Protein Metabolism

• Protein turnover occurs in all forms of life, with most proteins in the body constantly being synthesized and then degraded, permitting the removal of abnormal or unneeded proteins.
• Humans turnover 1 - 2% of their total body protein, principally muscle protein, each day.
• Approximately 75% of liberated amino acids are reutilized.
• Urea diffuses from the liver, and is transported in the blood to the kidneys, where it is filtered and excreted in the urine.
• A portion of the urea diffuses from the blood into the intestine, and is cleaved to CO2 and NH3 by bacterial urease.
• This ammonia is partly lost in the feces, and is partly reabsorbed into the blood.
• The rate of protein turnover varies widely for individual proteins, with short-lived proteins being rapidly degraded, having half-lives measured in minutes or hours, and long-lived proteins constituting the majority of proteins in the cell.
• There are two major enzyme systems responsible for degrading damaged or unneeded proteins: the ATP-dependent ubiquitin-proteasome system of the cytosol, and the ATP-independent degradative enzyme system of the lysosomes.
• Proteasomes degrade mainly endogenous proteins, that is, proteins that were synthesized within the cell.
• Lysosomal enzymes degrade primarily extracellular proteins, such as plasma proteins that are taken into the cell by endocytosis, and cell-surface membrane proteins that are used in receptor-mediated endocytosis.
• Proteins selected for degradation by the ubiquitin-proteasome system are first covalently attached to ubiquitin.
• Ubiquitination of the target substrate occurs through linkage of the alpha carboxyl group of the C-terminal glycine of ubiquitin to the epilson amino group of a lysine on the protein substrate.
• The consecutive addition of ubiquitin moieties generates a polyubiquitin chain.
• Proteins tagged with ubiquitin are recognized by a large, barrel-shaped, macromolecular, proteolytic complex called a proteasome, which functions like a garbage disposal.
• The proteasome unfolds, deubiquitinates, and cuts the target protein into fragments that are then further degraded to amino acids, which enter the amino acid pool.
• The half-life of a protein is influenced by the nature of the N-terminal residue, with proteins that have serine as the N-terminal amino acid being long-lived, and proteins with aspartate as the N-terminal amino acid having a short half-life.
• The products of transamination are an alpha keto acid (derived from the original amino acid) and glutamate.
• The two most important aminotransferase reactions are catalyzed by alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
• The first step in the catabolism of most amino acids is the transfer of their alpha amino group to alpha ketoglutarate.
• Glutamate produced by transamination can be oxidatively deaminated, or used as an amino group donor in the synthesis of nonessential amino acids.
• The presence of the alpha amino group keeps amino acids safely locked away from oxidative breakdown.
• Aminotransferases are named after the specific amino group donor, because the acceptor of the amino group is almost always α-ketoglutarate.
• Aspartate aminotransferase (AST) transfers amino groups from glutamate to oxaloacetate, forming aspartate, which is used as a source of nitrogen in the urea cycle.
• Removing the α-amino group is essential for producing energy from any amino acid, and is an obligatory step in the catabolism of all amino acids.
• Proteins rich in sequences containing proline, glutamate, serine, and threonine (called PEST sequences) are rapidly degraded and, therefore, exhibit short intracellular half-lives.
• alpha Ketoglutarate plays a pivotal role in amino acid metabolism by accepting the amino groups from most amino acids, thus becoming glutamate.
• Alanine aminotransferase (ALT) is present in many tissues and catalyzes the transfer of the amino group of alanine to α-ketoglutarate, resulting in the formation of pyruvate and glutamate.
• All aminotransferases require the coenzyme pyridoxal phosphate (a derivative of vitamin B6), which is covalently linked to the epilson-amino group of a specific lysine residue at the active site of the enzyme.
• All amino acids, with the exception of lysine and threonine, participate in transamination at some point in their catabolism.
• The transfer of amino groups from one carbon skeleton to another is catalyzed by a family of enzymes called aminotransferases.
• Aminotransferases are found in the cytosol and mitochondria of cells throughout the body, especially those of the liver, kidney, intestine, and muscle.
• Each aminotransferase is specific for one or, at most, a few amino group donors.
• The amino groups of most amino acids are ultimately funneled to glutamate by means of transamination with alpha ketoglutarate.
• Glutamate is unique in that it is the only amino acid that undergoes rapid oxidative deamination, a reaction catalyzed by glutamate dehydrogenase.
• The glutamine is transported in the blood to the liver where it is cleaved by glutaminase to produce glutamate and free ammonia.
• D-Amino acids are present in the diet, and are efficiently metabolized by the kidney and liver.
• Oxidative deamination of amino acids involves the liberation of the amino group as free ammonia (NH3) and occurs primarily in the liver and kidney.
• D-Amino acid oxidase is an FAD-dependent peroxisomal enzyme that catalyzes the oxidative deamination of these amino acid isomers, producing alpha keto acids, ammonia, and hydrogen peroxide.
• Two mechanisms are available in humans for the transport of ammonia from the peripheral tissues to the liver for its ultimate conversion to urea.
• The first transport mechanism, found in most tissues, uses glutamine synthetase to combine ammonia (NH3) with glutamate to form glutamine, a nontoxic transport form of ammonia.