logging in or signing up NUCLEOTIDES brijeshmukherjee Download Post to : URL : Related Presentations : Let's Connect Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Copy embed code: Embed: Flash iPad Dynamic Copy Does not support media & animations Automatically changes to Flash or non-Flash embed WordPress Embed Customize Embed URL: Copy Thumbnail: Copy The presentation is successfully added In Your Favorites. Views: 355 Category: Entertainment License: All Rights Reserved Like it (0) Dislike it (0) Added: February 14, 2013 This Presentation is Public Favorites: 1 Presentation Description No description available. Comments Posting comment... Premium member Presentation Transcript NUCLEOTIDES OF BIOMEDICAL IMPORTANCE: NUCLEOTIDES OF BIOMEDICAL IMPORTANCE DR BRIJESH MUKHERJEE Introduction:: Nucleotides are organic compounds made up of a PO 4 group, nitrogenous base & a sugar molecule. These are the building blocks of nucleic acids ( DNA and RNA ). They serve as sources of chemical energy (ATP, GTP), participate in cellular signalling (cAMP, cGMP) and function as important cofactors of enzymatic reactions (coA, FAD, FMN, NAD + ). Introduction: PO 4 Sugar Base C 2’, 3’, 5 ’ N 9 in Purines , N 1 in Pyrimidin es Ester bond -N-glycosidic bondHISTORY: HISTORY In 1869, Miescher discovered "nuclein" (DNA) in the cells from pus & later he separated it into a protein and an acid molecule. It came to known as nucleic acid after 1874. 1926 , Levene proposed “ Tetra nucleotide theory ” which states that Nucleic acid consists of only 4 nitrides as it gives 4 diff nucleotides on hydrolysis.PowerPoint Presentation: In 1950, Erwin Chargaff shows that the four nucleotides are not present in nucleic acids in stable proportions . 1957, Sir Alexander R.Todd of Cambridge University gave structure of nucleotide .PowerPoint Presentation: H H Ribonucleotide Deoxy-ribonucleotide NucleosideNucleotide nomenclature : Nucleotide nomenclatureNucleotide nomenclature : Nucleotide nomenclatureNitrogen Bases: Nitrogen Bases The bases are abbreviated by their first letters ( A, G, C, T , U ). The purines ( A, G ) occur in both RNA & DNA Among the pyrimidines, C occurs in both RNA & DNA, but T occurs in DNA, and U occurs in RNA.Some minor bases : Some minor bases Minor bases of DNA Minor bases of RNA 5-Methylcytidine occurs in DNA of animals and higher plants. N 6 -methyladenosine occurs in bacterial DNA.CLASSIFICATION: Adenosine nucleotides ATP, ADP, AMP, Cyclic AMP Guanosine nucleotides GTP, GDP, GMP, Cyclic GMP Uridine nucleotides UTP, UDP, UMP, UDP-G Cytosine nucleotides CTP, CDP, CMP and certain deoxy CDP derivatives of glucose, choline and ethanolamine Miscellaneous PAPS (active sulphate ), SAM (active methionine ), certain coenzymes like NAD+, FAD, FMN, Cobamide coenzyme, CoA CLASSIFICATIONPowerPoint Presentation: ADENOSINE CONTAINING NUCLEOTIDESATP (ADENOSINE TRIPHOSPHATE): Many synthetic reactions requires energy, e.g. arginosuccinate synthetase reaction in urea cycle ATP is required for the synthesis of Phospho creatine from creatine , synthesis of FA from acetyl CoA , synthesis of peptides and proteins from AA, formation of glucose from pyruvic acid, synthesis of glutamine, etc ATP is an important source of energy for muscle contraction, transmission of nerve impulses, transport of nutrients across cell membrane, motility of spermatozoa ATP is required for the formation of active methionine , which is required for methylation reaction ATP donates phosphate for a variety of phosphotransferase reactions e.g., hexokinase reaction ATP is required for formation of active sulphate , which is necessary for incorporation of SO4 in compounds like