BIOLCHEM 415 1st Edition Lecture 28 Outline of Last Lecture I. Diazotrophic microorganisms fix nitrogen II. Glutamate and glutamine are major entry points of NH4+ into metabolismIII. Amino acid carbons come from intermediates of glycolysisOutline of Current Lecture IV. Nucleotides are composed of a pentose sugar, a nitrogenous base, and at least 1 phosphateV. They can be synthesized from salvage pathways or de novo pathwaysCurrent LectureNucleotides- pentose sugar, nitrogenous base, at least 1 phosphate- pentose sugars- ribonucleotides- contain ribose sugar- deoxynucleotides- contain deoxyribose sugar- RNA less stable than DNA- because of 2’ – hydroxyl group- this breaks phosphodiester linkages in the sugar- numbered with primed numbers- nucleoside- pentose sugar + nitrogenous baseThese 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.- β-glycosidic linkageNitrogenous bases- purine or pyrimidine- purine double rings (6 and 5 members)- adenine and quinine- pyrimidine single 6 member ring- cytosine, uracil (RNA), and thymine (DNA)DNA/RNA nucleotide polymers- DNA- deoxyribonucleotides- usually genetic material- chromosomes, genes- RNA- ribonucleotides- genetic material of some virusesWhy do we study nucleotides?- energy (ATP)- coenzymes (FAD, NAD, etc)- second messengers (cyclic AMP)- building blocks- defects can cause diseases- we can target nucleotide defects for treatmentDe novo pathway for pyrimidine synthesis- first need a ring then attach an activated ribose- can create deoxyribonucleotides from ribonucleotides through a reduction1 – activate bicarbonate through phosphorylation- catalyst = carbamoyl phosphate synthetase II- product = carboxyphosphate2 – ammonia liberated from glutamate by carboxyphosphate- creates carbamic acid and has same catalyst as 13 – formation of carbamoyl phosphate by phosphorylation- same catalyst as 14 – carbamoyl aspartate formation- commited step- catalyzed by aspartate transcarbamoylase (ATCase)5 – formation of orotate- dehydration closes carbamoyl aspartate structure into a ring- forms dihydroorotate- oxidation then results in orotate6 – orotidylate and uridylate- orotate + activated ribose = orotidylate- decarboxylation = uridylate (UMP)Kinases convert NMPs to NDPs and NTPs- NMPs NDPs- nucleotide specific enzymes- NDPs NTPs- enzymes with broad specificitySynthesis of CTP- cytidylate synthase- UTP CTP- replacement of carbonyl group by amino groupSynthesis of Thymidylate (TMP)- thymidylate synthase catalyzes - ribonucleotide reductase- ribonucleotides deoxyribonucleotides- from deoxyUMPDe novo synthesis of purine bases- purine ring made first next activated ribose phosphate is added- IMP (inosinate) is the first product- purine ring assembled on ribose phosphate- initial committed step- catalyst = glutamine phosphoribosyl amidotransferase- replaces PPi with NH2- 9 steps- glycine carrier (1)- glutamine carrier (3)- aspartate (6) adds N- formyl-THF (2,8) activated C- bicarbonate (5)- AMP and GMP from IMP - regulate each other- GTP used for AMP synthesis and vice versaPurine and pyrimidine bases can be recycled from salvage pathwaysRibonucleotides reduced to deoxyribonucleotides- ribonucleotide reductase- 2’ –OH 2’ –H- non-specific- kinase: NDP NTPControl of purine nucleotide biosynthesis- feedback inhibition- AMP and GMP inhibit their own synthesis pathways- IMP, AMP, and GMP inhibit PRPP additionControl of pyrimidine nucleotide biosynthesis- inhibited by CTP- activated by purine ATPRegulate ribonucleotide reductase - 2 different allosteric sites- (1) overall activity and (2) substrate specificity1 – dATP inhibits2 – dATP activates pyrimidine synthesisAnticancer drugs block thymidylate synthesis- thymidylate synthase and dihydrofolate reductase- chemo targets- kill any rapidly growing cells- accounts for the side effectsF-dUMP- suicide inhibitor of thymidylate synthasePurine Catabolism- nucleotides have continuous turnover- adenosine deaminase : adenosine inosine- xanthine oxidase : hypoxanthine xanthine and uric acidAbnormal nucleotide metabolism leads to disease- adenosine deaminase (ADA) deficiency- SCID (severe combined immunodeficiency)- “bubble boy” disease- recurring infections and early death- gout- excess urate in blood- due to increase urate synthesis- urate can be useful for salvage pathways- allopurinol inhibits xanthine oxidase- therefoe urate levels decrease- Lesch-Nyham Syndrome- absence of the pathway enzyme
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