3 - Nucleotide Chemistry and Metabolism Flashcards
1
Q
Introductory notes in-class
A
- RNA came first - makes sense since it is closer to protein
- Some RNA molecules can act as enzymes even
- They catalyze their own replication - not all RNA molecules do this however
- Originally it was RNA world
- RNA is not stable enough to become the primary code of life
- Coenzymes with nucleotide - e.g. NADH, FADH2, etc.
- Second messengers with nucleotide - e.g. cyclic AMP, etc.
- More focus on Purines over pyrimidines (little clinical importance/implication)
- We need to know passively what they look like ; know which is which at least
- Just know what A, T, G, C, U look like passively; no drawing though
- pYrimidines - thYmine, cYtosine
2
Q
Introductory notes in-class (cont.)
A
- Don’t need to know any unusual bases
- Just be aware that they exist
- Xanthine is a purine
- Caffeine is a purine-like molecule; looks like Adenosine more than anything
- Adenosine can function as neurotransmitter; inhibitory
- Caffeine will competitively inhibit adenosine (which itself is inhibitory), leading to jitters?
- Pregnant women are advised to stay away from caffeine as the embryo may be using analogs instead of the adenosine
3
Q
In-class notes
A
- What does a nucleoside consist of?
- Sugar with a base; ribose and deoxyribose sugars
- What does a nucleotide consist of?
- Nucleoside with a phosphate group (either 1, 2, or 3 phosphates)
- What is 6-amino purine?
- Adenine
- What is 2-amino, 6-oxypurine?
- Guanine
- Where is there a beta-N-glycosidic bond between carbon 1 of a pentose and N9 of a purine or N1 of a pyrimidine?
- Sugar base linkage of a nucleoside
4
Q
The role of nucleotides
A
- Nucleotides are organic units that:
- Serve as the monomers for nucleic acids like RNA and DNA
- Are intermediates in synthesis of carbohydrates, lipids, and proteins
- Components of coenzymes
- Second messengers in signal transduction pathways
- Regulator compounds inhibiting or activating enzymes
5
Q
Nucleotide vs Nucleoside
A
- Nucleotide consists of a nitrogenous base, five carbon sugar (either ribose or 2-deoxyribose), and phosphate group(s)
- Nucleoside consists of the same structure as a nucleotide but lacks the phosphate group(s): nitrogenous base and five carbon sugar (ribose or 2-deoxyribose)
6
Q
Nucleotides
A
- Phosphate groups are responsible for negative charges associated with nucleotides (nucleic acids)
- Ribonucleoside monophosphate, diphosphate, and triphosphate
7
Q
Nucleosides
A
- A nucleoside consists of a nitrogen base added to either ribose or 2‐deoxyribose
- Purine nucleosides end in –osine, while pyrimidine nucleosides end in –idine
- Unless stated otherwise, the sugar is assumed to be ribose
- The purine and pyrimidine numbering systems run in different directions; clockwise vs. counter-clockwise
- Ribose is more common in the cell because it is used in common molecules like ATP and cAMP
8
Q
Nucleotide Terminology
A
- Purine and pyrimidine bases found in RNA and DNA
- Ribonucleotides are nucleotides in which the sugar is ribose
- Deoxyribonucleotides are nucleotides in which the sugar is 2-deoxyribose
9
Q
Chart of Bases and Nucleosides
A
Base: Nucleoside (ribose + base):
uracil uridine
cyotsine cytodine
thymine thymidine
hypoxanthine inosine
adenine adenosine
guanine guanosine
- d-adenosine + Pi –> (deoxy) d-AMP (found in DNA)
- d-thymidine + Pi –> d-TMP
- The above two are deoxyribonucleotides
10
Q
Unusual pyrimidines and purines
A
- Other unusual pyrimidines and purines can occur in DNA and RNA e.g., 5‐ methylcytosine.
- Xanthine derivatives include caffeine, theophylline (found in tea), and theobromine (found in cocoa)
11
Q
What is 6-amino purine?
A
adenine
12
Q
What is 2-amino 6-oxypurine?
A
guanine
13
Q
Synthesis of Nucleotides
A
- Purines: donated carbons and nitrogens are added to a preformed ribose 5‐phosphate.
- Essentially the base is being built as it is being attached to the sugar.
14
Q
Synthesis of nucleotides
A
- Pyrimidines: synthesized before being attached to ribose 5-phosphate
- Essentially the base is assembled and then attached to the sugar.