chondroitin SO4 In vivo ATP is converted to ADP, AMP and cyclic AMP which have important role to play in different biochemical processes ATP (ADENOSINE TRIPHOSPHATE)ATP IN UREA CYCLE: ATP IN UREA CYCLEATP IN FA SYNTHESIS: ATP IN FA SYNTHESISATP IN PHOSPHORYLATION REACTIONS: ATP IN PHOSPHORYLATION REACTIONSATP IN SYNTHESIS OF SAM: ATP IN SYNTHESIS OF SAMADENOSINE DI PHOSPHATE (ADP): ADP plays am important role as a primary PO4 acceptor in oxidative phosphorylation and photo phosphorylation in addition to its effect on control of cellular respiration, muscle contraction, etc ADP is also important as an activator of the enzyme glutamate dehydrogenase ADENOSINE DI PHOSPHATE (ADP)ACTVATION OF GLUTAMATE DEHYDROGENASE: ACTVATION OF GLUTAMATE DEHYDROGENASEADENOSINE MONO PHOSPHATE (AMP): AMP acts as an activator of several enzyme in the tissue In the glycolytic pathway, the enzyme phosphofructokinase is inhibited by ATP but the inhibition is reversed by AMP, the deciding factor for the reaction being ratio of ATP and AMP AMP can also act as an inhibitor of certain enzymes like fructose-1-6- bisphosphatase and adenylosuccinate synthetase In resting muscles, AMP is formed for ADP, by adenylate kinase ------------the AMP produced activates the phosphorylase b enzyme of muscle and increase breakdown of glycogen ADENOSINE MONO PHOSPHATE (AMP)AMP ROLE IN REGULATION: AMP ROLE IN REGULATIONAMP ROLE IN REGULATION: AMP ROLE IN REGULATIONGUANOSINE NUCLEOTIDES: The oxidation of succinyl CoA in the citric acid cycle involves phosphorylation of GDP to GTP GTP required for protein synthesis GTP is required in Rhodopsin cycle GUANOSINE NUCLEOTIDESGTP IN TCA CYCLE: GTP IN TCA CYCLEGTP IN RHODOPSIN CYCLE: GTP IN RHODOPSIN CYCLEURIDINE NUCLEOTIDES : UTP also has the role of a source of energy or an activator of substrates in metabolic reactions, like that of ATP, but more specific. When UTP activates a substrate, UDP-substrate is usually formed and inorganic phosphate is released. UDP-glucose enters the synthesis of glycogen. . UTP is used in the metabolism of galactose , where the activated form UDP- galactose is converted to UDP-glucose UDP- glucuronate is used to conjugate bilirubin to a more water-soluble bilirubin diglucuronide UDP- glucoronate and UDP- iduronate are used for the synthesis of MPS URIDINE NUCLEOTIDESUDP ROLE IN GLYCOGEN SYNTHESIS: UDP ROLE IN GLYCOGEN SYNTHESISCONJUGATION OF BILIRUBIN: CONJUGATION OF BILIRUBINUDP ROLE IN GALACTOSE METABOLISM: UDP ROLE IN GALACTOSE METABOLISMCYTIDINE NUCLEOTIDES: CDP- choline , CDP-glycerol, CDP-ethanolamine are involved in biosynthesis of phospholipids CMP-acetyl neuraminic acid is an important precursor of cell-wall in bacteria CMP- Sialic acid is present in salivary glands and may be concerned with the biosynthesis of salivary mucin CYTIDINE NUCLEOTIDESCDP DAG-------------->PHOPHATIDYL SERINE AND PHOSPHATIDYL EHONALAMINE: CDP DAG-------------->PHOPHATIDYL SERINE AND PHOSPHATIDYL EHONALAMINECDP CHOLINE----------------->PHOPHATIDYL CHOLINE: CDP CHOLINE----------------->PHOPHATIDYL CHOLINECMP N-ACETYL NEURAMINIC ACID: CMP N-ACETYL NEURAMINIC ACIDMISCELLANEOUS: PAPS ( Phosphoadenosine phosphosulphate ) Helps in biosynthesis of heparin For biosynthesis of choindroitin SO4 A, B, C, D Formation of sulpholipids Conjugation of phenols, indole , skatole to form “ethereal SO4” SAM (active methionine ) The methyl group (CH 3 ) attached to the methionine sulfur atom in SAM is chemically reactive. This allows donation of this group to an acceptor substrate in transmethylation reactions. More than 40 metabolic reactions involve the transfer of a methyl group from SAM to various substrates, such as nucleic