Purine Pyrimidine metabolism Flashcards
What percentage of dietary nucleotides do we use for energy?
less than 5%
about 95% of all nucleotides used in our cells is derived from de novo synthesis
Sources of nucleotides?
dietary (small amount) De novo synthesis (large amount) nucleic acid degradation Nuceloside degredation (salvage pathway) -can be excreted this way, breaks down into sugar and base
Purines?
G A
what rate determining enzyme is responsible for the synthesis of ribose-5-phosphate?
G6PD
Phosphoribosyl pyrophosphate? (PRPP)
ribose-5-phosphate to 5-phosphoribosyl-p-pyrophosphate
Rate limit step for purine production?
GLN-PRPP aminotransferase
5-phosphoribosyl-p-pyrophosphate to 5-phosphoribosylamine
Dividing step between ATP and GTP?
IMP
Adenylosuccinate synthase, makes Adenylosuccinate to make ATP
dehyrogenase I makes XMP, to make GTP
Purine salvage pathway?
Purines will do on to make Hypoxanthine guanine, and then onto to uric acid
HGPRT recycles Hypoxanthine guanine back into nucelotides
Deficiency in HGPRT?
this is called Lesch-Nyhan syndrome, a gentetic deficiency in this enzyme
can’t resalvage the nucelotides and therefore make uric acrd
Lesch-Nyhan Syndrome?
results from def in HGPRT
occurs in about 1 in 100, 000 live births
causes hyperuricemia and markedly increased uric aciduria
leads to juvenile onset of uric acid stone formation and gouty arthritis
self injurious behavior (self mutilation)
HGPRT degredation?
Hypoxanthine back into IMP
Guanine back into GMP
Bubble boy syndrome/ SCIDS?
severe combined immunodeficiency syndrome (SCIDs)
SCIDS?
deletion or mutation of adenosine deaminase results in this
accounts for nearly 15-20% of all SCID cases
deficiency is rare
infants inherited with an ADA deficiency have profound lymphocyte depletion, lack both cellular and humoral immune function
ADA?
adenosine deaminase
Adenosine to Idosine
without can’t degrade adenosine
Build up of adenosine from bubble boy causes?
increase in dATP, to shut off ribonucleotide reductase, can’t make dATP, dGTP, dCTP, can’t make B cells, T cells
receptor for ribonucleotide reductase shuts off with hight amounts of dATP
Formation of uric acid?
Xanthine (cross between both pathways of adenosine and guanine)
makes uric acid (xanthine oxidase)
Gout?
caused by overproduction or decreased excretion of uric acid
excess uric acid crystals precipitate
crystal formation sets off a series of inflammatory mediators (IL-1, IL-6, IL-8, TNFalpha)
Excretion of Uric acid?
through tubular epithelial cells, URAT1 (urate transporter) this helps reabsorb uric acid
urate into tubular filtrate
Block URAT1?
decreases reabsorption of uric acid, increasing excretion
Causes of hyperuricemia?
obesity hyperparathyoridism hypoparahyroidism hypothyroidism hyperthyoridism sepsis renal insufficiency etc
Effects of fructose on uric acid levels?
high fructose, cause increase in uric acid
Fructose uses ATP to make fructose-1-P and makes ADP, ADP is a precursor to making uric acid
Pathophysiology of Uric acid accumulation?
Monosodium urate crystals through a few means cause Caspase-1 to be made
this causes IL-1beta to be made, causing more to be made, also makes TNF and IL-6 (proinflammatory factors)
3 ways monosodium urate crystals cause inflammation?
- NADPH oxidase, increase ROS
- bind to CD14/TLR2/4
- K depletion
Other things urate crystals do?
complement activation, mast cells
activation of resident synovial cells
-neutrophil influx and chemotaxis
