and a deoxyribos sugar backbone?
Definition
Ribose sugars have a hydroxyl group on the 2 carbon, deoxy sugars dont
Term
What are the two types of synthesis of nucleotides?
Definition
1. De novo - assembly from small building blocks

2. Salvage - intact bases put on a sugar phosphate

Note: Salvage is energy preferable, but different tissues use different pathways
Term
What role does PRPP Synthetase play in nucleotide synthesis?
Definition
It takes the Hydroxyl group off of the 1 carbon in ribose sugars and replaces it with 2 phosphates strung together, which is a preferable leaving group for later reactions
Term
What is the major donator of nitrogen to purine rings?
Definition
Glutamine
Term
What is the process by which purines are de novo synthesized? What is the rate limiting, regulating, and committed step? What is the intermediate? What is the branch point? Where does this all take place?
Definition
1. Synthesis takes place by taking the activated sugar PRPP and adding glutamines side chain nitrogen by use of amido transferase, then single carbon and single nitrogen are added, many steps and you arrive at Inosine monophosphate

2. The addition of glutamine's nitrogen to PRPP is the rate limiting, committed, and regulated step

3. The intermedaite is IMP

4. IMP is the branch point that can go to either AMP or GMP

5. This all takes place in the cytoplasm
Term
Describe the regulation of de novo synthesis of purines
Definition
1. Product inhibition: GMP and AMP inhibit IMP, IMP inhibits PRPP conversion

2. Feedback inhibition: GMP and AMP inhibit PRPP conversion

3. Increased PRPP leads to more conversion to nucleotides
Term
Describe the de novo synthesis of pyrimidines. What part of this happens in the mitochondrion?
Definition
1. Amide from glutamine, single carbon source, energy (ATP) and carbamoyl phosphate synthase II make carbamoyl phosphate
2. This reacts with aspartate to make N-Carbamoyl aspartate
3. Ring closes yielding orotic acid
4. Orotic acid is put on sugar phosphate PRPP to give OMP
5. OMP is decarboxylated to give UMP

The closing of the ring and formation of double bond happen in the mitochondrion
Term
How is CTP made from UTP?
Definition
Substitution of an amino group for a carbonyl group at the 12 oclock position
Term
How are tri phosphates formed from mono phosphates?
Definition
Transfer of phosphate groups from ATP
Term
What is the rate limiting and regulated step in pyrimidine synthesis?
Definition
Conversion of glutamine and HCO3 to carbamoyl phosphate by CPSII
Term
Describe the feedback of the pyrimidine synthesis pathway
Definition
UTP and CTP inhibit the activity of carbamoyl phosphate synthase II
Term
What enzyme makes deoxy sugars from ribose sugars?
Definition
Ribonucleoside diphosphate reductase
Term
How is TMP made from dUMP?
Definition
Addition of a methyl group by thymidylate synthase
Term
Describe the process of breaking down purines?
Definition
1. Nucleic acids are broken down to nucleotides
2. Nucleotides lose their phosphates and become nucleosides
3. Nucleosides lose their nitrogens on the ring
4. Sugars are chopped off by a phosphate
Term
What problems arise from an incrase in uric acid concentration?
Definition
Stones forming in the kidney and it can lead to gout
Term
What steps in pyrimidine degradation are the same as purines? which are different?
Definition
The breakdown to the bases is the same (acid->nucleotide->nucleoside->lose nitrogen->sugar chopped by phosphate)

The bases, however can undergo further degradation
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