Protein Metabolism PDF

Protein Metabolism  Proteases: Hydrolyze the peptide bonds Greater Polypeptide Smaller polypeptide Oligopeptides Amino acids Depending on site of action Endopeptidases Carboxypeptidases Pepsin: Hydrolyzes ingested proteins at peptide bonds on the amino-...

Protein Metabolism  Proteases: Hydrolyze the peptide bonds Greater Polypeptide Smaller polypeptide Oligopeptides Amino acids Depending on site of action Endopeptidases Carboxypeptidases Pepsin: Hydrolyzes ingested proteins at peptide bonds on the amino- terminal side of Leusine and the aromatic amino acid residues Phenylalanine, Tryptophan, and Tyrosine. Trypsin: Cleaves the peptide bond in which carboxylic carbon is donated either by Lysine or Arginine. Both diamino monocarboxylic acids having +ve charge. Some times Histidine also, another positively charged amino acid  Amino acids are degraded to common intermediates of the Kreb’s cycle. 20 different a.a, each is a different entity and has a separate pathway. Contribution in energy production depends on type of organism, like carnovires, herbivores About 10% of energy comes from protein in humans Proteins are not stored in body, hence production of proteins is heavily dependent on metabolic circumstances Excess intake of protein Degradation accelerated Disturbed metabolism Degradation accelerated Starvation Degradation accelerated Metabolic Fates of Amino Groups Ammonia Ammoniotelic (Have gills) Urea Ureotelic Uric acid Uricotelic (Cloacal aperture)  Most amino acids are metabolized in the liver. Some of the ammonia generated in this process is recycled and used in a variety of biosynthetic pathways; the excess is either excreted directly or converted to urea or uric acid for excretion, depending on the organism. Excess ammonia generated in other (extrahepatic) tissues travels to the liver (in the form of amino groups) for conversion to the excretory form. Four amino acids play central roles in nitrogen metabolism: Glutamate, Glutamine, Alanine, and Aspartate. They are the ones most easily converted into citric acid cycle intermediates: Glutamate and Glutamine to α-ketoglutarate, Alanine to Pyruvate, and Aspartate to Oxaloacetate. Glutamate and glutamine are especially important, acting as a kind of general collection point for amino groups. Glutamine or glutamate or both are present in higher concentrations than other amino acids in most tissues. Transamination Takes place all over the body, to collect amino groups in one form PLP- Pyridoxal Phosphate, acts as a prosthetic group of the enzyme Oxidative deamination Takes place in liver, and released ammonia is converted to urea Glutamate dehydrogenase can use either NAD+ or NADP+ Glutamine Transports Ammonia in Bloodstream Glucose Alanine Cycle  Glucose-Alanine Cycle Alanine Transports Ammonia from Skeletal Muscles to the Liver Glutamate can transfer its α-amino group to pyruvate, a readily available product of muscle glycolysis, by the action of alanine aminotransferase. Vigorously contracting skeletal muscles operate anaerobically, producing pyruvate and lactate from glycolysis as well as ammonia from protein breakdown. These products must find their way to the liver, where pyruvate and lactate are incorporated into glucose, which is returned to the muscles, and ammonia is converted to urea for excretion.  Glucose-Alanine Cycle Advantages 1. Amino Nitrogen is transported in safe way without depleting the Kreb’s cycle intermediate α-Ketoglutarate 2. Excess Pyruvate produced due to anaerobic glycolysis is converted back to glucose in the liver and can be supplied back to the muscle Urea Cycle Links between the urea cycle and citric acid cycle  Regulation of Urea Cycle Rates of synthesis of the four urea cycle enzymes and carbamoyl phosphate synthetase I in the liver Carbamoyl phosphate synthetase I is allosterically ↑by N-acetylglutamate N-acetylglutamate is synthesized from acetyl-CoA and glutamate by Nacetylglutamate synthase The steady-state levels of N-acetylglutamate are determined by the concentrations of glutamate and acetyl-CoA (the substrates for N- acetylglutamate synthase) and arginine (an activator of N-acetylglutamate synthase, and thus an activator of the urea cycle). Pathways of Amino Acid Degradation FIGURE 18-15 Summary of amino acid catabolism Amino Acids Degraded to Oxaloacetate Catabolic pathway for Asparagine and Aspartate Amino Acids Degraded to Pyruvate Alanine Serine Cystein Glycine Threonine Tryptophan Serine can form Ethanolamine by the action of Serine Decarboxylase to form Phospholipids Transamination forms Mercapto Pyruvic acid, followed by removal of Sulphur atom in one of various forms. H2S, S2O3, SCN, SO2 etc Tetrahydrofolate (H4 folate)  Tetrahydrofolate (H4 folate) The oxidized form, folate, is a vitamin for mammals The one-carbon group undergoing transfer, in any of three oxidation states, is bonded to N-5 or N-10 or both. The most reduced form of the cofactor carries a methyl group, a more oxidized form carries a methylene group, and the most oxidized forms carry a methenyl, formyl, or formimino group. Enzyme Cofactors in 1-Carbon Transfer Reactions Biotin, Tetrahydrofolate and S-adenosylmethionine These cofactors transfer one-carbon groups in different oxidation states: Biotin transfers carbon in its most oxidized state, CO2 Tetrahydrofolate transfers one-carbon groups in intermediate oxidation states and sometimes as methyl groups S-adenosylmethionine transfers methyl groups, the most reduced state of carbon. In most human tissues, the degradation of threonine via glycine is a relatively minor pathway, accounting for 10% to 30% of threonine catabolism. It is more important in some other mammals. The major pathway in most human tissues leads to succinyl-CoA as described later in relevant section. Amino Acids Degraded to Acetyl-CoA Phenylalanine Tyrosine Tryptophan Lysine Leucine Isoleucine Threonine PKU- Phenylketonuria Alternative pathways for catabolism of phenylalanine in phenylketonuria  Phenylalanine and phenylpyruvate accumulate in the blood and tissues and are excreted in the urine—hence the name “Phenylketonuria.” Phenylacetate imparts a characteristic odor to the urine, which nurses have traditionally used to detect PKU in infants. The accumulation of phenylalanine or its metabolites in early life impairs normal development of the brain, causing severe intellectual deficits. Remedies 1. Phenylalanine restricted diet. 2. Phenylalanine ammonia lyase taken orally or injected subcutaneously to degrade phenylalanine in proteins ingested as part of a somewhat less restricted diet.  Alkaptonuria Alkaptonuria is the disease caused by the defective enzyme homogentisate dioxygenase. Less serious than PKU, this condition produces few ill effects, although large amounts of homogentisate are excreted and its oxidation turns the urine black. Individuals with alkaptonuria are also prone to develop a form of arthritis. Alkaptonuria is of considerable historical interest. Archibald Garrod discovered in the early 1900s that this condition is inherited, and he traced the cause to the absence of a single enzyme. Synthesis of Catecholamines from Tyrosine  Albinism: A genetic defect resulting in lack of pigmentation; white hair, pink skin etc. Melanin synthesis from Tyrosine is the defective process. Hydroxy Tyrosine forms pigments Tyrosine Dihydroxy Phenylalanine (DOPA) DOPA Quinone Melanin Voet & Voet Voet & Voet Lehninger Voet & Voet Voet & Voet Stryer Voet & Voet Lehninger Amino Acids Degraded to α- Ketoglutarate Glutamate Glutamine Arginine Proline Histidine Voet & Voet Amino Acids Degraded to Succinyl CoA Methionine Valine Threonine Isoleucine Voet & Voet Voet & Voet Lehninger