catabolism of a.a.pdf

Digestion and Catabolism of proteins and Amino Acids P R E S E NTAT I O N Dr. Ula Abbas Zeki Objectives of this lecture : Illustrate the digestion and absorption processes of the protein and A.A understand the Catabolism of amino acids including amino acids pool and ste...

Digestion and Catabolism of proteins and Amino Acids P R E S E NTAT I O N Dr. Ula Abbas Zeki Objectives of this lecture : Illustrate the digestion and absorption processes of the protein and A.A understand the Catabolism of amino acids including amino acids pool and steps of α amino group metabolism Explain diagnostic importance of aminotransferase enzymes ILO:K3, S12, A0  Amino acids are the basic structural units of peptides and proteins play variable roles in :  provision of energy  formation of a number of important biomolecules, including hormones, neurotransmitters, and signaling molecules.  Unlike fats and carbohydrates, the body doesn’t store amino acids. So ,amino acids must be obtained either from diet, synthesized de novo, or produced from the degradation of body protein. Any excess more than the biosynthetic needs will be rapidly degraded.  DIETAR Y PROTEIN DIGESTION Proteins are generally too large to be absorbed by the intestine, therefore, proteins must be hydrolyzed to yield di- and tripeptides as well as individual amino acids to be absorbed. Proteolytic enzymes responsible for degrading proteins are produced by three different organs: stomach, pancreas, and the small intestine  A. Digestion by gastric secretion The digestion of proteins begins in the stomach, which secretes gastric juice containing hydrochloric acid (HCl) and the proenzyme pepsinogen. HCl : stomach HCL is too dilute (pH 2–3) to hydrolyze proteins. secreted by the parietal cells of the stomach, its functions is kill some bacteria and to denature proteins, thereby making them more susceptible for subsequent hydrolysis by proteases. Pepsin: This acid-stable endopeptidase is secreted by the chief cells of the stomach as an inactive zymogen (or proenzyme), pepsinogen. In the presence of HCl, pepsinogen undergoes a conformational change and cleave itself to the active form (pepsin), which releases polypeptides and a few free amino acids from dietary proteins.  B. Digestion by pancreatic enzymes On entering the small intestine, the polypeptides produced in the stomach by the action of pepsin will be further cleaved to oligopeptides and amino acids by a group of pancreatic proteases that include both endopeptidases and exopeptidases. These enzymes are synthesized and secreted as inactive zymogens Their release and activation are mediated by the secretion of cholecystokinin, a polypeptide hormone of the small intestine.  Zymogen activation: Enteropeptidase (enterokinase), present on the luminal surface of the enterocytes of the brush border, converts the pancreatic zymogen trypsinogen to trypsin. Trypsin subsequently converts other trypsinogen molecules to trypsin. Thus, enteropeptidase unleashes a cascade of proteolytic activity , and trypsin is the common activator of all the pancreatic zymogens  Digestion abnormalities deficiency in pancreatic secretion (chronic pancreatitis, cystic fibrosis, or surgical removal of pancreas), lead to incomplete digestion and absorption of fat and protein>>>> abnormal appearance of lipids in the feces (steatorrhea) & undigested protein. Celiac disease is a malabsorption disease resulting from immune-mediated damage to the small intestine in response to ingestion of gluten (or gliadin produced from gluten), a protein found in wheat, barley, and rye.  C. Digestion of oligopeptides by small intestine enzymes The luminal surface of the enterocytes contains aminopeptidase, which repeatedly cleaves the N-terminal residue from oligopeptides to produce even smaller peptides and free amino acids.  D. Amino acid and small peptide intestinal absorption Most free amino acids are taken into enterocytes by sodium dependent secondary active transport mechanism Di- and tripeptides, however, are taken up by a proton-linked peptide transporter (PepT1). The peptides are then hydrolyzed to free amino acids, which are released from enterocytes into the portal system. These amino acids are either metabolized by the liver or released into the general circulation. Branched-chain amino acids (BCAA) are not metabolized by the liver but, instead, are sent from the liver to muscle via the blood.  