Lec 2 (Nucleotides) PDF

Lippincott’s illustrated reviews Chapter 22, Page 291 Lectures 2 Nucleotides 1  Specific Objectives By the end of this lecture students can able to: Describe the structure of nucleotides. Know the function of nucleotides. Differentiate betwee...

Lippincott’s illustrated reviews Chapter 22, Page 291 Lectures 2 Nucleotides 1  Specific Objectives By the end of this lecture students can able to: Describe the structure of nucleotides. Know the function of nucleotides. Differentiate between the bonds in nucleotides. Recognize de novo synthesis of purine nucleotides. 2  Chemical structure of nucleotide Nucleotides are composed of a nitrogenous base, a pentose monosaccharide, and one, two, or three phosphate groups. The nitrogenous bases belong to two families of compounds: the purines and the pyrimidines. Note: Pentose monosaccharide formed from glucose by hexose phosphate shunt (HMP shunt). 3 4  Nucleotide Function Nucleotides (Ribonucleoside and deoxyribonucleoside phosphates) are essential for all cells. They are the building blocks of RNA and DNA. 5  Nucleotides serve as carriers of activated intermediates in the synthesis of some carbohydrates, lipids, and conjugated proteins, for example, UDP-glucose and CDP-choline. 6  Nucleotides are structural components of several essential coenzymes, such as coenzyme A, FAD, NAD+, and NADP+. 7  Nucleotides, such as cyclic adenosine mono - phosphate (cAMP) and cyclic guanosine monophosphate (cGMP), serve as second messengers in signal transduction pathways. 8  Nucleotides play an important role as “energy currency” in the cell. Finally, nucleotides are important regulatory compounds for many of the pathways of intermediary 9metabolism, inhibiting or activating key enzymes.  Nitrogenous Bases A. Purine and pyrimidine structures Purine Bases Pyrimidine Bases DNA Adenine (A) Cytosine (C) Guanine (G) Thymine (T) RNA Adenine (A) Cytosine (C) Guanine (G) Uracil (U) 10  Structure of the Nitrogenous Bases 11 B. Nucleosides The addition of a pentose sugar to a base produces a nucleoside. If the sugar is ribose, a ribonucleoside is produced; if the sugar is 2-deoxyribose, a deoxyribonucleoside is produced. The carbon and nitrogen atoms in the rings of the base and the sugar are Numbered separately. 12  The ribonucleosides of A, G, C, and U are named adenosine, guanosine, cytidine, and uridine, respectively. The deoxyribonucleosides of A, G, C, and T have the added prefix, “deoxy-,” for example, deoxyadenosine. [Note: The compound deoxythymidine is often simply called 13 thymidine] C. Nucleotides The addition of one or more phosphate groups to a nucleoside produces a nucleotide. The first phosphate group is attached by an ester linkage to the 5'-OH of the pentose. Such a compound is called a nucleoside 5'-phosphate or a 5'-nucleotide. The type of pentose is denoted by the prefix in the names “5'-ribonucleotide” and “5'- deoxyribonucleotide.” 14 15  If one phosphate group is attached to the 5'-carbon of the pentose, the structure is a nucleoside mono - phosphate, like adenosine monophosphate (AMP) (also called adenylate). If a second or third phosphate is added to the nucleoside, a nucleoside diphosphate (for example, adenosine diphosphate or ADP) or triphosphate (for example, adenosine triphosphate or ATP) results. 16  The second and third phosphates are each connected to the nucleotide by a “high-energy” bond. [Note: The phosphate groups are responsible for the negative charges associated with nucleotides, and cause DNA and RNA to be referred to as “nucleic acids.”] 17  Purine Metabolism Synthesis of purine nucleotides Purine not synthesized as ring but synthesized as nucleotide. There are two types of synthesis pathways: A. De nove Synthesis Pathway B. Salvage Pathway 18 19  A. De nove Synthesis Pathway The atoms of the purine ring are contributed by a number of compounds, including amino acids (aspartic acid, glycine, and glutamine), CO2, and N10–formyltetrahydrofolate (derived from folic acid which is one of vitamin B complex numbered as B9). The purine ring is constructed primarily in the liver. 20 21  A. Synthesis of 5-phosphoribosyl-1- pyrophosphate (PRPP) PRPP is an “activated pentose” that participates in the synthesis and salvage of purines and pyrimidines. Synthesis of PRPP from ATP and ribose 5-phosphate is catalyzed by PRPP synthetase (ribose phosphate pyrophosphokinase). PRPP synthetase is X-linked enzyme activated by inorganic phosphate and inhibited by purine nucleotides (GMP, AMP, IMP, allopurinol and 6-mercaptopurine ) (end- product inhibition). 22 23  B. Synthesis of 5'-phosphoribosylamine Synthesis of 5'-phosphoribosylamine from PRPP and glutamine is first and the committed step in purine nucleotide biosynthesis. iI 24  The amide group of glutamine replaces the pyrophosphate group attached to carbon 1 of PRPP. Glutamine is N- donor. The enzyme, glutamine: phosphoribosylpyrophosphate amidotransferase, is inhibited by the purine 5'-nucleotides AMP and GMP—the end products of the pathway. Increase concentration of PRPP activates the enzyme. 25 C. Synthesis of inosine monophosphate, the “parent” purine nucleotide The next nine steps in purine nucleotide biosynthesis leading to the synthesis of inosine monophosphate (IMP, whose base is hypo - xanthine). This pathway requires ATP as an energy source. 26 Reference Book: Champe, P. C., Harvey, R. A. and Ferrier, D. R., 2005. Biochemistry “Lippincott’s Illustrated Reviews”, 5th or 6th Edition 27