Amino Acid Metabolism

How is atmospheric nitrogen fixed and assimilated into amino acids for use in biological systems?

● Biological nitrogen fixation is catalyzed by the enzyme nitrogenase, contained in microorganisms that live in soil and aquatic environments. Rhizobia are nitrogen-fixing soil bacteria that live symbiotically with root cells in leguminous plants; rhizobia produce NH4+, which the plant uses to generate glutamate and glutamine. Animals obtain nitrogen for amino acid synthesis and other biomolecules by eating plants and other animals.

● Industrial nitrogen fixation uses N2 and H2 gases under conditions of extreme temperature and pressure to produce NH3 by the Haber process. Liquid ammonia generated by this industrial process is used to produce agricultural fertilizers, which are the major source of biological nitrogen in developed countries.

● Nitrogenase is a large protein complex in nitrogen fixing bacteria that catalyzes an ATP-dependent redox reaction converting N2 into –> NH3. Three rounds of nitrogen reduction sequentially convert N2 –> diimine –> hydrazine –> 2 NH3; each reduction transfers 1 e to the nitrogenase complex with the hydrolysis of 2 ATP. Because 6 e are required to generate 2 NH3 from the reduction of N2and H2 is produced in a wasteful side reaction, a total of 8 e and 16 ATP are required.

● The incorporation of NH4+ into glutamate and glutamine is called ammonia assimilation and is mediated by three enzymes: (1) glutamine synthetase, (2) glutamate synthase, and (3) glutamate dehydrogenase.

● Aminotransferases play an important role in amino acid degradation and synthesis by transferring amino groups between amino acids and α-keto acids. For example, aspartate aminotransferase transfers the α amino group of aspartate to α-ketoglutarate to form glutamate and oxaloacetate. The aminotransferase reaction mechanism is a classic example of ping-pong enzyme kinetics, in which the first product of the reaction leaves the active site before the second substrate enters.

What reactions are required for amino acid degradation and how is excess nitrogen removed from the body by the urea cycle?

● Proteins destined for proteasomal degradation are tagged on lysine residues by covalent linkage of ubiquitin through its carboxyl-terminal glycine residue. The proteasome consists of a 20S core particle and two 19S regulatory particles, which together form the 30S proteasome. The 19S complexes serve as caps to regulate protein entry into and exit from the 20S proteolytic core.

● Ubiquitinating enzymes recognize specific residues at the N terminus of the target protein or a structural property of the protein, such as phosphorylation or misfolding. There are three classes of ubiquitinating enzymes: E1 enzymes attach ubiquitin to E2 enzymes, E2 enzymes conjugate ubiquitin to target proteins, and E3 enzymes recognize target proteins and facilitate ubiquitination by interacting directly with E2–ubiquitin and the target protein.

● The two nitrogens in urea are derived from (1) NH4+ released from the deamination of glutamate and glutamine and (2) incorporation of aspartate into the urea cycle intermediate argininosuccinate. The carbon atom in urea comes from CO2 (HCO3) produced in the citrate cycle, and the oxygen atom is derived from H2O.

● In the first reaction of the urea cycle, HCO3 and NH4+ are used to synthesize carbamoyl phosphate, which is then combined with ornithine to form citrulline. Citrulline is exported to the cytosol and activated by AMP before being converted to argininosuccinate when aspartate displaces the AMP. Argininosuccinate is cleaved to yield fumarate and arginine, followed by arginase cleavage to produce urea.

● Amino acids that give rise to pyruvate or citrate cycle intermediates are called glucogenic because pyruvate and oxaloacetate are precursors in the gluconeogenic pathway. In contrast, amino acids converted into acetyl-CoA or acetoacetyl-CoA are called ketogenic amino acids because they can give rise to ketone bodies.

What reactions are required for the synthesis of all 20 amino acids?

● The side chains of amino acids are derived from seven metabolic intermediates in three metabolic pathways: (1) the glycolytic pathway (3-phosphoglycerate, phosphoenolpyruvate, and pyruvate); (2) the pentose phosphate pathway (ribose-5-phosphate and erythrose-4-phosphate); and (3) the citrate cycle (α-ketoglutarate and oxaloacetate).

● Plants and bacteria synthesize all 20 amino acids, whereas animals synthesize only ,10 amino acids (nonessential amino acids), owing to evolutionary adaptation in which animals have diets rich in proteins containing the other ,10 amino acids (essential amino acids).

● The structures of the essential amino acids are more complex than those of the nonessential amino acids, which is reflected in the number of enzymatic reactions required to synthesize them. For example, alanine, serine, and aspartate are synthesized by all organisms using simple reaction pathways, whereas plants and bacteria synthesize tryptophan, histidine, and methionine by pathways requiring multiple enzymes.

● Regulation of metabolic flux through amino acid biosynthetic pathways is tightly controlled to maintain a pool of amino acids that optimally supports protein synthesis. The general principle of feedback inhibition plays a pivotal role in modulating flux through linked amino acid biosynthetic pathways.

● Aromatic amino acids are synthesized in plants, fungi, and bacteria by the shikimate pathway, which uses the substrates phosphoenolpyruvate and erythrose-4-phosphate to generate chorismate, the metabolic precursor to tryptophan, tyrosine, and phenylalanine.

What are examples of amino acid derivatives and how are they synthesized?

● The iron porphyrin ring of hemoglobin, myoglobin, and the cytochromes is derived from the amino acid glycine and is synthesized by a complex pathway requiring eight enzymes localized to either the mitochondrial matrix or the cytosol.

● Heme biosynthesis takes place in erythrocyte precursors in the bone marrow to produce hemoglobin and in liver cells to provide heme for enzymes. Numerous metabolic diseases called porphyrias have been linked directly to enzymes in the heme biosynthetic pathway.

● One of the products of hemoglobin degradation is bilirubin, a yellow metabolite that can accumulate in the blood and cause a condition called jaundice. Most bilirubin degradation products produced each day are excreted in the feces and urine.

● Tyrosine is the precursor to biomolecules required in metabolic signaling and neurotransmission (epinephrine and dopamine) and to pigments (eumelanins and pheomelanins).

● Two human diseases related to tyrosine metabolism are Parkinson disease, which is caused by a loss of dopamine producing cells in the brain, and albinism, which results from genetic defects in the enzyme tyrosinase.

● Nitric oxide (NO) is a soluble gas that functions as a potent vasodilator. NO is produced from arginine in a two-step oxidation reaction catalyzed by the enzyme nitric oxide synthase. Humans have three nitric oxide synthase enzymes: (1) the endothelial form involved in vasodilation, (2) the neuronal form required for neuronal signaling in the brain, and (3) the inducible form that is present in immune cells.

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