bioc
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- Purines
- adenine, quanine, hypoxanthine, xanthine, 2 rings
- Pyrimidines
- cytosine, uracil, thymine, 1 ring
- nucleotide
- nucleoside+phosphates
- Role of Nucleotides
- precursor to necleic acids, energy sources (especially adensosine and guanosine), sources of phosphate groups, second messengers (cAMP and cGMP)
- 1st regulatory point of purine de novo biosynthesis
- conversion of IMP to either XMP (to make GTP) or adenylosuccinate (to make ATP), inhibited by GMP and AMP respectively
- 2nd regulatory point of purine de novo biosynthesis
- If there is an excess of both GMP and AMP, the conversion of 5-phosporibosyl-1-pyrophosphate into 5 phosphoribosylamine by amidophosphoribosyltransferase is inhibited
- 3rd regulatory point of purine de novo biosynthesis
- If there is still an excess of AMP and GMP, they will inhibit the production of 5-phosporibosyl-1-pyrophosphate from ribose-5-phosphate by PRPP synthetase, a last resort, as the inhibition of PRPP production also inhibits pyrimidine production
- Possible pathways of IMP branching point
- IMPèXMPèGMPèGDPèGTP & IMP->adenylosuccinate->AMP->ADP->ATP
- Interconversion and degradation pathways of purines
- AMP(via adenosine deaminase)è Inosineè Hypoxanthine èXanthine èuric acid & a. GMPGuanineXanthineuric acid
- Salvage pathway of purines
- HGRPT is enzyme used, Hypoxanthine or guanine + PRPP --> IMP or GMP + Ppi, IMP goes to either AMP or GMP
- Major differince between purine and pyrimidine synthesis
- The purine ring is assembled onto the ribose 5 phosphate, whereas the pyrimidine ring is completely assembled separately and then added onto the ribose 5 phosphate
- Synthesis of CTP
- CTP synthase converts UTP to CTP, using a glutamine as an amino donor.
- Synthesis of Deoxyribonucleotides
- Ribonucleotide reductases use reduced thioredoxin to reduce ribonucleotides to deoxyribonucleotides. The newly oxidized thioredoxin is reduced by thioredoxin reductase.
- Synthesis of dTMP
- dUDP is dephosphorylated to make dUMP. Thymidylate synthase pulls a methyl group off of methylene-THF to make DHF and adds the methyl group to dUMP to make dTMP. THF is regenerated from DHF by DHF reductase reducing NADPH. Note: 3 reductases total are used to make dTMP.
- Biochemical basis of gout
- 1. Defects in PRPP synthetase activity lead to increased levels of PRPP, which accelerates the de novo synthesis of both purines and pyrimidines. This, in turn, leads to increased production of uric acid. 2. Low HGPRT activity also leads to increased levels of PRPP, which accelerates the de novo biosynthesis pathway. Also, the salvage pathway is inhibited, so more free bases persist and are converted to uric acid. Finally, less IMP and GMP means less feedback inhibition of the de novo pathway, further accelerating uric acid production.
- Treatment of gout
- 1. Colchicine: anti-inflammatory 2. Probnecide: increase uric acid excretion 3. Allopurinol: inhibition of xanthine oxidase, which is directly responsible for uric acid production
- Biochemical basis of Lesch-Nyhan disease
- Complete deficiency of HGPRT. With the salvage pathway nonfunctional, the body switches to the de novo pathway. The brain cannot use the de novo pathway effectively, however, and so cannot produce many purine nucleotides which are the basis of neurotransmitters like dopamine. The deficiency in dopamine production may lead to multiple neurological symptoms.
- Treatment of Lesch-Nyhan disease
- Allopurinol relieves gouty arthritis but not neurological symptoms
- Biochemical basis of SCID
- Sever combine immonodefiency disease is the loss of B- and T-lymphocytes leads to lack of immune response. Deficiency of adenosine deaminase leads to elevated levels of adenosine and deoxyadenosine which is toxic to lymphocytes.
- Biochemical basis of Purine Nucleotide Phosphorylase Defiency
- Enzyme defect leads to accumulation of dGTP, which inhibits CDP reductase
- Treatment of Purine Nucleotide Phosphorylase Defiency
- Blood transfusion, bone marrow transplant, ADA replacement therapy, gene therapy
- Biochemical basis of Orotic aciduria
- Deficiency in orotate/orotidine enzymes leads to a blockage of UTP and CTP production
- Treatment of Orotic aciduria
- Provide uridine or cytosine orally (not as nucleotides, since they can’t cross the membrane. Excess uridine will inhibit carbamyl phosphate synthetase II and lower the de novo synthesis of orotate.
- Hydroxyurea
- Anti-cancer drug that inhibits ribonucleotide reductase, which leads to a decrease inn DNA production and thus a decrease in cell proliferation
- 6-mercaptopurine
- Anti-cancer drug that inhibits de novo purine biosynthesis, which leads to a decrease in DNA production and thus decrease in cell proliferation
- 5-fluorouracil
- Anti-cancer drug that inhibits thymidylate synthetase which lowers dTTP production, which leads to decreased DNA production, which leads to decreased cell proliferation. This is given to glaucoma patients to prevent scar formation in the eye.
- Methotrexane
- Anti-cancer drug that inhibits dihydrofolate reductase.