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Clinical biochemistry second stage lecture 2 Dr.Thana Alsewedy General Amino Acid Metabolism The main role of amino acids is in the synthesis of structural and functional proteins. Unlike carbohydrates and fats, there is no storage form of proteins in the body.The body amino acid pool is always in a dynamic steady state. In an adult, the rate of synthesis of proteins balances the rate of degradation, so that nitrogen balance is maintained .the main reaction of amino acid are 1. The anabolic reactions where proteins are synthesized. 2. Synthesis of specialized products such as heme,creatine, purines and pyrimidines. 3. The catabolic reactions where dietary proteins and body proteins are broken down to amino acids. 4. Transamination: amino group is removed to produce the carbon skeleton (keto acid). The amino group liberated as ammonia is detoxified and excreted as urea. 5. The carbon skeleton is used for synthesis of nonessential amino acids. 6. It is also used for gluconeogenesis. Figure (1)General Amino Acid Metabolism REMOVAL OF NITROGEN FROM AMINO ACIDS The presence of the α-amino group keeps amino acids safely locked away from oxidative breakdown. 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. Once removed, this nitrogen can be incorporated into other compounds or excreted, with the carbon skeletons being metabolized. General structure of amino acid 1 Clinical biochemistry second stage lecture 2 Dr.Thana Alsewedy The first step in the catabolism of most amino acids is the transfer of their α - amino group to α -ketoglutarate where the products are α - ketoacids and glutamate. This transfer of amino groups from one carbon skeleton to another is catalyzed by a family of transaminases which are also called aminotransferases. Most of the amino acids undergo these reaction except lysine and threonine The main reaction of amino Acid : A. Transamination: the tunneling of amino groups to glutamate i. Transamination is the exchange of the alpha amino group between one alphaamino acid and another alpha keto acid,forming a new alpha amino acid. amino acid 1 + keto acid 2 → amino acid 2 +keto acid 1 ii. As an example, amino group is interchanged between alanine and glutamic acid (Fig. 14.8).In almost all cases, the amino group is accepted by alpha ketoglutaric acid so that glutamic acid is formed. The first step in the catabolism of most amino acids is the removal of their α-amino group to α-ketoglutarate (Figure 19.7). The products are an α-keto acid (derived from the original amino acid) and glutamate. aKetoglutarate plays a unique role in amino acid metabolism by accepting the amino groups from other amino acids, thus becoming glutamate. Glutamate produced by transamination can be actively deaminated, or used as an amino group donor in the synthesis of nonessential amino acids. The transfer of amino groups from one carbon skeleton to another is catalyzed by a family of enzymes called aminotransferases (formerly called transaminases). These enzymes are found in the cytosol of cells throughout the -body—especially those of the liver, kidney, intestine, and muscle. All amino acids, with the exception of lysine and threonine, participate in transamination at some point in their catabolism. [Note: These two amino acids lose their α-amino groups by deamination . 2 Clinical biochemistry second stage lecture 2 Dr.Thana Alsewedy Substrate specificity of aminotransferases: Each aminotransferase is specific for one or, at most, a few amino group donors. Aminotransferases are named after the specific amino group donor, because the acceptor of the amino group is almost always α-ketoglutarate. The two most important aminotransferase reactions are catalyzed by alanine aminotransferase and aspartate aminotransferase The enzymes catalysing the reaction as a group are known as amino transferases.These enzymes have pyridoxal phosphate as prosthetic group (Fig. 14.8). The reaction is readily reversible Fig. 14.8. Transamination reaction. In this example,enzyme is Alanine aminotransferase (ALT) andpyridoxal phosphate is the coenzyme. The reaction is readily reversible 3 Clinical biochemistry second stage lecture 2 Dr.Thana Alsewedy Mechanism of action of aminotransferases: All aminotransferases require the coenzyme pyridoxal phosphate (a derivative) of vitamin B6, which is covalently linked to the e-amino group of a specific lysine residue at the active site of the enzyme. Aminotransferases act by transferring the amino group of an amino acid to the pyridoxal part of the coenzyme to generateate pyridoxamine phosphate. The pyridoxamine form of coenzyme then reacts with an α-keto acid to form an amino acid at the same time regenerating the original aldehyde form of the coenzyme. Figure shows these two component the reaction catalyzed by aspartate aminotransferase 4 Clinical biochemistry second stage lecture 2 Dr.Thana Alsewedy Transminase of Clinical Importance Alanine transaminase (ALT) and Aspartate transaminase (AST) are the two most important transaminases of clinical importance. Function: 1- Degradation of a.as to form α- keto acids. 