Absorption abnormalities The small intestine and the proximal tubules of the kidneys have common transport systems for amino acid uptake. Any defect in one of these systems results in an inability to absorb particular amino acids into the intestine and into the kidney tubules. An example for that is Cystinuria Catabolism of Amino Acids  OVERALL NITROGEN METABOLISM A.A catabolism is part of the larger process of the metabolism of nitrogen- containing molecules. N enters the body in a variety of compounds present in food and leaves as urea, ammonia, and other products derived from amino acid metabolism. The role of body proteins in these transformations involves two important concepts: the amino acid pool and protein turnover  The amino acid The amino acid pool pool supplied by is depleted by 1) by the degradation of endogenous 1) synthesis of body protein (body) proteins, most of which are 2) consumption of amino acids as reutilized precursors of essential nitrogen- 2) amino acids derived from containing small molecules exogenous (dietary) protein 3) conversion of amino acids to glucose, 3) nonessential amino acids glycogen, fatty acids, and ketone bodies synthesized from simple or oxidation to CO2 + H2O intermediates of metabolism B. Protein turn over proteins are constantly synthesized and degraded (turned over), permit removal of abnormal or unneeded proteins. total amount of protein remains constant because the rate of protein synthesis is sufficient to replace the protein that is degraded.  A.A catabolism first phase : second phase : removal of the α-amino groups to form ammonia carbon skeletons of the α-keto acids are converted to & corresponding α-keto acids, which the intermediates of that can be metabolized to carbon carbon skeletons of amino acids. dioxide (CO2) and water (H2O), glucose, fatty acids, or part of the free ammonia is excreted in urine, but ketone bodies by the central pathways of metabolism. most is used in the synthesis of urea  01 NITROGEN REMOVAL FROM AMINO ACIDS  The presence of the α-amino group keeps amino acids safely locked away from oxidative breakdown so removing this group is essential for producing energy from any amino acid and it is an obligatory step in the catabolism of all a. a. Once removed, this nitrogen can be incorporated into other compounds or excreted as urea, and then the carbon skeletons being metabolized.  1.Transamination transfer of an amino group from an alpha-AA to an alpha-keto acid , which is an AA with an alpha-keto group (=O) to produce an α-keto acid and glutamate. The original AA loses an amino group and gains a keto group, becoming an alpha- keto acid, while the original alpha-keto acid loses its keto group and gains an amino, becoming a nonessential AA (glutamate). Glutamate  The reaction is catalyzed by aminotransferase enzymes that found in high concentrations in liver and requires coenzyme pyridoxal phosphate. Glutamate produced by transamination can be oxidatively deaminated or used as an amino group donor in the synthesis of nonessential amino acids. All amino acids, with the exception of lysine and threonine participate in transamination. Two important aminotransferase enzymes are alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ALT is present in many tissues mainly liver, also in kidney, skeletal muscle and heart. ALT transfers an amino group from alanine to alpha-ketoglutarate, forming pyruvate and glutamate. AST present in the heart, skeletal muscle, liver, kidney and RBC. AST transfers an amino group from aspartate to alpha-ketoglutarate, forming oxaloacetate and glutamate. Diagnostic value of Aminotransferases These enzymes are normally intracellular, and low levels that found in plasma represent the release of cellular contents during normal cell turnover. Elevated plasma levels indicate damage to cells rich in these enzymes. For example, physical trauma or a disease process can cause cell lysis, resulting in release of intracellular enzymes into the blood. AST and ALT, are of particular diagnostic value when they are found elevated in the plasma. a. Hepatic disease b. Nonhepatic disease: elevated in nearly all hepatic diseases Aminotransferases may be elevated in but are particularly high in nonhepatic diseases such as those conditions that cause extensive cell that cause damage to cardiac or necrosis, such as severe viral skeletal muscle. hepatitis, toxic injury.  2. Oxidative deamination: Amino group removal. process through which amino groups are removed from AAs, releasing free cytotoxic ammonia: ammonia → ammonium → urea via the urea cycle in the liver. Result of this reaction is α-keto acids that can enter the central pathways of energy metabolism and ammonia, which is a source of nitrogen in hepatic urea synthesis.  Oxidative deamination by glutamate dehydrogenase. Glutamate, that resulted from the transamination , is unique in that it is the only amino acid that undergoes rapid oxidative deamination, a reaction catalyzed by glutamate dehydrogenase [GDH] enzyme.  GDH, a mitochondrial enzyme, is unusual in that it can use either nicotinamide adenine dinucleotide (NAD⁺) or its phosphorylated reduced form (NADPH) as a coenzyme. The sequential action of transamination and the oxidative deamination of that glutamate (regenerating α-ketoglutarate) will provide a pathway by which the amino groups of most amino acids can be released as ammonia.  Nonoxidative deamination Certain a.a ex. serine , threonine, & cysteine are deaminated by specific lyases that require pyridoxal phosphate.  1.transamination A.A Glutamate + α keto acid 2.oxidative deamination NH3 + α keto acid 3.Go to the liver (Urea Cycle) Urea