BBMB 405 1st Edition Lecture 19 Outline of Last Lecture XVI Chapter 24 The biosynthesis of Amino Acids D Amino acids are precursors of many biomolecules XVII Chapter 25 Nucleotide Biosynthesis A Nucleotides can be synthesized by de novo or salvage pathways B The pyrimidine ring is assembled de novo or recovered by salvage pathways Outline of Current Lecture XVII Chapter 25 Nucleotide Biosynthesis B The pyrimidine ring is assembled de novo or recovered by salvage pathways C Purine bases can be synthesized de novo or recycled by salvage pathways D Deoxyribonucleotides are synthesized by reduction of ribonucleotides through a radical mechanism E Key steps in nucleotide biosynthesis are regulated by feedback inhibition F Disruption in nucleotide metabolism can cause pathological conditions Current Lecture XVII Chapter 25 Nucleotide Biosynthesis B The pyrimidine ring is assembled de novo or recovered by salvage pathways 1 Orotate acquires a ribose ring from PRPP to form a pyrimidine nucleotide and is converted into uridylate memorize reactions in this section 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 a b Orotic aciduria in humans caused by defiecency of UMPS orotate PRPP OMP PPi treated with dietary CMP and UMP can lead to mental and physical retardation and anemia can t make pyrimidine nucleotides c 2 Nucleotide moni di and triphosphates are interconvertible a UMP ATP UDP ADP b XDP YTP XTP YDP 3 CTP is formed by amination of UTP a UMP UDP UTP CTP b Conversion of UMP to UDP and UDP to UTP requires ATP c Conversion of UTP to CTP requires glutNH2 and ATP 4 Salvage pathways recycle pyrimidine bases C Purine bases can be synthesized de novo or recycled by salvage pathways stated in class do not repeat memorize whole pathway Know where each atom came from 1 The purine ring system is assembled on ribose phosphate a b Rate limiting step c Note glu is source of nitrogen d Controlled through mercaptopurine in cancer treatment molecule is converted to a nucleotide that is an active inhibitor of DNA synthesis excreted as thiocerate allopurinol stops xanthine oxidase which converts mercaptopurine to thiocerate 2 The purine ring is assembled by successive steps of activation by phosphorylation followed by displacement make IMP requires 4 high energy phosphates so it is more efficient to use salvage don t memorize pathway 3 AMP and GMP are formed from IMP a b Know pathway 4 Enzymes of purine synthesis pathway associated with one another in vivo D Deoxyribonucleotides are synthesized by reduction of ribonucleotides through a radical mechanism 1 Mechanism a tyrosyl radical is critical to action of ribonucleotide reductase a b NADPH is the source of electrons c Control production of deoxyribose hydroxyurea stops ribonucleotide reductase considered toxic but essential for human health 2 Stable radicals other than tyrosl radical are employed by other ribonucleotide reductases 3 Thymidylate is formed by methylation of deoxyuridylate dUMP synthesis UMP ATP ADP UDP NADPH NADP dUDP ADP dUMP ATP 4 Dihydrofolate reductase catalyzes regeneration of tetrahydrofolate a one carbon carrier a b Tetrahydrofolate is regenerated with NADPH c Extremely important for DNA synthesis 5 Several valuable anticancer drugs a b Fluorouracil consume to treat cancer not actual inhibitor but converted to active form Fluorodeoxyuridylate which inhibits thymyldilate suicide inhibitor c Fluorouracil is absorbed more efficiently by cancer cells than non cancer cells d FU PRPP via salvage fUMP ATP ADP fUDP NAPDH NADP fdUDP ADP ATP fdUMP inhibitor of thymidylate synthetase fdUTP e Fluorodeoxyuridylate is suicide inhibitor binds to enzyme and destroys so cell has to make new slow down or stop replication f Aminopterin or methotrexate inhibit dihydrofolate conversion to tetrahydrofolate g Trimethoprim used in urinary tract infection to slow down production of DNA in bacteria used at lower but effective doses and has minimal effects on animal cells E Key steps in nucleotide biosynthesis are regulated by feedback inhibition don t memorize but know general concept 1 Pyrimidine biosynthesis is regulated by asparatate transcarbamoylase 2 The synthesis of purine nucleotides is controlled by feedback inhibition at several sites AMP GMP inhibit own synthesis control cell division through energy supply feedback inhibition 3 The synthesis of deoxyribonucleotides is controlled by regulation of ribonucleotide reductase F Disruption in nucleotide metabolism can cause pathological conditions 1 The loss of adenosine deaminase activity results in severe combined immunodeficiency a b SCID deciency of adenosine deaminase in T cells inhibitor of ribonucleotide reductase slow DNA synthesis low T cell results in poor immune system response results in reoccurring infections result in early death bubble boy disease gene therapy may be cure 2 Gout is induced by high serum levels of urate Handout 2 27 3 Lesch Nyhan syndrome is dramatic consequence of mutations in salvage pathway enzyme decrease in salvage pathway activity symptom is self mutilation increase urate and incidence of kidney stones xanthine oxidase XO 4 Folic acid deficiency promotes birth defects such as spina bifida