Functions of nucleotides in biochemistry ● Building blocks of nucleic acids ● Cosubstrates and...
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Transcript of Functions of nucleotides in biochemistry ● Building blocks of nucleic acids ● Cosubstrates and...
![Page 1: Functions of nucleotides in biochemistry ● Building blocks of nucleic acids ● Cosubstrates and coenzymes ● Signaling.](https://reader036.fdocuments.us/reader036/viewer/2022062407/56649d0a5503460f949dc767/html5/thumbnails/1.jpg)
Functions of nucleotides in biochemistry
● Building blocks of nucleic acids
● Cosubstrates and coenzymes
● Signaling
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Structures of NAD, acetyl-CoA, and PAPS
© Michael Palmer 2014
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The RNA world hypothesis
© Michael Palmer 2014
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Why have cosubstrates become fossilized, whereas enzymes have not?
© Michael Palmer 2014
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Metabolic routes and pathways of nucleotides
● De novo synthesis
● Intestinal uptake of nucleosides
● Endogenous turnover (partial degradation/salvage)
● Degradation and excretion
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Overview of purine synthesis
© Michael Palmer 2014
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IMP synthesis (1)
© Michael Palmer 2014
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IMP synthesis (2)
© Michael Palmer 2014
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IMP synthesis (3)
© Michael Palmer 2014
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A bifunctional enzyme combines AIR carboxylase and SAICAR synthetase activities
© Michael Palmer 2014
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Synthesis of AMP from IMP
© Michael Palmer 2014
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Synthesis of GMP from IMP
© Michael Palmer 2014
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Feedback regulation in purine synthesis
© Michael Palmer 2014
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Overview of digestion and utilization of nucleic acids
© Michael Palmer 2014
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Utilization of ribose and deoxyribose
© Michael Palmer 2014
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Degradation of endogenous purine nucleotides (overview)
© Michael Palmer 2014
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Adenine nucleotide degradation
© Michael Palmer 2014
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The guanase and xanthine dehydrogenase/oxidase reactions
© Michael Palmer 2014
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Renal urate elimination: tubular reuptake and secretion
© Michael Palmer 2014
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Non-primates break down uric acid to allantoin
© Michael Palmer 2014
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Overview of purine salvage reactions
© Michael Palmer 2014
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Enzyme defects in purine degradation and salvage
© Michael Palmer 2014
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Gout
● Genetic or dietary factors cause chronically increased urate production or retention
● Urate has limited solubility and may form crystalline deposits, preferentially in joints and soft tissue
● Urate crystals activate inflammation and lead to arthritis that is painful and, in the long run, destructive
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Diets and drugs that may promote gout
● too much food, too rich in purines
● excessive fructose or sucrose
● alcoholic beverages—but not all kinds: beer yes, wine no
● anorexia nervosa (!)
● drugs that interfere with uric acid secretion: pyrazinamide, salicylic acid
● drugs that contain purines: dideoxyadenosine
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Gout: the fructose connection
© Michael Palmer 2014
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Drugs that affect purine degradation and elimination
© Michael Palmer 2014
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Acute urate nephropathy in tumor lysis syndrome
● Occurs during chemotherapy of malignancies, particularly with lymphomas and leukemias
● Chemotherapy causes acute decay of large numbers of tumor cells
● Degradation of nucleic acids from decaying cells produces large amounts of uric acid
● Uric acid in nascent urine exceeds solubility and precipitates, clogging up and damaging the kidney tubules
● Clinically manifest as acute kidney failure with high fatality rate
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Rasburicase, a better preventive treatment for urate nephropathy
© Michael Palmer 2014
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Synthesis of pyrimidines (1)
© Michael Palmer 2014
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Synthesis of pyrimidines (2)
© Michael Palmer 2014
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Degradation of pyrimidines
© Michael Palmer 2014
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β-Alanine may be used to synthesize carnosine
© Michael Palmer 2014
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Synthesis of deoxyribonucleotides
© Michael Palmer 2014
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The thymidylate synthase reaction
© Michael Palmer 2014
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Nucleotide antimetabolites as anticancer and antiviral drugs
© Michael Palmer 2014
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Dual action mode of 5-fluorouracil
© Michael Palmer 2014
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Inhibition of thymidylate synthase by 5-fluorouracil
© Michael Palmer 2014
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Mutagenesis through mispairing of the 5-FU iminol tautomer
© Michael Palmer 2014
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Thymine and various halogen analogues
© Michael Palmer 2014
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Indirect inhibition of thymidine synthesis by methotrexate
© Michael Palmer 2014
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Mercaptopurine inhibits purine synthesis
© Michael Palmer 2014
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Structure of cytosine arabinoside (araC)
© Michael Palmer 2014
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Metabolic activation and inactivation of araC
© Michael Palmer 2014
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Overexpression of 5′-nucleotidase in leukemic cells reduces survival rates
© Michael Palmer 2014
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Action mode of araCTP
© Michael Palmer 2014
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Dideoxyadenosine inhibits retroviral DNA polymerase
© Michael Palmer 2014
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Aciclovir and ganciclovir
© Michael Palmer 2014
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Aciclovir: mode of action on herpes virus
© Michael Palmer 2014
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Some more inhibitors of viral nucleic acid synthesis
© Michael Palmer 2014