2- Synthesis of non essential a.as from CHO. Diagnostic value: Transaminases are normally intracellular enzymes. These enzymes are abundant in heart and liver they are released as part of cell injury that occurs in Myocardial infraction (MI),infections hepatitis and damage to either organ They are elevated in the blood when damage to the cells producing these enzymes occurs. Increase level of both ALT & AST indicatespossible damage to the liver cells. Increase level of AST alone suggest damage to heart muscle ,skeletal muscle or kidney. . Assays of these enzyme activities in blood serum can be used both in diagnosis and monitoring the progress of a patient during treatment. 5 Clinical biochemistry second stage lecture 2 Dr.Thana Alsewedy B.Glutamate dehydrogenase ; Oxidative deamination of amino acid incontrast to transamination reactions that transfer amino groups the oxidative deamination by Glutamate dehydrogenase results in the liberation of the amino group as free ammonia These reactions occur primarily in the liver and kidney. They provide α-ketoacids that can enter the central pathway of energy metabolism ,and ammonia, which is a source of nitrogen in urea synthesis. Oxidative Deamination of Glutamate(Glutamate dehydrogenase) Glutamate dehydrogenase: As described above, the amino groups of most amino acids are ultimately funneled to glutamate by means of transamination with α-ketoglutarate. Glutamate is unique in that it is the only amino acid that undergoes rapid oxidative deamination reaction catalyzed by glutamate dehydrogenase (Figure 19.10). Therefore, the sequential action of transamination (resulting in the collection of amino groups from other amino acids onto α-ketoglutarate to produce glutamate and the subsequent oxidative deamination of that glutamate (regenerating α-ketoglutarate) provide a pathway whereby the amino groups of most amino acids can be released as ammonia. Coenzymes for Glutamate dehydrogenase is unusual in can use either NAD+ or NADP+ as a coenzyme. NAD+ is used primarily in oxidative deamination (the simultaneous loss of ammonia coupled with the oxidation of the carbon skeleton and NADPH is used in reductive amination (the simultaneous gain of ammonia coupled with the reduction of the carbon skeleton 6 Clinical biochemistry second stage lecture 2 Dr.Thana Alsewedy Regulation of Glutamate dehydrogenase The direction of the reaction depends on: 1- Availability of the substrates: --Relative conc. Of (α-ketoglutarate &NH3) and (glutamate). --Ratio of NADP : NADPH+H 2- Allosteric regulation: --Activators : ADP or GDP. -- Inhibitors : ATP ,GTP & NADH Transport of ammonia to the liver All tissues produce some ammonia from a variety of compounds. The level of ammonia in blood must be kept very low, because even slightly elevated concentrations (hyperammonemia) are toxic to the central nervous system 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, found in most tissues, uses glutamine synthetase to combine ammonia with glutamate to form non toxic transport form of ammonia (Figure 19.13). The glutamine is ported in the blood to the liver where is cleaved by glutaminase to produce glutamate and free ammonia Second transport mechanism involves the glucose-alanine “cycle.” Amino acids derived from skeletal muscle protein breakdown are converted to Alanine, which is transported to liver where it is deaminated to form pyruvate. Waste NH3 groups enter the urea cycle, while pyruvate is used for gluconeogenesis( synthesize glucose) which can enter the blood and be used by muscle a pathway called the glucose-alanine cycle. Glucose-Alanine Cycle i. Alanine is transported to liver, transaminated to pyruvate and converted to glucose. This glucose may again enter the glycolytic pathway to form pyruvate, which in turn,can be transaminated to alanine. ii. Glucose-alanine cycle is important in conditions of starvation (Fig. 9.30). Thus net transfer of amino acid (nitrogen) from muscle to liver and corresponding transfer of glucose (energy) from liver to muscle is effected. 7 Clinical biochemistry second stage lecture 2 Dr.Thana Alsewedy In Fasting State The muscle releases mainly alanine and glutamine of which alanine is taken up by liver and glutamine by kidneys Liver removes the amino group and converts it to urea and the carbonskeleton is used for gluconeogenesis. The brain predominantly takes up branched chain amino acids. In the Fed State Amino acids absorbed from the diet are taken up by different tissues. Both muscle and brain take up branched chain amino acids, and release glutamine and alanine. The glutamine is delivered to kidneys to aid in regulation of acid–base balance while alanine is taken up by liver. 8