Topic 2 Anabolism of Biomolecules (Part II)-2.pdf

Topic 2 Anabolism of Biomolecules (Part II) BIOL 2036SEF/S236F Cellular and Molecular Biology 2 Topic Covered ▪ ▪ Readings: Chapter 15, Biology Metabolism of Carbohydrates Metabolism of Fatty Acids ▪ ▪ Metabolism of Amino Acids Metabolism of Nucleotides 4 Lipids Metabolism 4 Oxidation of Fatty acid...

Topic 2 Anabolism of Biomolecules (Part II) BIOL 2036SEF/S236F Cellular and Molecular Biology 2 Topic Covered ▪ ▪ Readings: Chapter 15, Biology Metabolism of Carbohydrates Metabolism of Fatty Acids ▪ ▪ Metabolism of Amino Acids Metabolism of Nucleotides 4 Lipids Metabolism 4 Oxidation of Fatty acid ▪ Activation of fatty acids take place at outer mitochondrial membrane ▪ Transport fatty acyl CoA into mitochondria ▪ Degradation of acetyl CoA in the mitochondrial matrix through boxidation 5 ▪ Fatty acids are converted to CoA thioesters by acyl-CoA synthetase ▪ The PPi released is hydrolysed by a pyrophosphatase to 2 Pi ▪ Two phosphoanhydride bonds are consumed to activate one of the fatty acid to thioester Activation of fatty acids 6 Transport fatty acyl CoA into mitochondria ▪ The carnitine shuttle system ▪ Fatty acyl CoA is converted to acylcarnitine by carnitine acyltransferase 1 (CPT1) ▪ Acylcarnitine enters into mitochondrial matrix by translocase ▪ The acyl group then transferred back to CoA by carnitine acyltransferase 2 (CPT2) 7 8 ▪ B-oxidation is the catabolic process by which the fatty acids molecule are broke down in the mitochondria to produce acetylCoA ▪ Enzyme that involved are acylCoA dehydrogenase, enoyl-CoA hydratase, hydroxyacyl-CoA dehydrogenase and ketoacylCoA thiolase. Degradation of acetyl CoA 9 Degradation of acetyl CoA ▪ During B-oxidation NADH will be produced which catalyse by hydroxyaryl-CoA dehydrogenase ▪ FADH2 will also produce during the process which catalyse by acyl-CoA dehydrogenase. ▪ NADH and FADH2 are used by the electron transport chain to form ATP. 10 11 Lipid anabolism ▪ Lipid anabolism is also called lipogenesis. ▪ When glycerol binds with fatty acids, mono-/di-/tri-glycerides are formed. ▪ Almost any organic substrate can be used to synthesize lipids because lipids, amino acids, and carbohydrates can be converted to acetyl-CoA. 12 Fatty acid synthesis 13 Comparison of b-oxidation and fatty acid synthesis 5 Nucleotide Metabolism 15 Introduction ▪ Purines and pyrimidines are nitrogencontaining heterocycles, cyclic compounds whose rings contain both carbon and other elements. Nucleosides are derivatives of purines and pyrimidines that have a sugar linked to a ring nitrogen. ▪ ▶ ▪ ▶ Nucleotides are nucleosides with a phosphoryl group esterified to a hydroxyl group of the sugar. 16 17 Nucleoside (Adenosine) ▪ Nucleosides are derivatives of purines and pyrimidines that have a sugar linked to a ring nitrogen. Nucleotide (Adenosine Triphosphate) ▪ Nucleotides are nucleosides with a phosphoryl group esterified to a hydroxyl group of the sugar. Bases, Nucleosides and Nucleotides 18 ▪ Nucleic acids and nucleotides, are dietarily nonessential ▪ Degrade in the intestinal tract to mononucleotides, which may be absorbed or converted to purine and pyrimidine bases. 19 Process involved in nucleotides biosynthesis ▪ Synthesis from amphibolic intermediates (synthesis de novo). ▪ Phosphoribosylation of purines ▪ Phosphorylation of purine nucleosides. ▪ Conversion of purines, their ribonucleosides, Biosynthesis of purine nucleotides and their deoxyribonucleosides to mononucleotides involves so called “salvage reaction. ▶ Liver is the major site for purine nucleotide synthesis. ▶ Erythrocytes, polymorphonuclear leukocytes and brain cannot produce purines. ▶ Folic acid is essential for the synthesis of purine nucleotides. Folic (methotrexate) are employed to control cancer. 