acids, proteins, lipids and secondary metabolites. MISCELLANEOUSPowerPoint Presentation: Another major role of SAM is in polyamine biosynthesis. Here, SAM is decarboxylated by adenosylmethionine decarboxylase to form S - adenosylmethioninamine . This compound then donates its n- propylamine group in the biosynthesis of polyamines such as spermidine and spermine from putrescine SAM is required for cellular growth and repair. It is also involved in the biosynthesis of several hormones and neurotransmitters that affect mood, such as dopamine and serotonin. Methyltransferases are also responsible for the addition of methyl groups to the 2' hydroxyls of the first and second nucleotides next to the 5' cap in messenger RNAPHOSPHO ADENOSINE PHOSPHO SULPHATE: PHOSPHO ADENOSINE PHOSPHO SULPHATESYNTHESIS OF GAG’S FROM PAPS: SYNTHESIS OF GAG’S FROM PAPSS ADENOSYL METHIONINE: S ADENOSYL METHIONINETRANSMETHYLATION REACTIONS: TRANSMETHYLATION REACTIONSC AMP: C AMPFUNCTIONS: Mediator of hormone action- second messenger Regulates glycogen metabolism- ↑ cyclic AMP → glycogenolysis TG metabolism- ↑ c-AMP → lipolysis Cholesterol synthesis is inhibited by c AMP Cyclic AMP activates various steps of steroid synthesis Histamine ↑ cyclic AMP in parietal cells which in turn ↑ gastric secretion ↓ in cyclic AMP is involved in excitation of bitter taste receptors of tongue FUNCTIONSPowerPoint Presentation: 8. Cyclic AMP plays an important role in cell differentiation 9. Plays important role in insulin secretion, catecholamine biosynthesis and melatonin synthesis 10. Cyclic AMP modulates both transcription and translationACTION OF C-AMP: ACTION OF C-AMPC-AMP IN GLYCOGEN METABOLISM: C-AMP IN GLYCOGEN METABOLISMC-AMP AND LIPOLYSIS: C-AMP AND LIPOLYSISC-AMP AND CHOLESTEROL SYNTHESIS: C-AMP AND CHOLESTEROL SYNTHESISRole of c-AMP in prefrontal cortex disorders: Recent research suggests that c-AMP affects the function of higher-order thinking in prefrontal cortex through its regulation of ion channels called hyper polarization-activated cyclic nucleotide-gated channels (HCN). When c-AMP stimulates the HCN, the channels open, closing the brain cell to communication and thus interfering with the function of the prefrontal cortex. This research, especially the cognitive deficits in age-related illnesses, is of interest to researchers studying the brain Role of c-AMP in prefrontal cortex disordersC GMP: C GMPFUNCTIONS: Muscarinic action of acetylcholine on smooth muscles is mediated through c-GMP dependent phosphorylation Compounds like nitroglycerine, sodium nitrite, etc., cause smooth muscle relaxation and vasodilatation by ↑ c-GMP level PG-2 α has been shown to use c-GMP as second messenger for its action Insulin action in certain tissues may be mediated through c-GMP which activate the protein kinases , which in turn phosphorylates some enzyme to modulate their actions FUNCTIONSPowerPoint Presentation: It has been claimed that c-GMP as second messengers regulate the closing and opening of Na+ channels. In the dark there are high levels of c-GMP which bind to Na+ channels causing them to open. Reverse occur in light Nitric oxide (NO) produced in the tissues by the action of the enzyme “nitric oxide synthase” on arginine. It produces vasodilatation and lowering of BP by increasing the c-GMP levelsC-GMP AND NO: C-GMP AND NOINOSINE MONOPHOPHATE: Hypoxanthine ribonulcleotide , usually called IMP is a precursor of all purine nucleotide synthesized de-novo Inosinate can also be formed by de amination of AMP, a reaction which occurs particularly in muscles as a part of purine nucleotide cycle INOSINE MONOPHOPHATECLINICAL SIGNIFICANCE: Blood is stored in