TAMU BICH 411 - Nucleotide Synthesis and Degradation (5 pages)

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Nucleotide Synthesis and Degradation

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Nucleotide Synthesis and Degradation


Covering chapter 26, which is nucleotide degradation and synthesis.

Lecture number:
Lecture Note
Texas A&M University
Bich 411 - Comprehen Biochem Ii
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1st Edition BICH 411 Lecture 21 Outline of Last Lecture I Amino acid formation II Amino acid inhibitor herbicides III Amino acid catabolism IV Inborn Errors of Metabolism Outline of Current Lecture I Purine synthesis II Purine degradation III Pyrimidine Synthesis IV Pyrimidine Degradation Current Lecture the ribose of nucleotides can be source of energy think pentose phosphate pathway the purine and pyrimidine rings can t be used for energy Purine Synthesis N1 is from aspartate two other nitrogens N3 and N9 are from glutamine C4 C5 and N7 come from glycine C6 is from CO2 C2 and C8 are from THF figure 26 2 would be a good quiz question IMP is a precursor for AMP and GMP Step 1 ribose 5 phosphate is activated by ATP dependent pyrophosphate addition PP i which makes PRPP Ribose 5 Phosphate pyrophosphokinase is the enzyme in this reaction Step 2 5 phosphoribosyl alpha pyrophosphate PRPP glutamine H2O Phosphoribosylbeta amine glutamate PP The enzyme for this is glutamine PRPP amidotransferase This is the committed step These notes represent a detailed interpretation of the professor s lecture GradeBuddy is best used as a supplement to your own notes not as a substitute Step 3 Phosphoribosyl beta amine glycine ATP Glycinamide ribonucleotide GAR ADP Phosphate The enzyme is GAR synthetase Remember synthetases require ATP synthases don t Step 4 GAR N10 formyl THF FGAR THF The formyl group of N10 formyl THF transfers to GAR to form formylglycinamide ribonucleotide FGAR GAR transformylase is the enzyme Step 5 FGAR ATP Glutamine H2O FGAM ADP glutamate P This forms formylglycinamide ribonucleotide FGAM with the enzyme FGAM synthetase It essentially swaps the carbonyl for N Step 6 FGAM ATP AIR ADP P This forms 5 Aminoimidazole Ribonucleotide AIR with the enzyme AIR synthetase This reaction is similar to step 5 The first ring is built so now we need to build the second ring Step 7 AIR CO2 ATP CAIR ADP P This is a carboxylation reaction using AIR carboxylase to form Carboxyaminoimidazole ribonucleotide CAIR Step 8 CAIR aspartate ATP SAICAR ADP Pi This uses the enzyme AICAR transformylase to form N succinylo 5 aminoimidazole 4 carboxamide ribonucleotide SAICAR Step 9 SAICAR AICAR fumarate Adenylosuccinate lyase causes a cleavage of fumarate Fumarate then proceeds to the TCA cycle Step 10 AICAR N10 formyl THF FAICAR THF This reaction adds a carbon using the enzyme AICAR transformylase Step 11 FAICAR IMP H2O An amino group attacks the formyl group to close the second ring forming inosine monophosphate IMP The enzyme involved is IMP synthase 6 ATPs are used in all 5 in the reaction and 1 for the pyrophosphorylation good exam question Azaserine is an irreversible inhibitor of enzymes that rely on glutamine It binds to the glutamine binding sites Tetrahydrofolate THF carries one carbon units except CO2 biotin carries this this would be a good exam question Folate analogs are used as purine inhibitors for bacteria and tumors Sulfanamides are good against bacteria Methotrexate and aminopterin are good chemotherapeutic agents AMP and GMP are formed from IMP GTP is the energy for AMP formation while ATP is the energy for GMP formation AMP formation step 1 IMP Aspartate GTP Adenylosuccinate GDP P using adenylosuccinate synthetase Step 2 Adenylosuccinate AMP fumarate using adenylosuccinate lyase This kind of reaction was seen in IMP formation GMP formation step 1 IMP NAD H2O XMP NADH H using IMP dehydrogenase Step 2 XMP ATP Glutamine H2O GMP AMP PP Glutamate this last step is identical to the first two steps of IMP synthesis Purine biosynthesis is regulated at several steps see figure 26 6 to save purines hypoxanthine and guanine are recombined with PRPP to form more nucleotides this is the HGPRT pathway figure 26 7 shows this pathway without this pathway retardation and arthritis occur Lesch Nyhan syndrome Severe combined immunodeficiency syndrome SCID has an absence of adenosine deaminase Purine Degradation purines are degraded to uric acid nucleotidases change nucleotides to nucleosides nucleosides are degraded by purine nucleoside phosphorylase PNP the products are changed to xanthine by guanine deaminase and xanthine oxidase see figure 26 8 AMP IMP with AMP deaminase is the purine nucleoside cycle which converts aspartate to fumarate Fumarate then continues on to the TCA cycle anapleurosis Gout is a disease that occurs when uric acid accumulates Allopurinol inhibits xanthine oxidase and is used to treat gout Pyrimidine Synthesis unlike purines the ring is made before ribose 5 phosphate is involved Carbamoyl phosphate and aspartate are the precursors Carbamoyl phosphate synthetase II CPS II is cytostolic remember CPS I is in the mitochondria figure 26 13 shows the atom sources in pyrimidines good quiz question Step 1 CPS II forms carbamoyl phosphate from HCO3 2 ATP and glutamine this is the committed step since it s the only purpose for carbamoyl phosphate good test question Step 2 Aspartate transcarbamoylase ACT works to form carbamoyl aspartate Step 3 Dihydroorotase closes the ring and removes a water Step 4 the pyrimidine orotate is formed by DHO dehydrogenase Step 5 Orotate forms orotidine 5 phosphate with Orotate phosphoribosyltransferase Note that the ribose P comes from PRPP Step 6 UMP is formed with OMP decarboxylase metabolic channeling occurs using a multifunctional polypeptide enzyme What is the advantage Answer would make a good test question Check book UMP UDP UTP using nucleoside monophosphate diphosphate kinase CTP is formed from UTP and ATP using CTP synthetase Pyrimidine Degradation pyrimidines are reused to form more nucleotides using phosphoribosyltransferase Catabolism of cytosine and catabolism of thymine are not good energy sources cytosine breakdown forms beta alanine ammonium and CO2 Thymine breakdown forms betaaminoisobutyric acid ammonium and CO2 If the 2 position is reduced the nucleotide goes to DNA synthesis This occurs with ribonucleotide reductase and forms dNTP It maintains a balance of all the dNTPs dATP dGTP dCTP and dTTP The catalysis of the enzyme is turned off and on for regulation ATP activates and dATP inhibits The NDP substrates are controlled too ATP dATP dTTP and dGTP bind for regulation Thioredoxin is responsible for reduction using thioredoxin reductase good test question It provides the reducing power for ribonucleotide reductase Ribonucleotide reductase regulation might make a good quiz question see figure 26 23 Thymine nucleotides are made from dUMP

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