nucleic acids

Nucleic acids are polymers of nucleotides linked by phosphodiester bonds, forming a sugar-phosphate backbone with bases projecting inward (DNA) or available for pairing (RNA). DNA uses deoxyribose sugar and bases adenine (A), thymine (T), guanine (G), and cytosine (C), forming a double helix stabilized by hydrogen bonds (A-T: 2 bonds, G-C: 3 bonds) and base stacking. RNA uses ribose sugar, is typically single-stranded, and substitutes uracil (U) for thymine.

Purines (adenine, guanine) have a double-ring structure and are synthesized de novo using glycine, glutamine, aspartate, and CO2 with PRPP as a key precursor; purine synthesis is inhibited by drugs like methotrexate, 6-mercaptopurine, and mycophenolate. Pyrimidines (cytosine, thymine, uracil) have a single-ring structure, synthesized using aspartate and carbamoyl phosphate, with orotic acid as an intermediate; pyrimidine synthesis is targeted by 5-fluorouracil and leflunomide.

Clinical relevance includes: Lesch-Nyhan syndrome (HGPRT deficiency causing purine salvage pathway defect, leading to hyperuricemia, gout, self-mutilation), orotic aciduria (UMP synthase deficiency causing megaloblastic anemia unresponsive to B12/folate with orotic acid crystalluria), and SCID (adenosine deaminase deficiency causing toxic accumulation of dATP, impairing lymphocyte development).

Molecular biology techniques exploit nucleic acid properties: PCR amplifies DNA using primers and Taq polymerase; Southern blot detects DNA, Northern blot detects RNA, Western blot detects proteins. Understanding base pairing, melting temperature (higher with more G-C content due to triple hydrogen bonds), and enzyme mechanisms (helicase, DNA polymerase, RNA polymerase, topoisomerase) is essential for USMLE Step 1.

Mutations in nucleic acid sequences (point mutations, insertions, deletions, frameshifts) underlie genetic diseases, cancer, and pharmacogenomics, making nucleic acid biology foundational to molecular medicine, genetic testing, and gene therapy approaches.