acid-citrate –dextrose This ↓ the 2,3 BPG level Transfused blood can restore 2,3 BPG in 24-48 hours In severely ill patients however this is compromised and hence they suffer from tissue hypoxia This can be prevented by adding inosine (hypoxanthine-ribose) Inosine an uncharged molecule can enter RBC where ribose moiety is released, then phosphorylated , enters HMP pathway and converted to 2,3 BPG after entering glycolytic pathway via intermediates CLINICAL SIGNIFICANCEIMP METABOLISM: IMP METABOLISMSYNTHETIC ANALOGUES OF BIOMEDICAL IMPORTANCE: Synthetic analogues of nucleobases , nucleosides and nucleotides are recently of wide use in medical sciences and clinical medicine The heterocyclic ring structure or the sugar moiety is altered in such a way as to induce toxic effects when the analogues get incorporated into cellular constituents of the body SYNTHETIC ANALOGUES OF BIOMEDICAL IMPORTANCEPowerPoint Presentation: Theophylline Azathiopurine Azapurine SOME IMPORTANT SYNTHETIC DERIVATIVESUSES OF SOME ANALOGUES: Mercaptopurine is used to treat leukemia, pediatric non-Hodgkin's lymphoma, polycythemia vera , psoriatic arthritis, and inflammatory bowel disease (such as Crohn's disease and ulcerative colitis) Azapurine is used as antiviral and anticancer agent Thioguanine drug usage was originally as a cytostatic agent in chemotherapy for the treatment of acute lymphoblasic leukemia in children, but has been used less frequently in recent years because of safety concerns. However, it is becoming more widely used for treating ulcerative colitis (UC) and some autoimmune diseases. USES OF SOME ANALOGUESAllopurinol is a purine analogue. This drug is an inhibitor of the enzyme xanthine oxidase, which inhibit uric acid formation. The drug is widely used for the treatment of gout: Allopurinol is a purine analogue. This drug is an inhibitor of the enzyme xanthine oxidase , which inhibit uric acid formation. The drug is widely used for the treatment of goutNucleoside analogues : Range of antiviral products used to prevent viral replication in infected cells. The most commonly used is Acyclovir, although its inclusion in this category is uncertain, as it contains only partial nucleoside structure, as the sugar ring is replaced by an open-chain structure. These agents can be used against hepatitis B virus, hepatitis C virus, herpes simplex, and HIV. Once they are phosphorylated , they work as anti metabolites by being similar enough to nucleotides to be incorporated into growing DNA strands; but they act as chain terminators and stop viral DNA Polymerase Nucleoside analoguesNUCLEOSIDE ANALOGUES AS DRUGS: ANALOGUES DRUGS USES Deoxyadenosine analogues Didanosine , Vidarabine HIV Chemotherapy Deoxycytidine analogues Cytarabine , Emtricitabine Lamivudine Zalcitabine Chemothrapy HIV Hepatitis B HIV Deoxyguanosine analogues Abacavir Entecavir HIV Hepatitis B Deoxy-thymidine analogues Stavudine Telbivudine Zidovudine HIV Hepatitis B HIV Deoxyuridine analogues Idoxuridine Trifluridine HIV HIV NUCLEOSIDE ANALOGUES AS DRUGSNUCLEOTIDE ANALOGUES AS DRUGS: Tenofovir , also known as TDF is a so called ' prodrug ' with the active compound deactivated by a molecular side chain that dissolves in the human body allowing a low dose of tenofovir to reach the site of desired activity. It is approved in the USA for the treatment of both HIV and hepatitis B. Adefovir , also known as bis -POM PMPA, has trade names Preveon and Hepsera . It was not approved by the FDA for treatment of HIV due to toxicity issues, but a lower dose is approved for the treatment of hepatitis B. NUCLEOTIDE ANALOGUES AS DRUGS You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.