20 21 ▪ Biosynthesis Of Pyrimidine Nucleotides ▶ The catalyst for the initial reaction is cytosolic carbamoyl phosphate synthase II, *DO NOT mix up with mitochondrial carbamoyl phosphate synthase I, it is for urea synthesis. ▪ ▶ Phosphoribosyl pyrophosphate (PRPP), an early participant in purine nucleotide synthesis, is a much later participant in pyrimidine biosynthesis. ▪ ▶ Phosphoribosyl pyrophosphate (PRPP) acts as a cofactor for uridine monophosphate synthetase (UMPS) which converts orotic acid into UMP (precursor). ▪ ▶ Mammalian cells reutilize few free pyrimidines, “salvage reactions” convert the ribonucleosides (uridine and cytidine) and the deoxyribonucleosides (deoxythymidine and deoxycytidine) to their respective nucleotides. 22 23 1. FOLATE BIOCHEMISTRY ▪ ▪ ▪ Tetrahydrofolate is synthesized by two mechanisms: ▫ Conversion of folate to dihydrofolate and dihydrofolate to tetrahydrofolate is catalyzed by dihydrofolate reductase (DHFR). ▫ Methyltetrahydrofolate from liver stores is converted to tetrahydrofolate, a reaction that requires VITAMIN B12. Two steps in the conversion of 5phosphoribosylamine to IMP (purine synthesis) use tetrahydrofolate as a carbon donor. Tetrahydrofolate is also involved in the generation of dTMP from dUMP (pyrimidine synthesis) – this reaction is catalyzed by thymidylate synthase (see 2A below). 24 PYRIMIDINE SYNTHESIS A. The rate limiting step in DNA synthesis is the conversion of UMP to TMP, which is catalyzed by thymidylate synthase. B. Conversion of UMP to UDP is catalyzed Uridine monophosphate (UMP) by pyrimidine monophosphate kinase C. 5-fluorouracil is anti-cancer that targets Thymidine monophosphate (TMP) thymidylate synthase. D. One step in the degradation of thymidine 5-fluorouracil (5FU) nucleotides is catalyzed by dihydropyrimidine dehydrogenase; E. An inherited deficiency of this enzyme leads to greatly increased sensitivity to 5-FU. PURINE SYNTHESIS A. De novo purine synthesis Begins with the conversion of ribose-5-phosphate → 5-phosphoribosyl-1-pyrophosphate (PRPP; a cofactor) *Catalyze by PRPP synthetase (PRPS). B. The first committed step in purine synthesis is the formation of 5-phosphoribosylamine via the enzyme glutamyl amidotransferase (GPAT). C. IMP and GMP can also be created by via the “salvage pathway” whereby PRPP (cofactor) is combined with hypoxanthine or guanine bases by the actions of hypoxanthine-guanine phosphoribosyl transferase (HGPRT). D. The tetrahydrofolate also join and lead to the formation of XMP and AMP from IMP. E. One route for the degradation of purine nucleotides (occurs via conversion of IMP to uric acid. Two steps in that process, conversion of hypoxanthine to xanthine and xanthine to uric acid, are catalyzed by the enzyme xanthine oxidase. 25 26 CONVERSION OF RIBONUCLEOTIDES TO DEOXYRIBONUCLEOTIDES ▪ This reaction is catalyzed by ribonucleotide reductase. 27 ▪ Humans convert adenosine and guanosine to uric acid. Catabolism of purines ▪ Adenosine is first converted to inosine by adenosine deaminase. ▪ In mammals other than higher primates, uricase converts uric acid to the water soluble product allantoin. ▪ Since humans lack uricase, the end product of purine catabolism in humans is uric acid. ▪ Uric acid is degraded into allantoic acid and finally to ammonia in animals other than human 28 29 Catabolism of pyrimidines ▪ Pyrimidine catabolism are highly water-soluble: CO2, NH3, β-alanine, and β-aminoisobutyrate. ▪ Excretion of β-aminoisobutyrate increases in leukemia and severe x-ray radiation exposure due to increased destruction of DNA. ▪ Humans probably transaminate βaminoisobutyrate to methylmalonate semialdehyde, which then forms succinyl-CoA. ▪ Since the end products of pyrimidine catabolism are highly water-soluble, pyrimidine overproduction results in few clinical signs or symptoms. 30 31 ▪ Coordinated regulation of purine and pyrimidine nucleotide biosynthesis ensures their presence in proportions appropriate for nucleic acid biosynthesis and other metabolic needs. ▪ ▶ Pyrimidine nucleotides are synthesized from the precursors aspartate, glutamine and CO2, besides ribose 5-phosphate. are degraded to amino acids, nomely βalanine and β ▪ aminoisobutyrote which are then metabolized ▪ ▶ Pyrimidines 32 Thanks! 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