Catabolism of Pyrimidine Nucleotide[Nucleotide-Rupendra Shrestha].

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SRI RAMACHANDRA UNIVERSITY PORUR, CHENNAI – 600 116 DEPARTMENT OF HUMAN GENETICS Mr. RUPENDRA SHRESTHA Catabolism of pyrimidine nucleotides Department of Human Genetics/2012/Rupendra Shrestha

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Department of Human Genetics/2012/Rupendra Shrestha

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Nucleases ( DNA -а se and RNA - ase ) decompose nucleoproteins to oligonucleotides Department of Human Genetics/2012/Rupendra Shrestha

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Nucleotides structure Phosphodiesterases decompose oligonucleotides to mononucleotides Department of Human Genetics/2012/Rupendra Shrestha

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Nucleoti-dases – split off phosphoric acid with the formation of nucleosides Department of Human Genetics/2012/Rupendra Shrestha

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Nitrogenous bases Nucleosidases decompose nucleosides to nitrogenous base and pentose Department of Human Genetics/2012/Rupendra Shrestha

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Adenosine mononucleotide Phosphatases Nucleosidases DECOMPOSITION OF MONONUCLEOTIDE Department of Human Genetics/2012/Rupendra Shrestha

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Nucleoproteins (nucleic acids + proteins) Pepsin, gastricsin, HCl Nucleic acids Histones, protamines Nucleases (DNA-ases, RNA-ases) Oligonucleotides Mononucleotides Phosphodiesterases Nuclesides Phosphoric acid + + Phosphatases Nitrogenous bases + Pentose Nucleosidases DECOMPOSITION OF NUCLEIC ACIDS IN INTESTINE AND TISSUE Department of Human Genetics/2012/Rupendra Shrestha

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Phosphoric acid Nitrogenous bases Pentoses phosphorylation; ATP synthesis; synthesis of phospholipids; buffer systems; constituent of bones, cartilages oxidation with energy formation; synthesis of nucleotides ; synthesis of hexoses; synthesis of coenzymes oxidation to the end products DESTINY OF NITROGENOUS BASES, PENTOSES AND PHOSPHORIC ACIDS IN THE ORGANISM Department of Human Genetics/2012/Rupendra Shrestha

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Department of Human Genetics/2012/Rupendra Shrestha

Pyrimidine Ribonucleotide Synthesis:

Pyrimidine Ribonucleotide Synthesis Department of Human Genetics/2012/Rupendra Shrestha

Biosynthesis:

Biosynthesis Uridine Monophosphate (UMP) is synthesized first CTP is synthesized from UMP Pyrimidine ring synthesis completed first; then attached to ribose-5-phosphate N 1 , C 4 , C 5 , C 6 : Aspartate C 2 : HCO 3 - N 3 : Glutamine amide Nitrogen Department of Human Genetics/2012/Rupendra Shrestha

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Department of Human Genetics/2012/Rupendra Shrestha

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Department of Human Genetics/2012/Rupendra Shrestha

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Enzymes 1. E. coli 6 genes, 6 enzymes soluble, molecularly disperse Carbamoyl phosphate synthetase & aspartate transcarbamoylase are each composed of two kinds of polypeptide chains, but none of the enzymes is multifunctional. 2. Drosophila The first three enzymes are coded for by a single complex genetic locus. There is no evidence for a single protein or a multifunctional protein. Department of Human Genetics/2012/Rupendra Shrestha

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3. Mammalian cells A 243 kD protein contains the three enzyme activites in a single polypeptide chain. CAD catalyzes the first 3 steps: glutamine-dependent CPSase II, ATCase , and DHOase . A putative transition state analog, PALA, is O 3 PO-CH2-C(=O)-NH-HC(-COO - )-CH 2 -COO - N - phosphonoacetyl -L-aspartate Allosterically regulated by UTP, PRPP activates, The cells that are exposed to PALA ultimately developed resistance by increasing the amount of ATCase . These cells also contained equally increased amounts of carbamoyl phosphate synthetase II and dihydroorotase . George Stark give the enzyme its acronym CAD. This is an example of gene amplication in response to stress in eukaryotic cells. This is often a mechanism for drug resistance. Orotate phosphoribosyltransferase & orotidylate decarboxylase also exist on a single protein - UMP synthase. CAD and UMP synthase are cytosolic but dihydroorotate oxidase is mitochondrial - how is there communication? The intermediates must be transported into and out of the mitochondria. The multifunctional enzymes are examples of channeling - substrate-product-substrate passage without release to the medium Department of Human Genetics/2012/Rupendra Shrestha

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Department of Human Genetics/2012/Rupendra Shrestha

Catabolism Degradation Disintegration of Pyrimidine :

Catabolism Degradation Disintegration of Pyrimidine Department of Human Genetics/2012/Rupendra Shrestha

Degradation of Pyrimidine:

Degradation of Pyrimidine CMP and UMP degraded to bases by; Dephosphorylation Deamination Glycosidic bond cleavage Uracil reduced in liver, forming b -alanine Converted to malonyl-CoA  fatty acid synthesis for energy metabolism Department of Human Genetics/2012/Rupendra Shrestha

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Department of Human Genetics/2012/Rupendra Shrestha

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Department of Human Genetics/2012/Rupendra Shrestha

Regulatory Control of Pyrimidine Synthesis:

Regulatory Control of Pyrimidine Synthesis Department of Human Genetics/2012/Rupendra Shrestha

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Regulation Bacteria Major carbamoylphosphate synthetase inhibited by UMP ATCase inhibited by CTP, activated by ATP 2. Animals carbamoyl phosphate synthetase activated by ATP & PRPP inhibited by UTP & CTP OMP decarboxylase UMP is a noncompetitive inhibitor CTP synthetase activated by GTP inhibited by CTP Department of Human Genetics/2012/Rupendra Shrestha

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Department of Human Genetics/2012/Rupendra Shrestha

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Department of Human Genetics/2012/Rupendra Shrestha

Disorder of Pyrimidine Metabolism:

Disorder of Pyrimidine Metabolism Department of Human Genetics/2012/Rupendra Shrestha

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OROTACIDURIA inherited disorder of pyrimidine synthesis caused by a deficiency of the enzyme of orotate - phosphoribosyltransferase and decarboxylase . Sign and Symptoms : excess of orotic acid and its excretion with urine (1.0-1.5 g ) In addition to the characteristic excessive orotic acid in the urine, patients typically have Megaloblastic anaemia which cannot be cured by administration of vitamin B12 or folic acid It also can cause inhibition of RNA and DNA synthesis and failure to thrive. This can lead to mental and physical retardation Department of Human Genetics/2012/Rupendra Shrestha

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TREATMENT OF OROTACIDURIA Administration of cytidine monophosphate and uridine monophosphate reduces urinary orotic acid and the anaemia. Administration of uridine, which is converted to UMP, will bypass the metabolic block and provide the body with a source of pyrimidine Department of Human Genetics/2012/Rupendra Shrestha

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THANK YOU FOR KIND ATTENTION Department of Human Genetics/2012/Rupendra Shrestha

Rupendra speaks;" More u read ,the more confusion; confusion triggers our curiosity, curiosity on new things is searching for it that’s called research; researcher are honoured as scientists that’s we should aim in life”:

Rupendra speaks;" More u read ,the more confusion; confusion triggers our curiosity , curiosity on new things is searching for it that’s called research ; researcher are honoured as scientists that’s we should aim in life” Department of Human Genetics/2012/Rupendra Shrestha