4.5 Biochem hyperuricemia Flashcards
What causes gout? Does this always cause gout?
Hyperuricemia can cause buildup of crystals of monosodium urate.
Doesn’t always have to cause gout, many people live with hyperuricemia.
Why does urate bind with sodium to form the monosodium urate crystals in gout?
Urate is negatively charged and is neutralized by binding 1 positively charged sodium ion.
What is the only source of uric acid? What is it an end product of? What are the only ways of eliminating uric acid?
Nucleotide metabolism is only source of uric acid.
End product of nucleotide degradation.
Eliminated only through excretion in urine or feces.
Identify these structures.
What do they all have in common?
Uric acid (most oxidized purine).
Uracil (pyrimidine).
Urea.
Have the urea functional group, however all function in very different ways with different properties.
What are the 2 main causes of hyperuricemia?
Excessive production or uric acid.
Inadequate elimination of uric acid.
What are the sources (dietary and metabolic) of uric acid that we obtain? And how are they processed down to uric acid?
Dietary purines are oxidized to uric acid in the liver. Red meat, seafood, beer.
De-novo biosynthesized purines are catabolized to uric acid in liver. Fructose, Lesch Nyhan. (allopurinol, febuxostat, caffeine, salvage — can reduce).
Reabsorption through the urate1 transporter decreases elimination. Alcohol, fructose. (uricoserics, vitamin C — prevent).
How do these dietary substances cause increase in uric acid levels? (red meat, seafood, beer, fructose, alcohol,).
DNA and RNA are digested to nucleotides, absorbed by enterocytes, and catabolized down to uric acid. Red meat, seafood, plants etc all contain DNA and RNA that support this process.
Fructose and alcohol do not contain purines, but alter liver metabolism to produce purines.
These two processes increase purine concentration thereby stimulate purine degradation ===> uric acid.
The key regulatory step of DE-NOVO purine biosynthesis (glutamine-phosphoribosylpyrophosphate aminotransferase) is inhibited by AMP and GMP, why is this? What activates this step?
And what in the world does that long ass name mean?
IMP, AMP, and GMP are products of purine biosythesis: they are simply acting in feeback inhibition (negative feedback, etc) to downregulate the first step when they are already in excess.
Activated by high levels of PRPP (signalling high substrate, lets roll).
Transfering an amino group from glutamine to phosphoribosylpyrophosphate :-)
What is the foundation on which purines are built? The starting substrate for purine biosynthesis? The foundation used for purine salvage?
PRPP - Phosphoribosylpyrophosphate
Where does phosphoribosylpyrophosphate come from? (what are its precursors)
Ribose -> Ribose-5-phosphate -> Phosphoribosylpyrophosphate
What enzyme is in charge of making PRPP from Ribose-5-phosphate? Where does this origininal ribose-5-phosphate come from (what process in our body), and where does it gain its extra pyrophosphate group?
PRPP synthetase: makes R-5-P -> PRPP
It comes from the pentose phosphate pathway of metabolism.
It gets it pyrophosphate from ATP.
This is a key regulatory step to purine biosynthesis, why is PRPP synthetase inhibited by AMP and GMP, why is it activated by Pi?
Once again feedback inhibition is why it is regulated by GMP and AMP.
Phosphate activates this process because it is one of the molecules needed for this cycle and when it is present it signals that the molecules are there and ready to roll, “LETS GET THIS PURINE BIOSYNTHESIS GOING!!” -Pi.
What affect would being hyperglycemic have on purine metabolism?
Mass amounts of glucose will drive glucose into other pathways (ex: pentose phosphate pathway), this will create an excess of Ribose-5-phophate and will drive purine biosynthesis.
Glucose-6-phosphate -> Ribose-5-phosphate -> phosphoribosylpyrophosphate -> purines -> uric acid ===> GOUT
Von Gierke’s disease is an example of this.
Purine biosynthesis produces first an inosine monophosphate intermediate, how are GMP and AMP made?
IMP is oxidized to XMP.
XMP is transaminated (using ATP) to GMP.
AMP inhibits conversion of IMP -> AMP.
GMP inhibits conversion of IMP -> GMP.
ATP is needed to make GMP.
GTP is needed to make AMP.
Why?
(first really look at this diagram and understand what is being said).
MORE negative feedback!
You want a balanced amount of GMP and AMP, therefore you use the products to inhibit themselves and use their high energy molecules to produce one another which results in creation of themselves… (confusing but look, ATP to make GMP results in AMP. 1:1 ratio being produced of AMP and GMP!)
Look at adenine (or adenosine in this picture), hypoxanthine, xanthine, and uric acid.
Organize in order of increasing oxidation (really look at the structures and understand this, guarentee he will stick one of these on our test).
Look at inosine and hypoxanthine, classify each as a nucleotide, nucleoside, or nitrogenous base. Observe their structural relationship.
Adenine (or inosine) (least oxidized) -> hypoxanthine -> xanthine -> uric acid (most oxidized).
Inosine = nucleoside, hypoxanthine = nucleobase (lacking sugar). Same base.
Note this step. Take note of xanthine oxidase enzyme (relate it to pharm), see what it is doing. Note the red arrows.
It is oxidizing these compounds, catabolizing them.
Before this step you can go backwards and recover nucleotide bases etc. after you oxidize hypoxanthine, there is no returning.
Fexbustat and allopurinol inhibit this oxidation. Allopurinol acts as a purine and gets bound by XO and inhibits XO from binding hypoxanthine.
This is the purine salavage pathway in a nutshell. What exactly is HPRT doing here? What energy is used for this reaction?
Hypoxanthine-Guanine phosphorybosyltransferase (HGPRT or HPRT), is taking PRPP and a purine base (Guanine or Adenine, etc.) and sticking the ribose sugar from PRPP onto the base.
PRPP is activated by the pyrophosphate, therefore the energy comes from hydrolysis of pyrophosphate from PRPP.
What is happening in Lesch-Nyhan disease? (What is broken, what is the result?)
HPRT is inactivated by X-linked recessive mutations.
“Dam model of enzyme inhibition”.
Enzyme out leads to buildup of upstream substrates (guanine and hyposanthine) and depletion of its downstreatm products (GMP and AMP).
This signals the body to make more purines because you need more for GMP and AMP, all the while you are still breaking down perfectly good purines (hypoxanthine) that could be recycled.
All this excess making and breaking down of purines => high levels of uric acid.
Glucose first pass in the liver is low, however when fructose enters the liver in extremely high concentrations fructokinase becomes extremely active? What does this do to the energy in our body over time?
Unregulated activity of fructokinase causes a depletion in ATP and energy will plummit.
After 1-phophofructose enters glycolysis energy levels in the liver will surge.
When all this fructose metabolism is occuring in your liver, what is going on with purine sythnthesis, during the ATP depletion stage and during ATP increase?
ATP depletion (AMP buildup) = purine degradation, uric acid buildup in blood.
ATP increase = new production of purines.
