Amino Acids and Nucleotides Biosynthesis

Amino Acid and Nucleotide Biosynthesis

• Amino acid biosynthesis originates from intermediates of glycolysis and the citric acid cycle.
• Different amino acids originate from various metabolic precursors.
• Glutamine is derived from glutamate in a two-step process catalyzed by glutamine synthetase. Phosphorylation of glutamate creates a good leaving group, facilitating displacement by ammonia.
• Non-essential amino acids are synthesized from ammonia and keto acids through transamination.
• Transaminations utilize pyridoxal phosphate (PLP), the active form of vitamin B6, and are catalyzed by amidotransferases. PLP forms a Schiff base with the lysine residue of the aminotransferase.
• Bacteria synthesize all 20 amino acids, whereas mammals require some from their diet.

Biosynthesis of Amino Acids and Nucleotides

• Non-essential amino acids are derived from ammonia and keto acids via transamination.
• Transamination utilizes pyridoxal phosphate (PLP).
• PLP is the vitamin B6 active form
• PLP catalyzes reactions by amidotransferases.
• PLP's aldehyde group forms a Schiff base with the lysine residue of aminotransferase.

Overview of Amino Acid Synthesis

• Bacteria are capable of synthesizing all 20 amino acids.
• Mammals require some amino acids from their diet.
• Glutamate (or glutamine) provides the nitrogen atoms (N) for amino acid synthesis.
• The amino acids are synthesized from 7 intermediates of glycolysis and the citric acid cycle.
• The pentose phosphate pathway is involved in the synthesis process

α-Ketoglutarate, Pyruvate, 3-Phosphoglycerate, and Oxaloacetate Families

• Amino acids are classified based on their metabolic precursors.
• α-Ketoglutarate is a precursor for glutamate, glutamine, proline, and arginine.
• Pyruvate is a precursor for alanine, valine, leucine, and isoleucine.
• 3-Phosphoglycerate is a precursor for serine, glycine, and cysteine.
• Oxaloacetate is a precursor for aspartate, asparagine, methionine, threonine, and lysine.

Porphyrins

• Porphyrins are synthesized from succinyl CoA and glycine.

• The process involves ALA synthase, which produces α-aminolevulinic acid, and porphobilinogen synthase, which converts two molecules of α-aminolevulinic acid into porphobilinogen.

• Errors in porphyrin synthesis can lead to porphyria.

• The symptoms of porphyria relate to the accumulation of porphyrin precursors in body fluids and red blood cells.

• Porphyrias are often associated with urine discoloration and teeth fluorescence under UV light.

• Some porphyrias cause an increased sensitivity to UV light.

Heme Degradation and Bile Pigments

• Heme, derived from the breakdown of old red blood cells, is degraded to bilirubin.
• Biliverdin, a green pigment, is an early intermediate.
• Bilirubin, a yellow pigment, is transported in the bloodstream bound to serum albumin.
• Bilirubin is converted to urobilin, the main pigment in urine, and stercobilin, the pigment in feces, by intestinal microbes.
• Jaundice results from bilirubin accumulation, often due to liver diseases, bile duct blockages, or UDPGT deficiency.
• Infant jaundice can be treated with phototherapy.

Purine Biosynthesis

• Purine synthesis begins with PRPP (5-phosphoribosyl-1-pyrophosphate).
• Multiple enzymes, including glutamine-PRPP amidotransferase, are involved in the process.
• Feedback inhibition by purine nucleotides regulates purine synthesis.
• Some anticancer drugs, such as 6-mercaptopurine and 6-thioguanine, inhibit purine synthesis.

Pyrimidine Biosynthesis

• Pyrimidine synthesis produces the pyrimidine ring first and then attaches it to ribose-5-phosphate.
• Aspartate and carbamoyl phosphate provide atoms for the pyrimidine ring structure.
• UMP is phosphorylated to UTP.
• UTP can be converted to CTP via amination.

Ribonucleotide to Deoxyribonucleotide Conversion

• Ribonucleotides are converted to deoxyribonucleotides by ribonucleotide reductase.
• This involves using NADPH as a reducing agent and glutathione, and FAD.
• The conversion involves reduction of the 2'-C-OH bond to a 2'-H bond.

dTMP from dUMP

• dTMP is synthesized from dUMP.
• Thymidylate synthase catalyzes the reaction, utilizing methyl groups from tetrahydrofolate.
• 5-fluorouracil (5-FU), floxuridine, and capecitabine are thymidylate synthase inhibitors used as anticancer drugs.
• Methotrexate is an inhibitor of dihydrofolate reductase (DHFR) which is part of the pathway that produces tetrahydrofolate required for thymidylate synthase activity.

Purine and Pyrimidine Degradation

• Nucleases degrade DNA and RNA into individual nucleotides.
• Excess nucleotides are catabolized via salvage pathways or de novo pathways to avoid accumulation.
• Purine degradation produces uric acid, which is excreted in humans or converted to allantoin in most mammals.
• Pyrimidine degradation leads to the production of ammonia and urea, along with CAC intermediates.

Excess Uric Acid and Gout

• Excess uric acid can cause gout, characterized by the formation of sodium urate crystals in joints, primarily affecting males.
• Gout can be caused by overproduction or insufficient excretion of uric acid, and/or overconsumption of fructose.
• Treatment options include dietary modifications (avoiding purine-rich foods) and medications such as allopurinol (a xanthine oxidase inhibitor) or febuxostat (another xanthine oxidase inhibitor).
• The administration of porcine uric acid oxidase (uricase) can also be used to treat gout.

Drugs and Diseases

• Essential amino acids and coenzymes, such as pyridoxal phosphate (PLP), are necessary for biosynthesis.
• Certain drugs, such as 5-fluorouracil, 6-mercaptopurine, 6-thioguanine, and methotrexate, are used in treating specific diseases as well as in the synthesis of nucleotides.

This quiz explores the biosynthesis of amino acids and nucleotides, highlighting the pathways originating from glycolysis and the citric acid cycle. It covers essential concepts such as the roles of transamination and pyridoxal phosphate in amino acid synthesis, as well as dietary requirements in mammals versus bacteria. Test your knowledge on these fundamental biochemical processes!