#39 Biochemistry Nucleotide Metabolism I Lecture for Kevin Ahern's BB 451/551
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Uploaded on Feb 10, 2012
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1. Nucleotides consist of a) sugar, b) nitrogenous base, and c) phosphate
2. Nucleosides consist of a a) sugar and b) nitrogenous base
3. The sugars of nucleosides and nucleotides are either ribose (found in ribonucleotides of RNA) or deoxyribose (found in deoxyribonucleotides of DNA).
4. Unless otherwise specified, the term "nucleoside" will be used in this class to indicate either ribonucleosides (contain ribose) or deoxyribonucleosides (contain deoxyribose).
5. The term nucleoside phosphate is equivalent to a nucleotide (nucleoside + phosphate + base = nucleotide). This is true whether it is a monophosphate, diphosphate, or triphosphate.
6. The nitrogenous bases found in nucleotides include adenine (purine), guanine (purine), thymine (pyrimidine), cytosine (pyrimidine), and uracil (pyrimidine).
7. The bases adenine, guanine, and cytosine are found in both ribonucleotides and deoxyribonucleotides. Thymine is almost always found in deoxyribonucleotides. Uracil is found primarily in ribonucleotides and rarely in DNA, but does appear as a deoxyribonucleotide intermediate in thymidine metabolism.
8. Ribonucleotides are the building blocks of RNA and deoxyribonucleotides are the building blocks of DNA.
9. Nucleotides and nucleosides are made in cells by 1) salvage pathways or 2) de novo pathways.
10. In salvage pathways, nucleic acids can be broken down to nucleoside monophosphates or individual bases. Monophosphates be rephosphorylated to triphosphates. Alternatively, nucleoside monophosphates can lose a phosphate (becoming nucleosides) or can lose the phosphate and the sugar to become a base.
11. In de novo synthesis of nucleotides, ribonucleotides are synthesized first. Deoxyribonucleotides are made from ribonucleoside diphosphates. Atoms in the ring of pyrimidines come from aspartate and carbamoyl phosphate.
12. The enzyme carbamoyl phosphate synthetase has a catalytic strategy involving channeling of the substrates through the enzyme as catalysis occurs. This is important because some of the intermediates (such as carboxyphosphate and carbamic acid) are very unstable in aqueous solution.
13. The most important regulatory enzyme for the pathway of pyrimidine biosynthesis is ATCase, which plays an important role in balancing the amounts of purines and pyrimidines. The enzyme catalyzes the linkage of aspartate to carbamoyl phosphate.
14. The first pyrimidine nucleotide made in the de novo pyrimidine pathway is UMP.
15. UMP is phosphorylated to UDP (by uridine monophosphate kinase) and then to UTP (by nucleoside diphosphokinase = NDPK) before conversion to CTP. Each nucleoside monophosphate has a specific kinase to convert it to the diphosphate.
16. Conversion of UTP to CTP is catalyzed by the enzyme CTP synthase and it is inhibited by CTP.
17. The most important regulatory enzyme for the first part of purine biosynthesis is PRPP amidotransferase. It is inhibited fully by AMP and GMP, but is only partly inhibited (is still partly active) when only one of these molecules is present.
18. In the process of making IMP, fumarate is released, thereby connecting purine biosynthesis to the citric acid cycle.
19. The first purine-like intermediate in de novo purine biosynthesis is inosinic acid (or IMP), which has the purine-like base hypoxanthine linked to ribose (and ribose is linked to phosphate).
20. IMP can be converted to AMP or GMP. The pathway by which IMP leads to GMP is inhibited by GMP and uses energy from ATP, whereas the pathway where IMP is converted to AMP is inhibited by AMP and uses energy from GTP.
21. The pathway to GMP involves oxidation, whereas the pathway that leads to AMP uses aspartic acid to donate an amine and fumarate is again released.
22. Nucleoside monophosphates from de novo synthesis can be converted by kinases to nucleoside diphosphates and nucleoside triphosphates. Nucleoside diphosphate kinase (NDP kinase or NDPK) converts all nucleoside diphosphates to nucleoside triphosphates.
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