15
Q
Synthesis of PRPP
A
- Ribose 5-phosphate for nucleic acid synthesis
- 5-phosphoribosyl-1-pyrophosphate is just ribose 5-phosphate with PPi attached to it; that is Pyrophosphate gets the reaction forward
- PRPP synthetase
- Purine ribonucleotide is the product so it is an inhibitor naturally
16
Q
Pentose Phosphate Pathway and Nicotinamide Adenine
Dinucleotide (NADPH)
A
- Glucose 6-phosphate can yield NADPH (for reductive anabolic pathways), ribose 5-phosphate (for nucleic acid biosynthesis), and glyceraldehyde 3-phosphate & F 6-P (for glycolytic pathway)
- Production of NADPH is a irreversible oxidative reaction
17
Q
Purine nucleotide synthesis
A
- The purine nucleotides, AMP and GMP, exert feedback inhibition on PRPP synthetase and PRPP amidotransferase. They also exert feedback inhibition on the reactions leading from IMP to GMP and AMP
- IMP is from hypoxanthine , which is a purine
- Sufonamides are synthetic ; they don’t allow bacteria to make folic acid
- Sulfonamides are structural analogs of para-aminobenzoic acid that competitively inhibit bacterial synthesis of folic acid. Because purine synthesis requires tetrahydrofolate as a coenzyme,
the sulfa drugs slow down this pathway in bacteria. - Methotrexate dirsupt the metabolism of folic acid so further downstream; in the end does the same same, kills the organism;
- These drugs limit the amount of tetrahydrofolate available for use in purine synthesis and, thus, slow down DNA replication in mammalian cells. These
compounds are, therefore, useful in treating rapidly growing cancers, but are also toxic to all dividing cells. - ANTI-FOLATES are the types of the drugs above
- not really used interchangeably
19
Q
Synthesis of Purine Nucleotides
A
- Conversion of Inosine 5’monophosphate (IMP) to A(adenosine)MP and G(guanosine)MP
- Methods of control:
- Negative feedback, each nucleotide turns off production of itself
- Positive intervention
- Mycophenolic Acid
- Drug is a reversible uncompetitive inhibitor of IMP Dehydrogenase
- Drug deprives rapidly proliferating T and B cells of required nucleic acids, they can’t multiply and this weakens the immune system
- Used to prevent graft infection
- Ultimately you are making nucleotide NOT the bases i.e. AMP and GTP
- Right about of both must be made which is controlled by negative feedback
- Each nucleotide turns off production of itself at critical levels
- Cross-regulation: AMP production require GTP, GTP production requires ATP positive inhibition/intervention
20
Q
De Novo Sythesis of Purines
A
21
Q
Regulation of purine synthesis
A
My note says Dr. Marvit told us not to memorize this figure
23
Q
Salvage Pathways for Purines
A
- Purines that result from the normal turnover of cellular nucleic acids, or that are obtained from the diet and not degraded can be reconverted into nucleoside phosphates.
- The salvage pathways represent the only source of purine nucleotides for tissues that are not capable of synthesizing purines de novo
- While most tissues can synthesize purines de novo, this process is most active in the liver. The liver subsequently exports the products to other portions of the body.
- DNA is NOT an essential nutrient nor is RNA
- Our body will make it from destroying the old ones; recycling i.e. salvage pathways
- HGPRT enzyme doesn’t function –> x-linked recessive inherited disorder
- PRPP will build up as a result and its build up induce DE NOVO synthesis ; since GMP or AMP levels are down; excessive de novo purine synthesis
- When purines are degraded, they are made into uric acid NOT Urea
- Uric acid is a relatively powerful antioxidant; breakdown product functions as anti-oxidant
however, too much uric acid is BAD - Lesch-Nyhan Disease
24
Q
Digestion of dietary
nucleic acids
A
25
Q
DNA Molecule
A
Per Dr. Marvit: just know that there are 3,5 phosphodiester bonds there ; no details
26
Q
Degradation of Purine Nucleotides
A
- Degradation of dietary nucleic acids occurs in the small intestine, where a family of pancreatic enzymes hydrolyzes the nucleotides to nucleosides and free bases. Inside cells, purine nucleotides are sequentially degraded by specific enzymes, with uric acid as the end product of this pathway.
-
Adenosine Deaminase (ADA) Deficiency
- Causes severe combined immuno deficiency (SCID), involves both T and B cell disfunction
- Extremely large buildups of dATP
- Gout
- Treatment with allopurinal inhibits xanthene oxidase, results in accumulation of hypoxanthine and xanthene which are more soluble than uric acid
30
Q
Ribonucleotide Reductase
A
- Ribonucleotide reductase regulates the balance of the 4
deoxyribonucleotides required for the synthesis of DNA - Hydroxyurea is an inhibitor of ribonucleotide reductase.
Hydroxyurea is used in the treatment of certain cancers (via stopping production of DNA), myeeloproliferative disorders, and also of sickle cell anemia (independent of ribunucleotide reductase) - Uric acid is bigger than urea
- Sickle cell increase hemoglobin F, which has nothing to do with what’s shown here
- In the figure, it is easier to remove water than just trying to remove O; NADPH is the source of H
32
Q
Pyrimidine Synthesis
A
Unlike the synthesis of the purine ring, in which the ring is
constructed on a preexisting ribose 5‐phosphate, the pyrimidine ring is synthesized before being attached to ribose 5‐phosphate, which is donated by PRPP.
34
Q
Summary
A
