18.1 Structure and Function of Nucleotides

• Definitions: Nucleotides are the building blocks of nucleic acids and play key roles in various cellular processes.
  • Energy conversion reactions: Nucleotides assist in energy metabolism (e.g., ATP).
  • Signal transduction pathways: Nucleotides like cAMP act as secondary messengers.
  • Coenzyme-dependent reactions: Many enzymes require nucleotides in their active form (e.g., NAD, FAD).
  • Genetic information storage and transfer: Nucleotides form DNA and RNA, critical for heredity and protein synthesis.

Nucleotide Structure

• Components:
  • Nucleotide base: Can be classified as either purines (Adenine and Guanine) or pyrimidines (Cytosine, Thymine, and Uracil).
  • Ribose or Deoxyribose sugar: Ribose in RNA, Deoxyribose in DNA.
  • Phosphoryl group: Attached to the 5' carbon of the sugar.

Purines and Pyrimidines

• Purines:
  • Adenine (A): Found in both DNA and RNA.
  • Guanine (G): Also found in both DNA and RNA.
• Pyrimidines:
  • Cytosine (C): Present in DNA and RNA.
  • Thymine (T): Exclusive to DNA.
  • Uracil (U): Replaces Thymine in RNA.

ATP - The Most Abundant Nucleotide

• Functions: Central to energy conversion (energy currency of the cell), signal transduction, and receptor activation.
• Structure: Composed of adenine, ribose, and three phosphate groups.
  • Mechanism of Action: ATP donates a phosphate group to other molecules to energize them.

18.2 Purine Metabolism

• General Process: Purine biosynthesis occurs through two major stages involving multiple steps and enzymes.
• Stage 1: Involves the formation of Inosine Monophosphate (IMP) from phosphoribosyl pyrophosphate (PRPP), glutamine, glycine, and several transformations.
• Stage 2: Converts IMP to Adenosine Monophosphate (AMP) and Guanosine Monophosphate (GMP).
• Regulatory Mechanisms: Feedback inhibition utilized by end products (ATP, AMP, GMP) to regulate biosynthesis.

18.3 Pyrimidine Metabolism

• Processes: All carbon and nitrogen atoms in pyrimidines are derived from aspartate and carbamoyl phosphate.
• Key Products: UMP is the main product, which is then converted to CTP.
• Regulation: Feedback inhibition, allosteric regulation by ATP and CTP, with key regulatory enzymes such as Carbamoyl Phosphate Synthetase II.

18.4 Deoxyribonucleotide Metabolism

• Process: Derived from ribonucleotides through a reaction catalyzed by Ribonucleotide Reductase, converting nucleoside diphosphates (NDP) to deoxynucleoside diphosphates (dNDP).
• Mechanism: Requires two electrons from NADPH to reduce the ribose sugar, enabling the synthesis of DNA.

RNA World Hypothesis

• Concept: The idea that early life was based on RNA molecules that acted both as genetic material and catalysts (ribozymes).
  • Evolutionary Step: The transition from an RNA world to one dominated by DNA and proteins.

Inhibition and Treatment Strategies

• 5-Fluorouracil: A drug that inhibits thymidylate synthase, thus blocking DNA synthesis.
• Combination Therapies: Strategies to enhance cancer treatment efficacy by using multiple inhibitors targeting different aspects of cancer cell metabolism.

Gout and Related Disorders

• Gout: Caused by excessive production of uric acid, leading to joint and kidney issues due to purine metabolism defects.
• Enzyme Deficiencies: Such as HGPRT deficiency lead to disorders like Lesch-Nyhan syndrome characterized by neurological symptoms.
• Adenosine Deaminase Deficiency (ADA-SCID): Results in severe immune system issues, and gene therapy is an emerging treatment approach for affected individuals.