Biochemistry 1 - Nucleotide Metabolism

Flashcards covering nucleotide metabolism, DNA/RNA structure synthesis, and related concepts from Biochemistry 1 lecture notes.

Key topics in Biochemistry 1

Storage and expression of genetic information, nucleotide metabolism, DNA structure and replication, RNA structure and synthesis, protein synthesis, regulation of gene expression, biotechnology-detection of inherited disease.

Further topics in Biochemistry 1

Proteins, biochemistry of amino acids, biochemistry of proteins, portrait of allosteric protein, enzymes, nitrogen metabolism, disposal of nitrogen, metabolism of the carbon skeleton, conversion of amino acids to specialized products.

Central Dogma of Biology

Transcription, replication, translation. DNA replication yields two DNA molecules identical to the original one, ensuring transmission of genetic information. The sequence of bases in DNA is recorded as a sequence of complementary bases in mRNA. Three-base codons on mRNA direct the sequence of building a protein; recognized by tRNAs.

Nucleic Acids & Information Transfer

The information encoded in DNA is transcribed into RNA, then translated into the amino acid sequence of a protein. It contains C, N, O, and a high amount of P. Oswald, Avery, MacLeod, and McCarty demonstrated that DNA carries genetic information. Watson and Crick proposed the double helix model.

Gene

A segment of DNA containing information for the synthesis of a functional biological product (protein or RNA).

DNA (Deoxyribonucleic acid)

Storage of genetic information.

RNA (Ribonucleic acid)

Carriers of genetic information and catalysis.

Nucleotide Structure

Nitrogenous base + pentose sugar + phosphate.

Nitrogenous Bases

Derivatives of purines and pyrimidines.

Common Bases in DNA & RNA

DNA and RNA contain the same purine bases (A, G) and the pyrimidine base Cytosine (C).

Base found only in DNA

Thymine (T)

Base found only in RNA

Uracil (U)

Pentose in RNA

D-ribose.

Pentose in DNA

2'-deoxy-D-ribose.

Attachment of Base to Sugar

Linked via a β-N-glycosidic bond to the 1' carbon of pentose sugar.

Solubility of Nucleosides

Sugars make nucleosides more water-soluble than free bases.

Nucleotides

Phosphate ester of nucleosides.

Nucleoside

Nitrogenous base + ribose.

Common Ribonucleotides

Adenosine 5'-monophosphate, Guanosine 5'-monophosphate, Cytidine 5'-monophosphate, Uridine 5'-monophosphate.

Common Deoxyribonucleotide

Deoxythymidine 5' monophosphate (dTMP).

Modifications of Unusual Nucleotides

Methylation, hydroxymethylation, glycosylation, acetylation.

Other Functions of Nucleotides

Carriers of energy, recognition units, signal molecules, structural components of coenzymes, drive protein/lipid/carbohydrate synthesis.

Sources of Atoms in Purine Ring

Amino acids (aspartic acid, glycine, and glutamine), CO2, and tetrahydrofolate.

Synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP)

Ribose 5-phosphate is synthesized from the hexose monophosphate pathway; ribonucleotides are synthesized first then reduced to deoxyribonucleotides.

Enzyme Mediating Amide Group Replacement in PRPP Synthesis

Glutamine: phosphoribosyl pyrophosphate amidotransferase, inhibited by AMP, GMP, and IMP, activated by PRPP.

Significance of Glutamine:phosphoribosyl pyrophosphate amidotransferase reaction

Committed step in purine nucleotide synthesis.

Mycophenolic acid

An immunosuppressant that is a reversible, uncompetitive inhibitor of inosine monophosphate dehydrogenase; used to prevent graft rejection.

Conversion of NMP to NDP and NTP

Utilize nucleoside monophosphate kinases, ATP is the source of the transferred phosphate.

Key Enzymes in Purine Salvage Pathway

Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and adenine phosphoribosyl transferase (APRT).

Purpose of Salvage Pathway

Reconverting purines from turnover/diet into nucleoside triphosphates.

Degradation Product of Purines

Sequentially degraded into uric acid.

Adenosine Deaminase (ADA) Deficiency

Causes severe combined immunodeficiency (SCID) due to buildup of dATP inhibiting ribonucleotide reductase.

Gout

Characterized by hyperuricemia with acute arthritic joint inflammation due to uric acid crystals; treated with allopurinol.

Digestion of Dietary Nucleic Acids

Hydrolyze RNA and DNA into oligonucleotides; further hydrolyzed by pancreatic phosphodiesterases into mononucleotides; nucleotidases remove phosphate.

Sources of Carbon Atoms in Pyrimidine Rings

Glutamine, CO2, and aspartic acid.

Committed Step in Pyrimidine Synthesis

Carbamoyl phosphate from Glutamine and CO2.

Enzyme Mediating Carbamoyl Phosphate Synthesis

Carbamoyl Phosphate Synthetase II (CPS II) - inhibited by UTP, activated by ATP and PRPP.

Differences Between CPS I and CPS II

CPS I: Urea cycle, mitochondria, ammonia source. CPS II: Pyrimidine synthesis, cytosol, glutamine source.

Regulation of Pyrimidine Synthesis

UTP inhibits CPS II and CTP inhibits aspartate transcarbamoylase.

Orotic Aciduria

Low activity of orotidine phosphate decarboxylase and orotate phosphoribosyltransferase results in abnormal growth, megaloblastic anemia, and excretion of orotate.

Degradation of Pyrimidines

Can be opened and degraded to soluble structures like β-alanine and β-aminoisobutyrate.

Synthesis of 2'-deoxyribonucleotides

Synthesized from ribonucleoside diphosphate by ribonucleotide reductase.

Key Components in Deoxyribonucleotide Synthesis

Ribonucleotide reductase, with thioredoxin as the reducing agent, and NADPH for regeneration.

Regulation of Deoxyribonucleotide Synthesis

dATP inhibits, ATP activates; NTP binding to substrate specificity site affects conversion of NTP to dNTP.

Synthesis of Thymidine Monophosphate from dUMP

dUMP is converted into dTMP by thymidylate synthetase using N5, N10 –methylene tetrahydrofolate.

5-Fluorouracil

Inhibits thymidylate synthetase, anti-tumor agent.

Methotrexate

Inhibits DHF reductase, inhibits purine synthesis and dTMP methylation.