Molecular Biology: Nucleotides and Nucleic Acids

Nucleic Acid Metabolism

• Nucleic acids are polymers of nucleotides
• Nucleotides are the fundamental building blocks of nucleic acids
• Nucleotides consist of a sugar molecule (either ribose or deoxyribose), a phosphate group, and a nitrogen-containing base
• The nitrogenous base is either a purine or a pyrimidine
• RNA and DNA are polymers made of long chains of nucleotides
• RNA contains ribose, while DNA contains deoxyribose
• DNA contains the bases Adenine (A), Guanine (G), Cytosine (C), and Thymine (T). RNA contains Uracil (U) instead of thymine

Learning Objectives

• Students should be able to describe how nucleotides are synthesized in cells
• Distinguish between the two pathways for nucleotide biosynthesis: de novo and salvage pathways
• Describe the de novo and salvage synthesis of purines
• Understand the synthesis of IMP (precursor of adenine and guanine)
• Describe the synthesis of adenine and guanine from IMP
• Describe the de novo and salvage synthesis of pyrimidines
• Understand the synthesis of uracil, cytosine, and thymine
• Understand the degradative processes of purines and pyrimidines
• Explain the synthesis of deoxyribonucleotides from ribonucleotides

Functions of Nucleotides in Cells

• Precursors of DNA and RNA
• Chemical Energy Carriers (ATP, GTP)
• Components of co-factors (NAD+, FAD, Co-enzyme A)
• Components of activated biosynthetic intermediates (UDP-glucose)
• Cellular secondary messengers (cAMP, cGMP)

Nucleic Acids Metabolism

• Our bodies metabolize DNA and RNA breaking them down into their constituent parts: phosphate, pentose sugar, and nitrogenous bases
• DNA contains thymine, RNA contains uracil

Nucleotide Formation

• The base is added at the 1' position and phosphate groups are added at the 5' position

De Novo Synthesis of Purines

• Primarily occurs in the liver
• Begins with PRPP and leads to the formation of inosine 5'-monophosphate (IMP), the first fully formed nucleotide

Step 1: PRPP Production

• PRPP synthetase and ATP convert ribose-5-phosphate to phosphoribosyl-1-pyrophosphate (PRPP)
• The reaction releases AMP and consumes two high-energy phosphate bonds

Step 2: Synthesis of Inosine Monophosphate (IMP)

• The rate-limiting step in the synthesis is catalyzed by glutamine-PRPP amidotransferase
• Five moles of ATP, two moles of glutamine, one mole of glycine, one mole of CO2, one mole of aspartate, and two moles of formate are required to form IMP

Degradation of Purine Nucleotides

• The process generates uric acid, which is an insoluble compound and is excreted in the urine.

De Novo Synthesis of Pyrimidines

• Pyrimidine nucleotides are synthesized in a stepwise manner, beginning with the formation of carbamoyl phosphate and culminating in the creation of UMP.

Pyrimidine Degradation and Salvaging Reactions

• Various enzymes catalyze reactions that involve the breakdown of cytosine, uracil, and thymine
• Salvaging reactions recycle these pyrimidine bases.

Deoxyribonucleotide Synthesis

• Deoxyribonucleotides are derived from the corresponding ribonucleotides by direct reduction of the ribose sugar at carbon 2 (deoxypurines/deoxypyrimidines are formed).
• Ribonucleotide reductase catalyzes this reduction, yielding dADP, dGDP, dCDP, and dUDP.
• dTTP is created from dUTP after dUTP is created by reduction of UTP.

Regulation of dNTP Synthesis

• The overall activity of ribonucleotide reductase must be tightly controlled.
• ATP activation and dATP inhibition can influence enzyme activity.

Disorders of Nucleotide Metabolism

• Several inherited genetic disorders can affect nucleotide metabolism. These lead to a multitude of symptoms depending on the impacted enzyme.

Drugs that Affect Nucleotide Biosynthesis

• These drugs are often used in cancer treatment by inhibiting the enzymes related to the synthesis and replication of RNA or DNA.