Biosynthesis of nucleotides

Transcription

1 Biosynthesis of nucleotides De novo pathways De novo purine nucleotide synthesis Regulation of purine biosynthesis De novo pyrimidine nucleotides biosynthesis Salvage pathways Lesch-Nyhan syndrome

2 Why is the biosynthesis of nucleotides important? Nucleotides play a variety of important roles in all cells They are precursors of DNA and RNA. They are essential carriers of chemical energy a role primary of ATP and to some extent GTP. They are component of cofactors NAD, FAD, S-adenosylmethionine and coenzyme A, as well as of activated biosynthetic intermediates such as UDPglucose, and CDP-diacylglycerol Some such as camp, and cgmp, are also cellular second messengers. 2 types of pathways lead to nucleotides the de novo pathway and salvage pathway.

3 De novo pathways De novo synthesis of nucleotides begins with their metabolic precursors: amino acids, ribose 5-phosphate, CO 2 and NH 3. The de novo pathways for purine and pyrimidine biosynthesis appear to be nearly identical in all living organisms. The purine ring structure is built up one or a few atoms at atime, attached to ribose throughout the process. The pyrimidine ring is synthesized as orotate, attached to ribose phosphate, and then converted to the common pyrimidine nucleotides required in nucleic acid synthesis. Phosophoribosyl pyrophosphate (PRPP) is important in both purine and pyrimidine biosynthesis

4 De novo purine nucleotide synthesis begins with PRPP 2 parent purine nucleotides AMP and GMP This pathway begins with PRPP. This pathway beside shows the origin of the carbon and nitrogen atom of the purine ring system. Glutamine Glycine Formyl H folate Aspartate And ATP 11 Steps to form inosinate(imp)

5 Biosynthesis of AMP and GMP from IMP Conversion of inosinate to adenylate requires the insertion of amino group derived from aspartate, this takes place in two reactions. A crucial difference is that GTP rather than ATP is source of the high-energy phosphate in synthesizing adenylosuccinate. Gluanylate is formed by the NAD + - requiring oxidation of inosinate at C-2. Followed by addition of an amino group derived from glutamine. ATP is cleaved to AMP and PP in the final step.

6 Regulation of purine biosynthesis 3 major feedback mechanism: 1) Inhibition of glutamine-prpp aminotransferase by IMP, AMP and GMP. AMP and GMP act synergistically. 2) Inhibition of IMP dehydrogenase by GMP. Inhibition of adenylosuccinate synthetase by AMP does not affecting the formation of GMP. 3) Inhibition of PRPP synthesis by ribose phosphate pyrophosphokinase. This enzyme is inhibited by ADP and GDP.

7 De novo pyrimidine nucleotides biosynthesis The common pyrimidine ribonucleotides are CMP (Cytidylate) and UMP (uridylate). De novo pyrimidine nucleotide biosynthesis proceeds in the some what different manner from purine. The pyrimidine is constructed from carbamoyl phosphate and aspartate. The ribose 5-phosphate is then added to completed pyrimidine by orotate phosphoribosyltransferase.

8 Thymidylate is derived from dcdp and dump DNA contain thymine rather than uracil, and de novo pathway to thymine involve only deoxyribonucleotides. The immediate precursor of thymidylate (dtmp) is dump. Ribonucleotide reductase. Nucleoside diphosphate kinase Deaminase dutp ase Thymidylate synthase

9 Salvage pathways Free purine and pyrimidine bases are constantly released in the cells during the metabolic degradation of nucleotides. Free purine are in large part salvaged and reused to make nucleotides, in a pathway much simpler than de novo synthesis of purine nucleotides. One of the primary salvage pathways consists of a single reaction catalyzed by adenosine phosphoribosyltransferase, in which free adenine react with PRPP to yield the corresponding adenine nucleotide: Adenine +PRPP AMP + PP i Free guanine and hypoxanthine are salvaged in the same way by hypoxanthine-guanine phosphoribosyltransferase. A similar salvage pathway exists for pyrimidine bases in microorganism, and possible in mammals. A genetic lack of hypoxanthine-guanine phosphoribosyltransferase activity, seen almost exclusively in male children, results in a bizarre set of syndrome called Lesch-Nyhan syndrome

10 Lesch-Nyhan syndrome A genetic lack of hypoxanthine-guanine phosphoribosyltransferase activity, Children with this genetic disorder, which become manifest by the age of 2 years. Are sometimes poorly coordinated and mentally retarded. In addition, they are extremely hostile and show compulsive self-destructive tendencies. They mutilate themselves by biting off their fingers, toes, and lips