Bioc Lecture 6
|Describe purine synthesis: Note special similarities to other pathways.||1) NH4 comes off glutamine and is added to PRPP (2Pi cleaved to energise this). |
2) Whole glycine (aa containing NH4) whacked on.
3) Cofactor tetrahydrofolate adds a carbon on.
4) Another NH4 comes off glutamine and is added. This step requires energy.
5) 1st ring closed (requires energy).
6) CO2 brings a carbon in.
7) Whole aspartate whacked on (analogous to urea cycle).
8) Fumarate leaves
9) Cofactor tetrahydrofolate brings another carbon in.
10) close ring.
Makes IMP! (analogous to OMP).
|How do you go from IMP to G?||Oxidise the carbon first, then bring in NH4 from glutamine (requires ATP). (analogous of U-->C)|
|How do you go from IMP to A?||Whack on a whole aspartate, get rid of fumarate to leave just the NH4.|
|How do you change A and G into deoxy form?||Ribonucleotide reducatase enzyme! Acts on the DIphosphate form remember: GDP --> dGDP and ADP --> dADP.|
|How is purine synthesis regulated?||1) High levels of A and G feedback and inhibit PRPP synthesis (by PRPP synthetase). PRPP is the STARTING molecule of purine synthesis, so less PRPP = less purines made. |
2) High levels of AMP and GMP feedback and inhibit PRPP amidotransferase to stop PRPP from entering the pathway (this is at the START). PRPP itself may allosterically activate this enzyme.
3) At the branch point of IMP there is feedback inhibition and reciprocal inhibition.
- Feedback Inhibition: High levels of GMP inhibit IMP going down the GMP branch. High levels of AMP inhibit IMP going down the AMP branch.
- Reciprocal Inhibition: GMP branch requires ATP (product of AMP branch) for energy. AMP branch requires GTP (product of GMP branch) for energy. If you happen to have more activity down the GMP branch, you'll make more GTP which will increase activity in the AMP branch. If you happen to have more activity down the AMP branch, you'll make more ATP which will increase activity in the GMP branch. = a means of ensuring both branches' activities are balanced.
Regulation is necessary so that energy isn't needlessly used!
|Why is purine synthesis regulated at the START of the pathway?||Stops the pathway before any energy has been used - stops needless energy consumption.|
|Describe salvaging of purines:|| 1) Adenine: Start with a free adenine base. Add PRPP (2Pi leave in energising this) so you have AMP nucleotide. This can make ATP or make IMP (myokinase rxn).|
2) Guanine: Start with a free guanine base. Add PRPP (2Pi leave in energising this) so you have GMP nucleotide. This can make GTP.
|What is the correlation between gout and purines?||Gout is caused by build-up of uric acid (which is a break-down product of purines) in joints.|
|Describe purine degradation:||A nucleotide (AMP) is broken down to hypoxanthine. G nucleotide (GMP) is broken down to xanthine --> uric acid. Hypoxanthine can also be broken down to xanthine which is then converted to uric acid.|
|In people with gout, why is there too much uric acid?||1) Genetic DEFECT IN ENZYMES that regulate purine synthesis - so get too much purines synthesised (loss of feedback inhibition), so more enter the degradation pathway --> uric acid.|
2) Genetic DEFECT IN KIDNEY TRANSPORTER that would usually transport uric acid into the urine, but with defect uric acid isn't cleared from body.
3) DRUGS that treat other disorders may cause defects in transporter (SECONDARY development of gout).
4) Lots of purines in the DIET, exceed salvage pathway needs, so excess purines are degraded into uric acid.
|How do you treat gout?||Allopurinol. Competitively inhibits the enzymes that would usually turn hypoxanthene and xanthene through to uric acid. This slows down the synthesis of uric acid, thereby giving the body extra time to excrete out excess uric acid.|